TRANSPLANTATION

OF THE LIVER
Third Edition

Ronald W. Busuttil, MD, PhD

William P. Longmire, Jr., Chair in Surgery
Distinguished Professor and Executive Chairman
UCLA Department of Surgery
Chief, Division of Liver and Pancreas Transplantation
David Geffen School of Medicine at UCLA
Los Angeles, California

Göran B.G. Klintmalm, MD, PhD

Chief and Chairman
Annette C. and Harold C. Simmons Transplant Institute
W.W. Caruth Chair in Organ Transplant Immunology
Professor of Surgery, Texas A&M College of Medicine
Vice Chair, Department of Surgery
Division Chief, Transplant Surgery
Dallas, Texas

ERRNVPHGLFRVRUJ
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899

TRANSPLANTATION OF THE LIVER, THIRD EDITION ISBN: 978-1-4557-0268-8

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Library of Congress Cataloging-in-Publication Data

Transplantation of the liver (Busuttil)

Transplantation of the liver / [edited by] Ronald W. Busuttil, Göran B.G. Klintmalm. -- Third edition.
   p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-4557-0268-8 (hardback : alk. paper)
I. Busuttil, Ronald W., editor. II. Klintmalm, Göran B., editor. III. Title.
    [DNLM: 1. Liver Transplantation. 2. Liver Diseases--surgery. WI 770]
RD546
617.5’5620592--dc23
2014037966

Executive Content Strategist: Michael Houston

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Printed in the United States of America

Last digit is the print number: 9 8 7 6 5 4 3 2 1

 Contributors

Kareem Abu-Elmagd, MD, PhD Lars Bäckman, MD, PhD

Professor of Surgery Professor of Surgery
Digestive Disease Institute Director, Transplantation Surgery
Transplantation Center Uppsala University Hospital
Cleveland Clinic Uppsala, Sweden
Cleveland, Ohio Organ Allocation: The European Models
Leukocyte Chimerism—Meaning and Consequences
Talia B. Baker, MD
Chul-Soo Ahn, MD, PhD Associate Professor of Surgery
Professor of Surgery Northwestern University
Hepatobiliary Surgery and Liver Transplantation Director, Living Donor Liver Transplant
Asan Medical Center Comprehensive Transplant Center
Ulsan University College of Medicine Chicago, Illinois
Seoul, South Korea Minimally Invasive Living Donor Hepatectomy
Dual Grafts for Transplantation
William F. Balistreri, MD
Reza Allamezadeh, MD Professor of Pediatrics and Medicine
Clinical Instructor Director, Pediatric Liver Care Center
Department of Medicine Gastroenterology, Hepatology, and Nutrition
Nephrology Division Children’s Hospital Medical Center
Kidney Transplant Program Cincinnati, Ohio
David Geffen School of Medicine at UCLA Transplantation for Cholestatic Liver Disease
Los Angeles, California in Children
Renal Failure in Adults
Rafael Bañares, MD
Estella M. Alonso, MD Professor and Head of Medicine
Professor of Pediatrics Liver Unit
Northwestern University Feinberg School of Medicine Hospital General Universitario Gregorio Marañón
Medical Director Faculty of Medicine
Liver Transplant Program Complutense University of Madrid
Chicago, Illinois Madrid, Spain
General Criteria for Pediatric Transplantation Current Clinical Status of Extracorporeal Devices

Maria H. Alonso, MD Angeles Baquerizo, MD, PhD

Associate Professor Transplant and Hepatobiliary Surgeon
Division of Pediatric General and Thoracic Surgery Scripps Center for Cell and Organ Transplantation
University of Cincinnati La Jolla, California
Surgical Director Current Clinical Status of Extracorporeal Devices
Kidney Transplant Program
Cincinnati Children’s Hospital Medical Center Lokesh Bathla, MD
Cincinnati, Ohio Fellow, Section of Transplant Surgery
Transplantation for Hepatic Malignancy in Children University of Nebraska Medical Center
Omaha, Nebraska
Nancy L. Ascher, PhD Intestinal and Multivisceral Transplantation
Professor and Chair
Department of Surgery William Bennet, MD, PhD
Isis Distinguished Professor in Transplantation Senior Surgeon
Leon Goldman, MD, Distinguished Professor in Director of Liver Transplantation
Surgery Transplant Institute
Division of Transplant Surgery Sahlgrenska University Hospital
University of California, San Francisco Gothenburg, Sweden
San Francisco, California Organ Allocation: The European Models
Rejection After Transplantation
v
vi Contributors

Marina Berenguer, MD Sherilyn Gordon Burroughs, MD

University Valencia Assistant Professor of Surgery
Department of Medicine Weill-Cornell Medical College
Hepatology and Liver Transplantation Unit General Surgery and Organ Transplantation
La Fe Hospital and CIBEREHD Center for Liver Disease and Transplantation
National Network Center for Hepatology and The Methodist Hospital
Gastroenterology Research Houston, Texas
Hospital Universitario La Fe Donor Selection and Management
Valencia, Spain
Transplantation for Hepatitis C Ronald W. Busuttil, MD, PhD
William P. Longmire, Jr., Chair in Surgery
Gabriela A. Berlakovich, MD Distinguished Professor and Executive Chairman
Associate Professor UCLA Department of Surgery
Department of Surgery Chief, Division of Liver and Pancreas Transplantation
Division of Transplantation David Geffen School of Medicine at UCLA
Medical University of Vienna Los Angeles, California
Vienna, Austria Surgical Anatomy of the Liver; Influence of Transplantation
Organ Allocation: The European Models on Liver Surgery; Transplantation for Cholangiocarcinoma;
Transplantation for Biliary Atresia in Children; Management
Jorge A. Bezerra, MD of Portal Hypertensive Hemorrhage; Extended Criteria
Professor of Pediatrics Donors; Recipient Hepatectomy and Grafting; Arterial
Division of Gastroenterology, Hepatology, and Reconstruction; Portal Vein Thrombosis and Other Venous
Nutrition Anomalies; Retransplantation; Situs Inversus and Polysplenia
Cincinnati Children’s Hospital Medical Center Syndrome; Graft Failure; Arterial Complications After
Cincinnati, Ohio Transplantation; Outcome Predictors in Transplantation;
Transplantation for Cholestatic Liver Disease in Children Long-Term Functional Recovery and Quality of Life;
Ischemia-Reperfusion Injury in Liver Transplantation
Jacob L. Bilhartz, MD
Fellow, Division of Gastroenterology Juan Carlos Caicedo, MD
Department of Pediatrics Assistant Professor of Surgery
University of Michigan and C.S. Mott Children’s Northwestern Memorial Hospital
Hospital Northwestern University
Ann Arbor, Michigan Chicago, Illinois
Transition of Pediatric Patients to Adulthood Minimally Invasive Living Donor Hepatectomy

Robert S. Brown, Jr., MD Andrew M. Cameron, MD

Frank Cardile Professor of Medicine and Pediatrics Associate Professor
(in Surgery) Department of Surgery
Columbia University College of Physicians and Johns Hopkins Medical Institutions
Surgeons Baltimore, Maryland
Medical Director, Transplant Initiative Management of Portal Hypertensive Hemorrhage
New York-Presbyterian, Morgan Stanley Children’s
Hospital Jeffrey Campsen, MD
Columbia University Medical Center Assistant Professor of Surgery
Director, Center for Liver Disease and Division of Transplant Surgery
Transplantation University of Utah Health Sciences Center
New York-Presbyterian Hospital/Columbia University Salt Lake City, Utah
Medical Center Transplant-Related Malignancies
New York, New York
Current Indications, Contraindications, Delisting Criteria, Elizabeth J. Carey, MD
and Timing for Transplantation Assistant Professor of Medicine
Gastroenterology and Hepatology
Andrew Burroughs, MD Mayo Clinic Arizona
Professor of Hepatology Scottsdale, Arizona
The University of London Monitoring and Care
Consultant Physician and Hepatologist
Royal Free Hospital Ian C. Carmody, MD
London, United Kingdom Associate Professor of Surgery
Organ Allocation: The European Models Transplant Services
Ochsner Medical Center
New Orleans, Louisiana
Treatment of Acute and Chronic Rejection
 Contributors vii

J. Michael Cecka, MD Ana J. Coito, PhD

Professor Professor of Surgery
Director of Clinical Research Dumont-UCLA Transplantation Research Center
UCLA Immunogenetics Center Department of Surgery
Department of Pathology and Lab Medicine David Geffen School of Medicine at UCLA
University of California, Los Angeles Los Angeles, California
Los Angeles, California Ischemia-Reperfusion Injury in Liver Transplantation
ABO, Tissue Typing, and Crossmatch Incompatibility
Thomas Collins, MD
See-Ching Chan, MBBS, MS, PhD Clinical Associate Professor of Surgery
Professor Transplantation and Hepatobiliary Surgery
Department of Surgery Director of Surgical Skills Lab
University of Hong Kong Transplant Fellowship Program Director
Hong Kong, China Director of Liver Transplant
Outcomes of Living Donor Transplantation: The Eastern University of Iowa
Perspective; Adult Living Donor Right Hepatectomy and Iowa City, Iowa
Recipient Operation Donation After Cardiac or Brain Death: Regulatory and
Ethical Principles
Michael Charlton, MD
Professor of Medicine Jeffrey S. Crippin, MD
Department of Gastroenterology and Hepatology Professor of Medicine
Mayo Clinic and Foundation Marilyn Bornefeld Chair in Gastrointestinal Research
Rochester, Minnesota and Treatment
Transplantation for Nonalcoholic Steatohepatitis Internal Medicine
Washington University School of Medicine
Ali Cheaito, MD St. Louis, Missouri
Assistant Professor of Surgery Transplantation for Sclerosing Cholangitis
David Geffen School of Medicine at UCLA
Los Angeles, California David C. Cronin II, MD, PhD, MHCM
Arterial Complications After Transplantation Professor
Department of Surgery
Pauline W. Chen, MD Medical College of Wisconsin
Clinical Instructor Milwaukee, Wisconsin
Department of Surgery Ethics in Living Donor Transplantation
David Geffen School of Medicine at UCLA
Surgeon Gabriel M. Danovitch, MD
Dumont-UCLA Liver Cancer Center Professor of Medicine
and Transplant Center Department of Medicine
Los Angeles, California Nephrology Division
Treatment of Acute and Chronic Rejection Medical Director
Kidney Transplant Program
Srinath Chinnakotla, MD David Geffen School of Medicine at UCLA
Associate Professor Los Angeles, California
Department of Surgery Renal Failure in Adults
University of Minnesota Medical School
Minneapolis, Minnesota Gary L. Davis, MD
Graft-Versus-Host Disease Professor of Medicine
Director, General and Transplant Hepatology
Ruben Ciria, MD Medicine
Fellow, King’s Healthcare Partners Baylor Healthcare System and Baylor University
Kings College Hospital FT NHS Trust Medical Center
Institute of Liver Studies Dallas, Texas
London, United Kingdom Natural History of Hepatitis C; Recurrent Hepatitis C
Auxiliary Transplantation After Transplantation

Pierre-Alain Clavien, MD, PhD Gloria de la Rosa, MD, PhD

Professor and Chairman Medical Doctor
Department of Surgery Spanish National Transplant Organization
Division of Visceral and Transplant Surgery Madrid, Spain
University Hospital Zurich Organ Allocation: The European Models
Zurich, Switzerland
Principles of Liver Preservation
viii Contributors

Anthony J. Demetris, MD Douglas G. Farmer, MD

Professor Professor of Surgery
Department of Pathology Liver Transplant Surgery
University of Pittsburgh Dumont-UCLA Transplant Center
Pittsburgh, Pennsylvania Los Angeles, California
Histopathology of Liver Transplantation; Leukocyte Situs Inversus and Polysplenia Syndrome
Chimerism—Meaning and Consequences
Constantino Fondevila, MD, PhD
Joseph DiNorcia, MD General Surgery
Assistant Professor of Surgery Hospital Clinic
Division of Hepatobiliary, Pancreas, and Abdominal Barcelona, Spain
Organ Transplantation Extracorporeal Perfusion for Resuscitation of Marginal Grafts
Keck School of Medicine of USC
Los Angeles, California John L.R. Forsythe, MBBS, MD
Extended Criteria Donors Transplant Unit
Consultant Transplant Surgeon
John P. Duffy, MD Royal Infirmary of Edinburgh
Hepatobiliary and Abdominal Transplant Surgeon Edinburgh, United Kingdom
Nazih Zuhdi Transplant Institute Organ Allocation: The European Models
Integris Baptist Medical Center
Oklahoma City, Oklahoma Alyson N. Fox, MD
Arterial Reconstruction; Long-Term Functional Recovery Assistant Professor of Medicine
and Quality of Life Center for Liver Disease and Transplantation
New York Presbyterian Hospital-Weill Cornell Medical
Francisco A. Durazo, MD Center
Associate Clinical Professor of Medicine and Surgery New York, New York
Digestive and Liver Diseases Current Indications, Contraindications, Delisting Criteria,
Dumont-UCLA Transplant Center and Timing for Transplantation
University of California, Los Angeles
Los Angeles, California Ira J. Fox, MD
Unusual Indications for Transplantation Professor of Surgery
University of Pittsburgh School of Medicine
Bijan Eghtesad, MD Director, Center for Innovative Regenerative Therapies
Staff Surgeon Children’s Hospital of Pittsburgh of UPMC and the
Hepato-Pancreato-Biliary/Liver Transplant Surgery McGowan Institute for Regenerative Medicine
Cleveland Clinic Pittsburgh, Pennsylvania
Cleveland, Ohio Liver and Hepatocyte Xenotransplantation
Leukocyte Chimerism—Meaning and Consequences;
Graft-Versus-Host Disease Joel E. Frader, MD, MA
A Todd Davis Professor of Academic General Pediatrics
Jean C. Emond, MD Professor of Medical Humanities and Bioethics
Professor of Surgery Department of Pediatrics
Vice Chair and Chief of Transplantation Feinberg School of Medicine
New York-Presbyterian Hospital Northwestern University
Columbia University Medical Center Chicago, Illinois
New York, New York Ethical Decisions in Transplantation
Postoperative Care of Pediatric Transplant Recipients
Emily M. Fredericks, PhD
Carlos O. Esquivel, MD, PhD Associate Professor of Pediatrics
Professor of Surgery and Chief Division of Child Behavioral Health
Division of Abdominal Transplantation Surgery University of Michigan and C.S. Mott Children’s Hospital
Stanford School of Medicine Ann Arbor, Michigan
Stanford, California Transition of Pediatric Patients to Adulthood
Survival and Quality of Life in Children
James M. Fulmer, MD
Sheung Tat Fan, MS, MD, PhD, DSc Staff Radiologist
Sun C.Y. Chair Professor of Surgery Baylor University Medical Center
Department of Surgery American Radiology Associates, PA
The University of Hong Kong Dallas, Texas
Hong Kong, China Transplantation for Primary Hepatic Malignancy;
Outcomes of Living Donor Transplantation: The Eastern Transplantation for Budd-Chiari Syndrome
Perspective
 Contributors ix

John J. Fung, MD, PhD Michael D. Green, MD, MPH

Chairman of the Digestive Disease Institute Professor
Cleveland Clinic Pediatrics, Surgery, and Clinical and Translational
Cleveland, Ohio Research
Leukocyte Chimerism—Meaning and Consequences University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania
Juan F. Gallegos-Orozco, MD Pretransplantation Evaluation: Infectious Disease
Assistant Professor of Medicine
Division of Gastroenterology, Hepatology, and Rick Harrison, MD
Nutrition Medical Director
University of Utah Health Sciences Center Mattel Children’s Hospital UCLA
Salt Lake City, Utah Department of Pediatrics
Transplant-Related Malignancies University of California, Los Angeles
Los Angeles, California
Juan Carlos García-Valdecasas, MD Postoperative Intensive Care Management in Children
Professor of Surgery
General Surgery Jeanette M. Hasse, PhD, RD, LD, FADA, CNSC
Hospital Clinic Transplant Nutrition Manager
Barcelona, Spain Baylor Annette C. and Charles C. Simmons Transplant
Extracorporeal Perfusion for Resuscitation of Marginal Institute
Grafts Baylor University Medical Center
Dallas, Texas
Till Gerling, MD, PhD Nutritional Aspects of Transplantation in Adults
Medical Staff
Eurotransplant International Foundation Nigel D. Heaton, MD
Leiden, The Netherlands Professor of Transplant Surgery
Organ Allocation: The European Models King’s Healthcare Partners
Kings College Hospital FT NHS Trust
R. Mark Ghobrial, MD Institute of Liver Studies
Director, Liver Center London, United Kingdom
Chief, Liver Transplantation Surgery Auxiliary Transplantation; Split Liver Transplantation
Director, Immunobiology Research Center for Pediatric and Adult Recipients
The Methodist Hospital System
Houston, Texas Amelia J. Hessheimer, MD, PhD
Donor Selection and Management Resident
General Surgery
Antoinette S. Gomes, MD Hospital Clinic
Professor of Radiological Sciences and Medicine Barcelona, Spain
Radiological Sciences Extracorporeal Perfusion for Resuscitation of Marginal
David Geffen School of Medicine at UCLA Grafts
Los Angeles, California
Radiological Evaluation in Transplantation Jonathan R. Hiatt, MD
Professor of Surgery
Stevan A. Gonzalez, MD Vice Dean for Faculty
Division of Hepatology Vice Chair for Education
Department of Medicine Surgery
Annette C. and Harold C. Simmons Transplant David Geffen School of Medicine at UCLA
Institute Los Angeles, California
Baylor All Saints Medical Center Influence of Transplantation on Liver Surgery
Dallas, Texas
Natural History of Hepatitis C Curtis D. Holt, Pharm D
Clinical Professor
Elisa J. Gordon, PhD, MPH Department of Surgery
Research Associate Professor Division of Liver and Pancreas Transplantation
Comprehensive Transplant Center David Geffen School of Medicine at UCLA
Northwestern University Feinberg School of Los Angeles, California
Medicine Infections After Transplantation
Chicago, Illinois
Ethical Decisions in Transplantation
x Contributors

Johnny C. Hong, MD Fady M. Kaldas, MD

Associate Professor of Surgery Assistant Professor of Surgery
The Mark B. Adams Chair in Surgery, Hepatobiliary Division of Liver and Pancreas Transplantation
Surgery, and Organ Transplantation Department of Surgery
Chief, Division of Transplant Surgery David Geffen School of Medicine at UCLA
Department of Surgery Los Angeles, California
Medical College of Wisconsin Extended Criteria Donors
Director, Solid Organ Transplantation Joint Program at
Medical College of Wisconsin-Froedtert Health- Igal Kam, MD
Children’s Hospital of Wisconsin-BloodCenter of Professor of Surgery
Wisconsin Division of Transplant Surgery
Milwaukee, Wisconsin University of Colorado, Denver
Transplantation for Cholangiocarcinoma; Outcome Aurora, Colorado
Predictors in Transplantation; Ischemia-Reperfusion Injury Living Donor Transplantation: Evaluation and Selection
in Liver Transplantation in Adults

Abhinav Humar, MD Burnett “Beau” S. Kelly, Jr., MD, MBA

Professor of Surgery Assistant Professor
Department of Surgery Surgery
University of Pittsburgh School of Medicine Vanderbilt University
Pittsburgh, Pennsylvania Nashville, Tennessee
Split Liver Transplantation for Two Adult Recipients Donor Selection and Management

Samar H. Ibrahim, MD Vandana Khungar, MD

Gastroenterology, Hepatology, and Nutrition Fellow in Transplant Hepatology
Children’s Hospital Medical Center Division of Digestive and Liver Diseases
Cincinnati, Ohio Columbia University College of Physicians and
Transplantation for Cholestatic Liver Disease in Children Surgeon
Center for Liver Disease and Transplantation
Toru Ikegami, MD New York Presbyterian Hospital-Weill Cornell Medical
Assistant Professor Center
Department of Surgery and Science New York, New York
Graduate School of Medical Sciences Current Indications, Contraindications, Delisting Criteria,
Kyushu University and Timing for Transplantation
Fukuoka, Japan
Small-for-Size Syndrome Khalid Khwaja, MD
Senior Staff Surgeon
Mohamad H. Imam, MD Lahey Clinic Medical Center
Department of Gastroenterology and Hepatology Burlington, Massachusetts
Mayo Clinic Organ Allocation: The U.S. Model
Rochester, Minnesota
Transplantation for Primary Biliary Cirrhosis Kevin King, RN, BSN, CCTC
Adult Post–Liver Transplant Coordinator
Yukihiro Inomata, MD, PhD Division of Liver and Pancreas Transplant
Professor and Chairman Ronald Reagan UCLA Medical Center
Department of Transplantation and Pediatric Surgery Los Angeles, California
Kumamoto University Role of the Posttransplant Clinical Nurse Coordinator
Kumamoto, Japan
Living Donor Transplantation in Children Milan Kinkhabwala, MD
Professor of Surgery
Sally E. Jensen, PhD Chief, Division of Transplantation
Research Assistant Professor Director, Abdominal Transplantation
Medical Social Sciences Montefiore Medical Center
Northwestern University Feinberg School of Medicine Albert Einstein College of Medicine
Chicago, Illinois New York, New York
Ethical Decisions in Transplantation Surgical Anatomy of the Liver

Sheila Jowsey, MD
Assistant Professor of Psychiatry
Psychiatry and Psychology
Mayo Clinic
Rochester, Minnesota
Psychiatric Assessment of Transplant Candidates
 Contributors xi

Allan D. Kirk, MD, PhD Alan Langnas, DO

Chairman of Surgery Chief, Section of Transplantation
Duke University School of Medicine Department of Surgery
Durham, North Carolina University of Nebraska Medical Center
Long-Term Toxicity of Immunosuppressive Therapy; Omaha, Nebraska
Immunosuppressive Biologic Agents Intestinal and Multivisceral Transplantation

Michelle M. Kittleson, MD, PhD Charles R. Lassman, MD

Director, Post-Graduate Education in Heart Failure and Professor of Pathology and Laboratory Medicine
Transplantation Vice Chair of Clinical Education
Cedars Sinai Heart Institute Director of Pathology Residency Training Program,
Los Angeles, California Surgical Pathology Fellowship
Pretransplantation Evaluation: Cardiac Chief of Liver Pathology, Renal Pathology
Department of Pathology and Laboratory Medicine
Göran B.G. Klintmalm, MD, PhD David Geffen School of Medicine at UCLA
Chief and Chairman Los Angeles, California
Annette C. and Harold C. Simmons Transplant Pathology of Nonneoplastic Disease After Transplantation
Institute
W.W. Caruth Chair in Organ Transplant Immunology Sung-Gyu Lee, MD, PhD
Professor of Surgery, Texas A&M College of Medicine Professor of Surgery
Vice Chair, Department of Surgery Hepatobiliary Surgery and Liver Transplantation
Division Chief, Transplant Surgery Asan Medical Center
Dallas, Texas Ulsan University College of Medicine
The History of Liver Transplantation; Transplantation for Seoul, South Korea
Primary Hepatic Malignancy; Transplantation for Dual Grafts for Transplantation
Budd-Chiari Syndrome; Recipient Hepatectomy and
Grafting; Combined Liver-Kidney Transplantation; Henry C. Lin, MD
Clinical Management of Necrotic Liver Before and After Clinical Instructor
Transplantation; Postoperative Intensive Care Department of Pediatrics
Management in Adults; Postoperative Management Beyond Northwestern University Feinberg School of Medicine
the Intensive Care Unit: Adults; Graft-Versus-Host The Siragusa Transplantation Center
Disease; Induction and Maintenance of Immunosuppression; Children’s Memorial Hospital
Novel Immunosuppression in Patients with Hepatic Chicago, Illinois
Malignancies; Outcome Predictors in Transplantation General Criteria for Transplantation in Children

Gregory D. Kunder, RN, BSN, CCTC Chung-Mau Lo, MD

Adult Post–Liver Transplant Supervisor Chair Professor and Head
Surgery, Division of Liver and Pancreas Transplant Department of Surgery
Ronald Reagan UCLA Medical Center University of Hong Kong
Los Angeles, California Hong Kong, China
Role of the Posttransplant Clinical Nurse Coordinator Adult Living Donor Right Hepatectomy and Recipient
Operation
Jerzy W. Kupiec-Weglinski, MD, PhD
Professor of Surgery, Pathology, and Laboratory Steven Lobritto, MD
Medicine Professor of Pediatrics
Joan S. and Ralph N. Goldwyn Chair in Immunobiology NewYork-Presbyterian Hospital
and Transplantation Research Columbia University Medical Center
Director, Dumont-UCLA Transplantation Research New York, New York
Center Postoperative Care of Pediatric Transplant Recipients
Vice-Chairman (Research)
Department of Surgery Jayme E. Locke, MD, MPH
David Geffen School of Medicine at UCLA Assistant Professor of Surgery
Los Angeles, California Abdominal Transplant Surgery
Ischemia-Reperfusion Injury in Liver Transplantation Director, Incompatible Kidney and Kidney Paired
Donation Programs
John R. Lake, MD Director, CTI Outcomes Research Center
Professor of Medicine UAB School of Medicine
University of Minnesota Medical School Birmingham, Alabama
Minneapolis, Minnesota Management of Portal Hypertensive Hemorrhage
Transplantation for Hepatitis C
xii Contributors

Michael R. Lucey, MD James F. Markmann, MD, PhD

Professor of Medicine Chief, Division of Transplant Surgery
Chief, Division of Gastroenterology and Hepatology Claude E. Welch Professor of Surgery
Department of Medicine Harvard Medical School
University of Wisconsin School of Medicine and Public Department of Surgery
Health Massachusetts General Hospital
Madison, Wisconsin Boston, Massachusetts
Transplantation for Alcoholic Liver Disease Retransplantation

Malcolm MacConmara, MB, BCh Mercedes Martinez, MD

Fellow, Abdominal Organ Transplant Surgery Assistant Professor of Pediatrics
Department of Surgery NewYork-Presbyterian Hospital
Emory University School of Medicine Columbia University Medical Center
Atlanta, Georgia New York, New York
Immunosuppressive Biologic Agents Postoperative Care of Pediatric Transplant Recipients

Yoshihiko Maehara, MD, PhD Rafael Matesanz, MD

Professor and Chairman Founder and Director
Department of Surgery and Science Spanish National Transplant Organization
Graduate School of Medical Sciences Madrid, Spain
Kyushu University Organ Allocation: The European Models
Fukuoka, Japan
Small-for-Size Syndrome Tara McCoy, MD
Department of Psychiatry and Psychology
Martin L. Mai, MD Mayo Clinic
Assistant Professor Rochester, Minnesota
Medical Director Psychiatric Assessment of Transplant Candidates
Pretransplant Kidney-Pancreas
Department of Transplantation Suzanne V. McDiarmid, MD
Mayo Clinic College of Medicine Professor of Pediatrics and Surgery
Jacksonville, Florida Chief, Division of Pediatric Gastroenterology,
Pretransplantation Evaluation: Renal Hepatology, and Nutrition
Director, Pediatric Liver Transplantation
Masatoshi Makuuchi, MD, PhD David Geffen School of Medicine at UCLA
President Los Angeles, California
Japanese Red Cross Medical Center Special Considerations for Immunosuppression in Children;
Professor Emeritus Transplantation for Metabolic Disease in Children
University of Tokyo
Tokyo, Japan Greg J. McKenna, MD
Adult Living Donor Left Hepatectomy and Recipient Associate Professor
Operation Department of Surgery
Texas A&M Health Science Center
Kathy Manley, RN, BSN, CCTC College of Medicine
Program Manager Abdominal Transplant Surgeon
Abdominal Transplant Director of Transplant Research
Baylor University Medical Center Baylor University Medical Center
Dallas, Texas Dallas, Texas
Role of the Clinical Nurse Coordinator The History of Liver Transplantation; Postoperative
Intensive Care Management in Adults; Induction and
Victor J. Marder, MD Maintenance of Immunosuppression
Professor of Neurology
Department of Medicine Marian G. Michaels, MD, MPH
Pediatrics Professor of Pediatrics and Surgery
David Geffen School of Medicine at UCLA Division of Pediatric Infectious Diseases
Los Angeles, California Children’s Hospital of Pittsburgh of UPMC
Transplantation for Hematological Disorders Pittsburgh, Pennsylvania
Pretransplantation Evaluation: Infectious Disease
 Contributors xiii

Marta I. Minervini, MD Michael A. Nalesnik, MD

Assistant Professor of Pathology Professor of Pathology
Division of Transplantation Pathology Division of Transplantation Pathology
University of Pittsburgh School of Medicine University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania Pittsburgh, Pennsylvania
Histopathology of Liver Transplantation Histopathology of Liver Transplantation

Constance Mobley, MD Jaimie D. Nathan, MD

Assistant Professor of Surgery Assistant Professor
Weill-Cornell Medical College Division of Pediatric General and Thoracic Surgery
Surgeon Surgical Director
Houston Methodist Hospital Intestinal Transplant Program
Houston, Texas Cincinnati Children’s Hospital Medical Center
Molecular and Cellular Basis of Liver Failure Cincinnati, Ohio
Transplantation for Hepatic Malignancy in Children
Deok-Bog Moon, MD, PhD
Professor of Surgery Peter Neuhaus, MD, PhD
Hepatobiliary Surgery and Liver Transplantation Chairman and Director
Asan Medical Center Department of General, Visceral, and Transplantation
Ulsan University College of Medicine Surgery
Seoul, South Korea Charité-Universitätsmedizin
Dual Grafts for Transplantation Campus Virchow Klinikum
Berlin, Germany
Elisa A. Moreno, MD Technical Problems: Biliary
Assistant Professor
Department of Psychiatry Jose M. Nieto, DO
David Geffen School of Medicine at UCLA Borland-Groover Clinic
Los Angeles, California Jacksonville, Florida
Psychiatric Assessment of Transplant Candidates; Transplantation for Autoimmune Hepatitis
Neuropsychiatric Complications
Ifeoma Nwadei, MD
Ferdinand Mühlbacher, MD General Surgery Resident
Professor and Head Department of Surgery
Department of Transplantation Emory University School of Medicine
Medical University of Vienna Atlanta, Georgia
Board of Directors of the University Clinic for Surgery Immunosuppressive Biologic Agents
Transplant Center General Hospital
Vienna, Austria John O’Grady, MD
Transplantation for Metastases Honorary Senior Lecturer
Consultant Hepatologist
Paolo Muiesan, MD Institute of Liver Studies
Liver Transplantation and Hepato-Pancreato-Biliary King’s College Hospital
Surgery London, United Kingdom
Queen Elizabeth Hospital Transplantation for Fulminant Hepatic Failure
Birmingham, United Kingdom
Organ Allocation: The European Models Jacqueline G. O’Leary, MD, MPH
Medical Director
Noriko Murase, MD Inpatient Liver and Transplant Unit
Associate Professor of Surgery Annette C. and Harold C. Simmons Transplant Institute
Thomas E. Starzl Transplantation Institute Baylor University Medical Center
Department of Surgery Dallas, Texas
University of Pittsburgh School of Medicine Late Complications and Recurrence of Disease After
Pittsburgh, Pennsylvania Transplantation
Leukocyte Chimerism—Meaning and Consequences
Kim M. Olthoff, MD
Bita V. Naini, MD Donald Guthrie Professor of Surgery
Assistant Professor of Pathology Division of Transplantation
Department of Pathology and Laboratory Medicine Department of Surgery
David Geffen School of Medicine at UCLA University of Pennsylvania
Los Angeles, California Philadelphia, Pennsylvania
Pathology of Nonneoplastic Disease After Transplantation Outcomes of Living Donor Transplantation: The Western
Perspective
xiv Contributors

Nicholas Onaca, MD Phuong-Chi T. Pham, MD

Attending Liver Transplant Surgeon Professor of Medicine
Surgical Director, Kidney Transplantation David Geffen School of Medicine at UCLA
Annette C. and Harold C. Simmons Transplant Institute Los Angeles, California
Baylor University Medical Center Chief of Nephrology
Dallas, Texas Olive View-UCLA Medical Center
Clinical Management of Necrotic Liver Before and After Sylmar, California
Transplantation; Novel Immunosuppression in Patients Renal Failure in Adults
with Hepatic Malignancies; Transplantation for Primary
Hepatic Malignancy Phuong-Thu T. Pham, MD
Professor of Medicine
Justin Parekh, MD, MAS Director of Outpatient Services
Clinical Instructor Department of Medicine
Department of Surgery Nephrology Division
Division of Transplantation Kidney Transplant Program
University of California, San Francisco David Geffen School of Medicine at UCLA
San Francisco, California Los Angeles, California
Rejection After Transplantation Renal Failure in Adults

Chong Parke, MD Jeffrey L. Platt, MD

Clinical Instructor Professor of Surgery
Department of Medicine Professor of Microbiology and Immunology
Nephrology Division Transplantation Biology
Kidney Transplant Program University of Michigan
David Geffen School of Medicine at UCLA Ann Arbor, Michigan
Los Angeles, California Liver and Hepatocyte Xenotransplantation
Renal Failure in Adults
Elizabeth A. Pomfret, MD, PhD
Andreas Pascher, MD Associate Professor of Surgery
Associate Professor of Surgery Tufts University School of Medicine
Deputy Chair, Department of Surgery Chairman, Department of Transplantation
Director, Transplant Program Lahey Hospital and Medical Center
Department of Visceral and Transplantation Surgery Burlington, Massachusetts
Charité-Universitätsmedizin Organ Allocation: The U.S. Model
Campus Virchow Klinikum
Berlin, Germany Paige M. Porrett, MD, PhD
Technical Problems: Biliary Fellow in Abdominal Organ Transplantation
Department of Surgery
Guido G. Persijn, MD, PhD University of Pennsylvania
Medical Director Philadelphia, Pennsylvania
Eurotransplant International Foundation Outcomes of Living Donor Transplantation: The Western
Leiden, The Netherlands Perspective
Organ Allocation: The European Models
Raja Rajalingam, PhD
Henrik Petrowsky, MD Associate Professor
Professor of Surgery UCLA Immunogenetics Center
University of Zurich Pathology and Laboratory Medicine
Vice Chair University of California, Los Angeles
Department of Visceral and Transplant Surgery Los Angeles, California
Head, Section of Hepatobiliary and Pancreatic Surgery ABO, Tissue Typing, and Crossmatch Incompatibility
Program Director
HPB and Liver Transplant Fellowship Jorge Rakela, MD
University Hospital Zurich Professor of Medicine
Zurich, Switzerland Gastroenterology and Hepatology
Principles of Liver Preservation; Graft Failure; Ischemia- Mayo Clinic Arizona
Reperfusion Injury in Liver Transplantation Scottsdale, Arizona
Monitoring and Care
 Contributors xv

Steven S. Raman, MD John F. Renz, MD, PhD

Associate Clinical Professor of Radiology Professor of Surgery
Department of Radiology Director, Liver Transplant Program
David Geffen School of Medicine at UCLA University of Chicago School of Medicine
Los Angeles, California Chicago, Illinois
Imaging Techniques for Partial Grafting The Donor Operation; Surgical Anatomy of the Liver

Michael A.E. Ramsay, MD Lucas Restrepo, MD, PhD

Chairman Clinical Assistant Professor of Neurology
Anesthesiology and Pain Management Comprehensive Stroke and Vascular Neurology
Baylor University Medical Center Program
Dallas, Texas Department of Neurology
Portopulmonary Hypertension and Hepatopulmonary David Geffen School of Medicine at UCLA
Syndrome; Anesthesia for Liver Transplantation Los Angeles, California
Neurological Complications
Parmjeet Randhawa, MD
Professor of Pathology John P. Roberts, MD
Division of Transplantation Pathology Professor and Chief
University of Pittsburgh School of Medicine Department of Surgery
Pittsburgh, Pennsylvania Division of Transplantation
Histopathology of Liver Transplantation University of California, San Francisco
San Francisco, California
Robert R. Redfield III, MD Rejection After Transplantation
Chief Resident in General Surgery
Department of Surgery Bruno Roche, MD
Hospital of the University of Pennsylvania Université Paris-Sud
Philadelphia, Pennsylvania Hospital Staff
Genetic and Genomic Potential in Liver Transplantation Hôpital Paul Brousse, Centre Hépato-Biliaire
Villejuif, France
Alan Reed, MD, MBA Transplantation for Hepatitis A and B
Professor of Surgery
Transplantation and Hepatobiliary Surgery Susanne Rasoul Rockenschaub, MD
Director, UIHC Organ Transplant Center Department of Transplantation
Director, Division of Transplantation and Hepatobiliary Medical University of Vienna
Surgery Vienna, Austria
University of Iowa Carver School of Medicine Liver Transplantation for Metastases
Iowa City, Iowa
Donation After Cardiac or Brain Death: Regulatory and Lainie Friedman Ross, MD, PhD
Ethical Principles Carolyn and Matthew Bucksbaum Professor of Clinical
Ethics
Elaine F. Reed, PhD Departments of Pediatrics, Medicine, and Surgery
Professor of Pathology and Lab Medicine Co-Director
Director, UCLA Immunogenetics Center Institute for Translational Medicine
Department of Pathology and Lab Medicine Associate Director
University of California, Los Angeles MacLean Center for Clinical Medical Ethics
Los Angeles, California University of Chicago
ABO, Tissue Typing, and Crossmatch Incompatibility Chicago, Illinois
Ethics in Living Donor Transplantation
David J. Reich, MD
Professor and Chief Richard Ruiz, MD
Division of Multiorgan Transplantation and Attending Liver Transplant Surgeon,
Hepatobiliary Surgery Surgical Director, Pancreas Transplantation
Vice Chairman Annette C. and Harold C. Simmons Transplant
Department of Surgery Institute
Drexel University School of Medicine Baylor University Medical Center
Hahnemann University Hospital Dallas, Texas
Philadelphia, Pennsylvania Combined Liver-Kidney Transplantation; Postoperative
Donation After Cardiac Death Management Beyond the Intensive Care Unit: Adults;
Long-Term Toxicity of Immunosuppressive Therapy
xvi Contributors

Frederick C. Ryckman, MD Kareem Sassi, MD

Professor of Surgery/Transplantation Department of Medicine
Professor, Division of Pediatric General and Thoracic Ronald Reagan UCLA Medical Center
Surgery Los Angeles, California
Senior Vice President, Medical Operations Transplantation for Autoimmune Hepatitis
Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio Milda R. Saunders, MD
Transplantation for Hepatic Malignancy in Children Assistant Professor
Department of Medicine
Sammy Saab, MD, MPH Faculty, MacLean Center for Clinical Medical Ethics
Professor of Medicine and Surgery Living Donor Advocate Physician
UCLA Digestive Disease Center University of Chicago
David Geffen School of Medicine at UCLA Chicago, Illinois
Los Angeles, California Ethics in Living Donor Transplantation
Transplantation for Autoimmune Hepatitis
Gabriel T. Schnickel, MD
Victor Sai, MD Senior Staff Surgeon
Clinical Instructor Henry Ford Transplant Institute
Department of Radiology Henry Ford Medical Center
David Geffen School of Medicine at UCLA Detroit, Michigan
Los Angeles, California Portal Vein Thrombosis and Other Venous Anomalies
Imaging Techniques for Partial Grafting
Anil Seetharam, MD
Faouzi Saliba, MD Fellow, Internal Medicine
Associate Professor Washington University School of Medicine
Gastroenterology and Hepatology St. Louis, Missouri
University of Paris IX Transplantation for Sclerosing Cholangitis
Villejuif, France
Current Clinical Status of Extracorporeal Devices Kentaro Setoyama, MD
Department of Surgery
Luiz C. Sampaio, MD McGowan Institute for Regenerative Medicine
Assistant Medical Director Children’s Hospital of Pittsburgh of UMPC
Regenerative Medicine Research Pittsburgh, Pennsylvania
Texas Heart Institute Liver and Hepatocyte Xenotransplantation
Houston, Texas
Stem Cells and Liver Regeneration Imtiazuddin Shaik, MD
Assistant Professor of Surgery
Didier Samuel, MD, PhD Department of Transplantation and Hepatobiliary Surgery
Professor of Hepatology New York Medical College
University of Paris-Sud Valhalla, New York
Hospital Staff Treatment of Acute and Chronic Rejection
Paul Brousse Hospital
Hepatobiliary Center Abraham Shaked, MD, PhD
Villejuif, France Eldridge L. Eliason Professor of Surgery
Transplantation for Hepatitis A and B Penn Transplant Institute
University of Pennsylvania
Keiji Sano, MD Philadelphia, Pennsylvania
Professor Genetic and Genomic Potential in Liver Transplantation
Department of Surgery
Teikyo University School of Medicine Ken Shirabe, MD, PhD
Tokyo, Japan Associate Professor
Adult Living Donor Left Hepatectomy and Recipient Department of Surgery and Science
Operation Graduate School of Medical Sciences
Kyushu University
Eizaburo Sasatomi, MD, PhD Fukuoka, Japan
Assistant Professor of Pathology Small-for-Size Syndrome
Division of Transplantation Pathology
University of Pittsburgh School of Medicine Ashwani K. Singal, MD
Pittsburgh, Pennsylvania Department of Gastroenterology and Hepatology
Histopathology of Liver Transplantation Mayo Clinic and Foundation
Rochester, Minnesota
Transplantation for Nonalcoholic Steatohepatitis
 Contributors xvii

Yuji Soejima, MD, PhD Yasuhiko Sugawara, MD

Associate Professor Associate Professor
Department of Surgery and Science Department of Surgery
Graduate School of Medical Sciences University of Tokyo
Kyushu University Tokyo, Japan
Fukuoka, Japan Biliary and Vascular Reconstruction in Living Donor
Small-for-Size Syndrome Transplantation; Adult Living Donor Left Hepatectomy
and Recipient Operation
Thomas E. Starzl, MD
Professor of Surgery Riccardo A. Superina, MD
University of Pittsburgh School of Medicine Department of Surgery
Pittsburgh, Pennsylvania Northwestern University Feinberg School of Medicine
Leukocyte Chimerism—Meaning and Consequences Siragusa Transplantation Center
Children’s Memorial Hospital
Randolph H. Steadman, MD Chicago, Illinois
Professor and Vice Chair General Criteria for Transplantation in Children
Anesthesiology
David Geffen School of Medicine at UCLA Akinobu Taketomi, MD, PhD
Los Angeles, California Professor
Portopulmonary Hypertension and Hepatopulmonary Department of Gastroenterological Surgery I
Syndrome Hokkaido University Graduate School of Medicine
Sapporo, Japan
Zoe Stewart, MD, PhD Small-for-Size Syndrome
Surgical Director
Kidney and Living Donor Transplant Program Jayant A. Talwalkar, MD, MPH
Assistant Professor of Surgery Associate Professor of Medicine
Transplantation and Hepatobiliary Surgery Gastroenterology/Hepatology
University of Iowa Carver School of Medicine Mayo Clinic
Iowa City, Iowa Rochester, Minnesota
Donation After Cardiac or Brain Death: Regulatory and Transplantation for Primary Biliary Cirrhosis
Ethical Principles
Koichi Tanaka, MD
Marvin J. Stone, MD Chairman of the Board of Directors
Director of Oncology Medical Education Kobe International Frontier Medical Center
Associate Medical Director Kobe, Japan
Baylor Charles A. Sammons Cancer Center Living Donor Transplantation in Children
Clerkship Director of Internal Medicine
Baylor University Medical Center William D. Tap, MD
Dallas, Texas Sarcoma Oncology, Melanoma, and Sarcoma Service
Transplantation for Primary Hepatic Malignancy; Memorial Sloan-Kettering Cancer Center
Transplantation for Budd-Chiari Syndrome New York, New York
Transplantation for Hematological Disorders
Thomas B. Strouse, MD
Maddie Katz Professor Doris A. Taylor, MD
Vice Chair for Clinical Affairs Director, Regenerative Medicine Research
Psychiatry and Biobehavioral Sciences Texas Heart Institute
David Geffen School of Medicine at UCLA Houston, Texas
Los Angeles, California Stem Cells and Liver Regeneration
Neuropsychiatric Complications
Greg Tiao, MD
Mark L. Sturdevant, MD Associate Professor
Assistant Professor of Surgery Azizkhan Chair of Pediatric Surgery
Department of Surgery Division of Pediatric General and Thoracic Surgery
University of Pittsburgh School of Medicine Surgical Director
Pittsburgh, Pennsylvania Liver Transplant Program
Split Liver Transplantation for Two Adult Recipients Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio
Transplantation for Hepatic Malignancy in Children
xviii Contributors

Myron J. Tong, MD, PhD Hani M. Wadei, MD

Professor Instructor in Medicine
Digestive Diseases/Gastroenterology Department of Transplantation
Physician, Hepatology Assistant Professor
David Geffen School of Medicine at UCLA Mayo Clinic College of Medicine
Los Angeles, California Jacksonville, Florida
Unusual Indications for Transplantation Pretransplantation Evaluation: Renal

James F. Trotter, MD Kenneth Washburn, MD

Medical Director Professor of Surgery
Transplant Hepatology Transplant Center
Annette C. and Harold C. Simmons Transplant Institute University of Texas Health Science Center
Baylor University Medical Center San Antonio, Texas
Dallas, Texas U.S. Trends in Transplantation
Transplantation for Budd-Chiari Syndrome; Living Donor
Transplantation: Evaluation and Selection in Adults; Peter F. Whitington, MD
Postoperative Management Beyond the Intensive Care The Sally Burnett Searle Professor of Pediatrics and
Unit: Adults; Late Complications and Recurrence of Transplantation
Disease After Transplantation Department of Pediatrics
Northwestern University Feinberg School of Medicine
Hideaki Uchiyama, MD, PhD Siragusa Transplantation Center
Director Children’s Memorial Hospital
Department of Surgery Chicago, Illinois
Fukuoka City Hospital General Criteria for Transplantation in Children
Fukuoka, Japan
Small-for-Size Syndrome Drew J. Winston, MD
Division of Liver and Pancreas Transplantation
Parsia Vagefi, MD David Geffen School of Medicine at UCLA
Assistant Professor of Surgery Los Angeles, California
Transplant Associates Infections After Transplantation
Boston, Massachusetts
Retransplantation David Wojciechowski, DO
Assistant Clinical Professor of Medicine
Hugo E. Vargas, MD Division of Nephrology
Professor of Medicine University of California, San Francisco
Chair San Francisco, California
Division of Hepatology Novel Immunosuppressive Drugs
Mayo Clinic
Phoenix, Arizona Deborah J.L. Wong, MD, PhD
Monitoring and Care Division of Hematology/Medical Oncology
David Geffen School of Medicine at UCLA
Robert S. Venick, MD Los Angeles, California
Assistant Professor Transplantation for Hematological Disorders
Pediatrics and Surgery
David Geffen School of Medicine at UCLA Heidi Yeh, MD
Los Angeles, California Transplant Associates
Transplantation for Biliary Atresia in Children; Boston, Massachusetts
Transplantation for Metabolic Disease in Children Retransplantation

Hector Vilca-Melendez, MD, PhD Hasan Yersiz, MD

Consultant Transplant Surgeon Professor of Surgery
King’s Healthcare Partners Division of Liver and Pancreas Transplantation
Kings College Hospital FT NHS Trust David Geffen School of Medicine at UCLA
Institute of Liver Studies Los Angeles, California
London, United Kingdom The Donor Operation
Split Liver Transplantation for Pediatric and Adult Recipients
Tomoharu Yoshizumi, MD, PhD
Flavio Vincenti, MD Associate Professor
Professor of Clinical Medicine and Surgery Department of Surgery and Science
Kidney Transplant Service Graduate School of Medical Sciences
University of California, San Francisco Kyushu University
San Francisco, California Fukuoka, Japan
Novel Immunosuppressive Drugs Small-for-Size Syndrome
 Contributors xix

Ali Zarrinpar, MD, PhD Qiuheng Zhang, PhD

Assistant Professor Assistant Professor
Division of Liver and Pancreas Transplantation Pathology and Laboratory Medicine
David Geffen School of Medicine at UCLA David Geffen School of Medicine at UCLA
Los Angeles, California Los Angeles, California
Molecular and Cellular Basis of Liver Failure; Influence of ABO, Tissue Typing, and Crossmatch Incompatibility
Transplantation on Liver Surgery
Michael A. Zimmerman, MD
Yuan Zhai, MD Associate Professor
Associate Professor of Surgery Surgical Director
Dumont-UCLA Transplantation Research Center Pancreas Transplant Program
Department of Surgery Division of Transplant Surgery
David Geffen School of Medicine at UCLA University of Colorado
Los Angeles, California Denver, Colorado
Ischemia-Reperfusion Injury in Liver Transplantation Novel Immunosuppression in Patients with Hepatic
Malignancies
 Foreword

Over the past 50 years, liver transplantation has advanced pool. These included the acceptance of cadaveric livers
dramatically and is considered the definitive treatment that were once discarded, the division of one organ for
for most types of liver failure, both acute and chronic, as transplantation into two recipients, and the scrupulously
well as for hepatocellular carcinoma in both children and careful use of live volunteer donors. Another way of
adults. Although most other solid organs were attempted stretching the supply is to reduce the need for retrans-
to be experimentally transplanted close to 100 years ago, plantation. In the past, such hopes depended almost
liver transplantation was not reported until 1952 by Vit- exclusively on the development of more potent immuno-
torio Staudacher from Milan, Italy. With the first human suppressive drugs. Almost all were designed to attack spe-
liver transplant performed in 1963, the stage was set for cific targets in the immunologic cascade of rejection.
advances in organ preservation, immunosuppression, and However, some of the most promising possibilities are
surgical technical refinements that led to the first success- instead based on strategies that exploit leukocyte chime-
ful human liver transplant performed on July 27, 1967. rism-dependent mechanisms of alloengraftment and
With the advent of cyclosporine in 1980 and tacrolimus acquired tolerance.
10 years later, the future was primed for substantial
change. Now in 2015, Drs. Busuttil and Klintmalm have success-
fully created the third edition of Transplantation of the
With this better immunosuppression, a rapid prolifera- Liver. The latest edition adds to the first two by increas-
tion on new centers began in the mid-1980s. Two of the ing the number of chapters from 89 in the second edition
largest and most successful programs were founded by to 107 in the current one. Topics that have been expanded
Dr. Ronald Busuttil in 1983 and Dr. Göran Klintmalm in upon include many of the new problems that face the
1985. In 1995, these surgeons published a state-of-the-art liver transplant community today, such as the use of death
book on liver transplantation. The various chapters were after cardiac donation (DCD) grafts; liver transplantation
contributed by surgeons, internists, and pediatricians for the treatment of cholangiocarcinoma; management of
with extensive experience and expertise in various aspects portopulmonary hypertension; an expanded analysis of
of patient selection, the operation itself, and preoperative the use of extended criteria donors; extracorporeal resus-
and postoperative care. Immunologists and others who citation of grafts; combined liver-kidney and multiorgan
provided essential components of the substructure also transplantation; management of the HCV epidemic; and
were represented. The book was a great success at every discussion of the current treatment of antibody-mediated
level of the healthcare hierarchy, from students to rejection of liver grafts, which was not considered a major
professors. problem before.

By the time of the book’s launch in 1995, the combina- As in the previous edition, each chapter is followed by a
tion of acceptable results and the number of centers with Pearls and Pitfalls section that alerts the reader to specific
well-trained surgeons had made liver replacement the points that might otherwise be missed. Some of these sec-
universally accepted “last court of appeal” for virtually all tions are so helpful that it may be beneficial to peruse the
patients dying of nonneoplastic liver disease and for a Pearls and Pitfalls before tackling the main text.
selected subgroup of those with malignant hepatic tumors
that could not be removed with conventional subtotal In both the inaugural and second editions of Transplanta-
hepatic resection. It was also apparent, even from a casual tion of the Liver, I concluded my Foreword as follows:
reading of the first edition of Transplantation of the Liver,
that organ supply had already become the principal deter- The creation of a genuine classic is a cause for wonder,
rent to further expansion of these services. Liver xeno- which inevitably increases with time. Years from now, Drs.
transplantation was discussed as a potential way to deal Busuttil and Klintmalm are apt to look back at their work
with the impending crisis; however, with the opposition product and ask themselves how they had been able in their
by the public, as well as within the profession, to using earlier life to construct something this good.
closely related species (e.g., the baboon) as donors, this
possibility was and still remains remote. They have, in fact, succeeded in raising the bar yet again
and making their work product even better in the third
In 2005, the second edition of Transplantation of the Liver edition of Transplantation of the Liver.
was published. In that text, Busuttil and Klintmalm and
their contributing authors emphasized practical ways of Thomas E. Starzl, MD, PhD
expanding or more efficiently utilizing the human organ

xxi
 Preface: A New Chapter

The first edition of Transplantation of the Liver was pub- transplant pioneers for the benefit of current clinicians in
lished in 1996. At that time, the practice of liver trans- the field who may not have had the opportunity to inter-
plantation had developed internationally and was act with them personally. We highly recommend this
acknowledged as the definitive treatment for virtually all chapter for every reader.
types of end-stage liver disease. The first edition was
designed to serve as a platform to codify what had evolved Several new chapters reflect recent developments in the
in the development of liver transplantation since 1963, specialty. In “Part I: General Considerations,” we have
when Dr. Thomas E. Starzl performed the first clinical incorporated a chapter that discusses regulatory and ethi-
liver transplant. Additionally, it focused on the many cal issues in organ donation, including donation after car-
advances in the field that had developed since that senti- diac death versus brain death. We have expanded “Part II:
nel event. Patient Evaluation: Adult” with two new chapters. One
chapter focuses on liver transplantation for cholangiocar-
In 2005 the second edition was published, and by that cinoma, and the other examines nonalcoholic steatotic
time a revolutionary change in organ allocation had been hepatitis (NASH), a diagnosis that may very well overtake
enacted by the Organ Procurement and Transplantation hepatitis C as the most common indication for liver trans-
Network (OPTN), which had a significant impact on the plantation in many countries during the next few years. A
practice of liver transplantation. Based on the Model for new chapter on pulmonary hypertension and hepatopul-
End-Stage Liver Disease (MELD) and the Pediatric monary syndrome has also been included in “Part IV:
Model for End-Stage Liver Disease (PELD), the new Special Considerations in Patient Evaluation.”
allocation system completely altered the algorithm for
patient evaluation, maintenance, wait listing, and priority A chapter on extended criteria donors was added to “Part
for transplantation. Since the implementation of these V: Operation,” reflecting the ever-increasing need for
changes, there has been a dramatic shift toward organs donors that necessarily compels us to accept donors
being allocated to the sickest of recipients and to patients whom we rarely used when the first edition of this text-
with hepatocellular carcinoma and other primary hepatic book was published. “Part VI: Split and Living Donor
malignancies who were allowed to be listed because they Transplantation” has been greatly expanded as a direct
fulfilled the approved exception criteria. As a result, this result of the substantial increased experience and knowl-
current edition thoroughly discusses these changes in edge in this field. Chapters on biliary and vascular recon-
indications, the benefits, and the potential risks. structions, small-for-size syndrome, minimally invasive
living donor hepatectomy, and dual grafts for transplan-
As editors, our ambition has always been that this text- tation have been added. “In Part VII: Unusual Operative
book would be considered state of the art while concur- Problems,” a new chapter on the varied techniques of
rently keeping the format for general reference. To that arterial reconstruction is featured.
end, we have completely updated all of the chapters and
added new ones to reflect new knowledge and expertise. Two new chapters can be found in “Part VIII: Postopera-
tive Care.” The first broaches an increasingly common
The third edition of Transplantation of the Liver essen- yet delicate challenge: the transition of pediatric patients
tially follows the same format as its predecessors. The to adulthood. This topic was not adequately addressed in
Pearls and Pitfalls sections have been expanded signifi- prior editions and is a growing issue that puts a very spe-
cantly as these summaries are intended to serve as salient cial and novel demand on the transplant care team. The
words of wisdom from experienced mentors to share with second new chapter concerns recurrent hepatitis C after
their less-experienced counterparts in the field. liver transplantation, which is a significant problem today.
Hopefully, with the new drugs that have recently become
As in the previous editions, when recruiting new authors, available, this will be primarily of historical ­interest by
we turned to individuals recognized for their expertise in the time the fourth edition is contemplated. The complex
a particular specialty. When possible, we strived to have and difficult complication of graft-versus-host disease
different views that might apply to a specific issue or was given a separate chapter in “­ Part X: Immunology of
problem because, in many cases, successful approaches Liver Transplantation.” Along with the maturation of
are often varied. Furthermore, all chapters have been liver transplantation, large numbers of patients are living
updated to be relevant to our current practice. Chapter 1, several decades after transplantation. Thus, we thought it
on the history of liver transplantation, has been entirely prudent to address the effect of long-term toxicity of
reworked to illustrate the tremendous contributions of immunosuppressive therapy with a new chapter in

xxiii
xxiv Preface: A New Chapter

“Part XI: Immunosuppression.” Finally, in “Part XIII: father of liver transplantation, Dr. Starzl, as leaders of our
Future Developments in Liver Transplantation,” there own programs. We appreciate being able to pass this
are two new chapters that look to the future. The first mantle along through our textbook and our respective
chapter discusses stem cell and liver regeneration, and the fellowship programs. We dedicate this work to Dr. Starzl
second focuses on extracorporeal perfusion to resuscitate and his contemporary pioneers Drs. Roy Calne, Rudolph
marginal grafts. Pichlmayr, and Henri Bismuth. May this text serve as an
ode to their vision and the legacy that they have created
It has been extremely gratifying personally and profes- worldwide.
sionally to watch our field develop and flourish before our
eyes. We both feel very fortunate and humbled to have Ronald W. Busuttil, MD, PhD
the opportunity to safeguard the mantle created by the
Göran B.G. Klintmalm, MD, PhD
 Acknowledgments

We wish to express our appreciation to Colleen Devaney the invaluable mentorship of Dr. Thomas E. Starzl, this
and Therese Dangremond for their tireless efforts and work would not have been possible.
dedication to the third edition of Transplantation of the
Liver. Without their commitment to excellence, as well as Ronald W. Busuttil, MD, PhD
Göran B.G. Klintmalm, MD, PhD

xxv
 CHAPTER 1

The History of Liver

Transplantation
Greg J. McKenna • Göran B.G. Klintmalm

CHAPTER OUTLINE

INTRODUCTION: THE GENESIS OF LIVER HUMAN TRIALS: THE HUMAN LIVER TRANSPLANT
TRANSPLANTATION TRIALS RESUME IN 1967
ANIMAL MODELS: PREREQUISITES FOR CANINE HUMAN TRIALS: ADVANCEMENTS TO THE
REPLACEMENT RECIPIENT OPERATION
ANIMAL MODELS: PATHOLOGY OF LIVER ORGAN PRESERVATION: IN SITU PERFUSION
REJECTION
IMMUNOSUPPRESSION: THE NEW AGE OF
IMMUNOSUPPRESSION: HOST IRRADIATION AND CYCLOSPORINE
CYTOABLATION
REGULATORY DEVELOPMENT: NATIONAL
IMMUNOSUPPRESSION: 6-MERCAPTOPURINE INSTITUTES OF HEALTH CONSENSUS COMMITTEE
AND AZATHIOPRINE AND “THE STAMPEDE”
ANIMAL MODELS: TOWARD LIVER ORGAN PRESERVATION: COLD STORAGE
TRANSPLANTATION BY KIDNEY TRANSPLANT
IMMUNOSUPPRESSION: FURTHER
EXPERIENCE
ADVANCEMENTS USING TACROLIMUS
HUMAN TRIALS: THE HUMAN KIDNEY
ORGAN SUPPLY: MARGINAL DONORS
TRANSPLANT TRIALS
ORGAN SUPPLY: SPLIT-LIVER PROCEDURES
HUMAN TRIALS: THE HUMAN LIVER TRANSPLANT
TRIALS OF 1963 ORGAN SUPPLY: LIVING DONOR
TRANSPLANTATION
HUMAN TRIALS: THE LIVER TRANSPLANT
MORATORIUM ORGAN SUPPLY: XENOTRANSPLANTATION
IMMUNOSUPPRESSION: ANTILYMPHOCYTE REGULATORY DEVELOPMENT: NATIONAL ORGAN
GLOBULIN TRANSPLANT ACT OF 1984 AND BEYOND
ORGAN PRESERVATION: EXTRACORPOREAL REGULATORY DEVELOPMENT: EQUITABLE ORGAN
HYPOTHERMIC PERFUSION AND EX VIVO ALLOCATION AND THE MELD SCORE
PERFUSION ORGAN PRESERVATION: EXTRACORPOREAL
ANIMAL MODELS: DEMONSTRATION OF HEPATIC MACHINE PERFUSION SYSTEMS
TOLEROGENICITY SUMMARY

The history of liver transplantation is a complicated story of organ supply that inspired advances and regulatory
to tell—it is a story of great successes and tragic failures. It developments that helped bring the field into maturation.
is a story of both individual heroics and the power of col- The modern framework and procedures for organ
laboration. It is a story that has many overlapping themes transplantation were born from the bold efforts of a
that all evolved simultaneously—there were developments small number of centers in North America and Europe
in immunosuppression, creation of animal models, between 1954 and 1967. It was a time when it would
advances in organ preservation, and the results from have been easy to have been marginalized from the
human trials. Each of these themes unfolded at the same mainstream, when the conventional wisdom was that
time. And at that same time, the story was affected by issues transplanting tissue from one human to another was at

2
 1 The History of Liver Transplantation 3

TABLE 1-1 Milestones of Liver Transplantation

Year Description Reference
1952 First report on liver transplantation (Vittorio Staudacher, University of Milan) 1
1955 First report on auxiliary liver transplantation (C. Stuart Welch, Albany Medical College) 5
1958-1960 Formal research programs of total hepatectomy and liver replacement in dogs 14,128
1960 Azathioprine introduced for organ transplantation 39,40
1963 Azathioprine-prednisone cocktail introduced for organ transplantation 50
1963 In situ preservation-procurement method described 129
1963 First human liver transplantation (Thomas Starzl, University of Colorado) 53
1966 First liver xenotransplantation (chimpanzee donor) 23
1966 Antilymphocyte globulin introduced for organ transplantation 65
1967 First successful liver transplantation (Thomas Starzl, University of Colorado) 16
1967-1968 Acceptance of brain death concept 130
1968 First successful liver transplantation in Europe (Roy Calne, University of Cambridge) 78
1976 Improved slush liver preservation permits long-distance procurement 25,26
1979 Systematic use of arterial and venous grafts for cadaver organ revascularization 24
1979 Cyclosporine introduced for organ transplantation 89
1980 Cyclosporine-prednisone introduced for organ transplantation 90
1981 80% 1-year liver recipient survival reported using cyclosporine-prednisone 91
1983 Introduction of pump-driven venovenous bypass without anticoagulation 57,58
1983-1984 U.S. Consensus Development Conference concludes liver transplantation is a “clinical service” 92
1984 Standardization of in situ preservation-procurement techniques for multiple cadaver organs 54,55
1984 First reduced-size graft liver transplantation (Henri Bismuth, Paul Brousse Hospital, Paris) 84
1984 First ex situ reduced-size graft liver transplantation (Rudolf Pichlmayr, University of Hannover) 103
1984 National Organ Transplant Act introduced in the United States 119,131
1987 UW solution introduced for organ preservation (F. Belzer, J.H. Southard, University of Wisconsin) 28
1987 First report on extensive marginal donor use (Leonard Makowka, University of Pittsburgh) 100
1987 Scientific Registry of Transplant Recipients created in the United States 121
1989 Tacrolimus introduced for organ transplantation 97
1989 First living donor liver transplantation (Russell Strong, Stephen Lynch, University of Queensland) 108
1994-1998 First right lobe living donor liver transplantation (Yoshio Yamaoka, Kyoto University) 109,110
1995 First in situ split-liver transplantation (Xavier Rogiers, University of Hamburg) 106
2000 First successful ex vivo porcine xenoperfusion (Marlon Levy, Baylor University Medical Center) 118
2002 MELD score introduced in the United States for organ allocation 132
2006 Donor Risk Index score to quantify marginal donor risk (Sandy Feng, University of Michigan) 102
2010 First report of liver hypothermic machine perfusion (James Guarrera, Columbia University) 121

MELD, Model for End-Stage Liver Disease; UW, University of Wisconsin.

best, not possible, and at worst, an unethical undertak- preservation, human trials, regulatory developments, and
ing. Although kidney transplantation opened the door organ supply (Table 1-1).
to the possibility of “transplantation,” it was liver
transplantation that truly became the driving force
behind the innovations and discoveries that ultimately INTRODUCTION: THE GENESIS OF LIVER
advanced the entire field of transplantation. Liver TRANSPLANTATION
transplantation drove the progress in developing
immunosuppression, the improvements in organ pres- The transplantation of all of the other major organs
ervation, and the advances in anesthesia and intensive can be traced back to the early 1900s,1,2 but for liver
care unit care. The research and models created for transplantation the first reported liver transplant was
liver transplantation gave insight into the metabolic in 1952 at the fifty-fourth Congress of the Italian Soci-
interrelations of the intra-abdominal organs, provided ety of Surgery. In 1952 Vittorio Staudacher from the
an understanding of liver-based inborn errors of University of Milan (Fig. 1-1) published a series of
metabolism, and fostered an understanding of liver experiments in which the first description of the tech-
growth and regeneration. nique of liver transplantation in four dogs was out-
The story of liver transplantation unfolds through six lined.3,4 This first liver transplant was an orthotopic
related themes that weave back and forth at different liver transplant, where the host liver was removed and
points throughout the timeline. It is helpful to view this fully replaced by the donor allograft, and in his report
complicated history through the lens of the following six Staudacher clearly describes the procedure in five steps
topics: animal models, immunosuppression, organ that resemble the modern transplant operation. In the
4 PART I General Considerations

m
enu
uod
D

er
Dr. Vittorio Staudacher

liv
or
University of Milan

Don
Milan, Italy
Aorta
Hepatic a.
FIGURE 1-1 n The first liver transplantation was performed in IVC Splenic a.
1952 on a dog by Vittorio Staudacher at the University of Milan. Portal v. L. gastric a.
The results were presented to the fifty-fourth Congress of the Celiac axis
Italian Society of Surgery in 1952. This landmark surgery
remained unknown for many decades before it came to the Common
attention of researchers. (From Busuttil RW, De Carlis LG, Mihay- iliac
lov PV, et al. The first report of orthotopic liver transplantation in the a.v.
western world. Am J Transpl. 2012;12:13851387.)

discussion Staudacher commented that no one had

reported a liver transplant previously. Although Stau- FIGURE 1-2 n Auxiliary liver homotransplantation in dogs (the
dacher’s achievements were known by some colleagues Welch procedure). Note that the reconstituted portal venous
in Italy, his work went essentially unnoticed for almost inflow is from the inferior vena caval bed rather than from the
splanchnic organs. Biliary drainage was with cholecystoduode-
6 decades. nostomy. a., Artery; IVC, inferior vena cava; L, left; v., vein. (From
In 1955 C. Stuart Welch of Albany Medical College Starzl TE, Marchioro TL, Rowlands DT Jr, et al. Immunosuppression
reported the first heterotopic liver transplant in a one- after experimental and clinical homotransplantation of the liver. Ann
page article published in Transplantation Bulletin, the Surg. 1964;160:411-439.)
forerunner of the present day journal Transplantation.5
For more than 50 years, Welch’s report was considered
the first reported liver transplant until the recent discov- regeneration were governed by the amount of portal
ery of Staudacher’s published work. In Welch’s “auxil- venous inflow (known as the “flow hypothesis” of hepatic
iary liver transplant,” a hepatic allograft was implanted homeostasis). Because the portal vein of the auxiliary
into the right paravertebral gutter of dogs without dis- liver allograft received ample systemic blood from the
turbing the native liver.5 Welch followed up this publi- host vena cava, it was felt that the atrophy was not
cation with a more complete description published in related to blood flow but was instead ascribed to immu-
Surgery in 1956.6 These auxiliary livers were revascular- nological factors. It would be more than 10 years before
ized by anastomosing the allograft hepatic artery to the the cause of the auxiliary allograft atrophy was fully
recipient aortoiliac system, and by an end-to-end anas- appreciated and the idea of rejection being the culprit
tomosis of the allograft portal vein to the host inferior was refuted. It ultimately became apparent that the atro-
vena cava (Fig. 1-2). By including a short length of phy was due to the absence of hepatotrophic factors
donor retrohepatic vena cava, Welch avoided anasto- such as insulin, which are present in high concentrations
mosing multiple hepatic veins and instead required just in the splanchnic circulation but were missing from the
one anastomosis; the upper end of the caval segment of systemic blood from the vena cava that perfused the aux-
the graft was anastomosed to the recipient vena cava, iliary liver.7-10
and the lower end was ligated. In 1960 Michael Francis Addison Woodruff of the
In contrast to other types of transplanted organs, an University of Otago Dunedin School of Medicine in
auxiliary liver transplant allograft underwent a marked New Zealand published a compendium of work in
shrinkage beginning within 3 to 4 days of the surgery. transplantation11 up to 1959, and at that time the only
Initially the atrophy was attributed to liver rejection. references to liver transplantation were Welch’s two
The central dogma at the time was that liver size and articles on heterotopic liver transplantation5,6 and a
 1 The History of Liver Transplantation 5

Upper vena cava

anastomosis

Homograft
liver

Ligated
common duct
Gastroduodenal
a. (tied) Anastomosis
of hepatic a.
Hepatic a.
(tied)

Cholecysto-
duodenostomy

Lower vena cava

anastomosis
I.
V.
C. Repaired portacaval
Portal anastomosis
shunt

FIGURE 1-3 n Completed liver replacement in the dog. The fact that the recipient was a dog rather than a human is identifiable only
by the multilobar appearance of the liver. a., Artery; I.V.C., inferior vena cava; P.V., portal vein. (From Brettschneider L, Daloze PM,
Huguet C, et al. The use of combined preservation techniques for extended storage of orthotopic liver homografts. Surg Gynecol Obstet.
1968;126:263-274.)

brief report by Jack Cannon of University of Califor- of studying these metabolic relationships.18,19 In these
nia, Los Angeles (UCLA) published in 1956 that investigations the Northwestern University group pio-
described the liver transplant activities in animals per- neered a new method of total hepatectomy in which the
formed at the recently founded UCLA School of Med- host’s retrohepatic inferior vena cava was preserved,20
icine.12 This article by Cannon was considered for (heralding the approach that would come to be known
many years to be the first experimental description of as the piggyback variation of liver transplantation in
an orthotopic liver transplant, until the recently dis- humans21-23). For liver replacement in the dog, it was
covered work of Staudacher.3 simpler to excise the host retrohepatic vena cava along
However, by the time Woodruff’s book was pub- with the native liver and to replace it with the compa-
lished in 1960, there were already two centers—the rable caval segment of the donor. The vena caval anas-
Peter Bent Brigham Hospital in Boston13 and North- tomosis above and below the liver and the hepatic
western University in Chicago14—that both indepen- arterial and biliary tract anastomoses were performed
dently began studying liver transplantation in 1958, with conventional methods13,14 (Fig. 1-3). When differ-
each center looking at the field from different vantage ent means of portal revascularization were systemati-
points. The investigations from the Brigham Hospital cally tested in the laboratory at the Northwestern
were done under the direction of Francis D. Moore,13,15,16 University program (Fig. 1-4), it was discovered that
and because the focus came from a center with an estab- any deviation from the normal portal supply resulted in
lished history with kidney transplantation, this group reduced survival.
approached liver transplantation from an immunologi- The research teams at Northwestern University in
cal perspective with a therapeutic objective. In contrast, Chicago and the Brigham Hospital in Boston were
the work from the Northwestern University group led unaware of each other’s activities until late 1959, and
by Thomas E. Starzl14,17 stemmed from work regarding direct contact between the programs was not estab-
the metabolic interrelationships of the liver with the lished until the 1960 meeting of the American Surgical
pancreas and intestine, which evolved from earlier Association. By then the cumulative total of liver
investigations done at the University of Miami in the replacement procedures in nonimmunosuppressed
field of hepatotrophic physiology. In this circumstance, dogs was 111 (80 at the Northwestern University pro-
liver replacement was being performed for the purpose gram,14 31 at the Brigham Hospital program13). The
6 PART I General Considerations

Diaphragm

Liver
IVC

PV PV PV

IVC IVC

A B C
FIGURE 1-4 n Alternative methods of portal vein revascularization. A, Reverse Eck fistula. B, With small side-to-side portacaval shunt.
C, Anatomically normal. Survival was best with C. IVC, Inferior vena cava; PV, portal vein. (From Starzl TE, Kaupp HA Jr, Brock DR, et al.
Reconstructive problems in canine liver homotransplantation with special reference to the postoperative role of hepatic venous flow. Surg
Gynecol Obstet. 1960;111:733-743.) IVC, Inferior vena cava; PV, portal vein.

outcomes from these canine liver transplants were

published in 1960 in separate papers and in different
journals.

Gallbladder
ANIMAL MODELS: PREREQUISITES L iv
FOR CANINE REPLACEMENT er

Ringer
The two prerequisites for perioperative survival of canine bottle
liver transplant were independently established in each
laboratory, both at the Brigham Hospital in Boston and at Hepatic a.
Northwestern University in Chicago. The first require- Portal v.
ment for a successful canine liver replacement was preven-
tion of ischemic injury to the allograft. At the Brigham
Hospital program this was accomplished by immersing the
liver in iced saline. At the Northwestern University pro-
gram the method of hypothermia was influenced by F.
John Lewis, who along with Norman Shumway pioneered
total body hypothermia for open heart surgery while at the IVC Aorta
University of Minnesota.24 The livers were cooled by the
intravascular infusion of chilled lactated Ringer solution
(Fig. 1-5) and monitoring core temperature with thermal
probes. This now-universal step in preservation of organs
had never been used before, apparently because of the fear
of damaging the microcirculation. In time, better liver
preservation was obtained by altering the osmotic, oncotic,
and electrolyte composition (i.e., Collins,25 Schalm,26 and
University of Wisconsin solutions27-29).
The second prerequisite for successful canine liver Bottle
replacement was avoiding damage to the recipient (blood)
splanchnic and systemic venous beds when venous drain- FIGURE 1-5 n Cooling of the canine hepatic allograft by infusion
age was obstructed during the host hepatectomy and graft of chilled lactated Ringer solution into the donor portal vein. The
implantation. In both laboratories this was accomplished animals were simultaneously exsanguinated. a., Artery; IVC,
inferior vena cava; v., vein. (From Starzl TE, Kaupp HA Jr, Brock
by using external venovenous bypasses to decompress the DR, et al. Reconstructive problems in canine liver homotransplanta-
venous drainage, although the particular details of the tion with special reference to the postoperative role of hepatic
bypasses differed at each center. venous flow. Surg Gynecol Obstet. 1960;111:733-743.)
 1 The History of Liver Transplantation 7

ANIMAL MODELS: PATHOLOGY OF LIVER the first examples of acquired immunological tolerance in
REJECTION humans.
Exploring a substitute for irradiation, Willard Good-
Until 1960 the kidney had been the only organ allograft win, a urologist from UCLA, pretreated recipients with
whose unmodified rejection had been systematically stud- myelotoxic doses of cyclophosphamide and methotrex-
ied. With development of the canine liver replacement ate.34 One recipient had a prolonged survival of 143 days
models at each of the two programs, the pathology of rejec- and had rejection that was successfully reversed several
tion in a transplanted liver could now be studied. These ini- times with prednisone. Despite these initial moderate
tial histopathological assessments were done by David Brock successes with cytoablation, it quickly became apparent
at the Northwestern University program and Gustav Dam- that cytoablation by medication was not going to be a fea-
min at the Brigham Hospital program. Most of the trans- sible means through which liver transplantation might
planted canine livers were destroyed in about 5 to 10 days. occur.
The pathological examination of the transplanted livers
typically showed a heavy concentration of mononuclear
cells, both in the portal triads and in and around the central IMMUNOSUPPRESSION:
veins, all with extensive hepatocyte necrosis.16,17
A curious exception was noticed in the sixty-third liver 6-MERCAPTOPURINE
replacement experiment. The serum bilirubin level reached AND AZATHIOPRINE
a peak at 11 days but then progressively declined.17 The pre-
dominant histopathological findings in the allograft by day The real advances needed for liver transplantation
21 were more those of repair and regeneration rather than required the arrival of the era of drug immunosuppres-
rejection. This was the first recorded exception to the exist- sion, and 6-mercaptopurine (6-MP) is generally consid-
ing dogma that once rejection was initiated, it was an ines- ered the drug that heralded in this era. Much of the initial
capable process. Five years later, similar observations were research that would be crucial for immunosuppression
made by Ken A. Porter of St Mary’s Medical School in Lon- for liver transplantation was studied in kidney transplant
don, assessing the allografts of long-surviving canine liver models. In 1950, working at Wellcome Research Labora-
recipients from experiments done at the University of Colo- tories, Gertrude Elion and George Hitchings35 used
rado program, where rejection had developed and then innovative drug development methods to create 6-MP
spontaneously reversed under stable daily doses of (work for which they received the Nobel Prize in medi-
azathioprine.30 cine in 1988). The researchers Robert Schwartz and Wil-
liam Dameshek at Tufts Medical School in Boston first
established that 6-MP was immunosuppressive36,37 and
IMMUNOSUPPRESSION: HOST not require overt bone marrow depression to be success-
IRRADIATION AND CYTOABLATION ful. Using a skin allograft model in rabbits, William
Meeker Jr. and Robert Good at the University of Min-
Just when the surgical research in nonimmunosuppressed nesota showed 6-MP provided a modest prolongation of
dogs began to lose momentum, it was dramatically revital- skin allograft survival.38 Upon learning of the immuno-
ized. From January 1959 to February 1962, there were suppressive potential of 6-MP, both Roy Calne (then a
seven successful human kidney transplantations performed, surgical trainee) in London39 and Charles Zukoski at the
the first by Joseph Murray31 at the Brigham Hospital in Medical College of Virginia in Richmond40 indepen-
Boston (work for which he received the 1990 Nobel Prize in dently performed experiments using transplant models
medicine) then six more times by the independent teams led with canine kidney allograft, reporting survival of up to
by Jean Hamburger32 and Rene Kuss,33 both of whom were 40 days.
in Paris (Table 1-2). For these seven transplants the immu- After developing 6-MP, Elion and Hitchings used
nosuppression came from preconditioning the patients with their drug development techniques to synthesize an imid-
sublethal doses of 4.5 Gy total body irradiation. The first azole derivative of 6-MP called azathioprine, a prodrug of
two recipients (they received fraternal twin kidneys) had 6-MP that required processing in the liver to become
continuous graft function for more than 2 decades without active and thereby prolonged the effects of the drug. By
any further posttransplant immunosuppression. They were the end of 1960, both Zukoski, working with David

TABLE 1-2 Kidney Transplantation: 6 Months or Greater Survival as of March 1963

Date Program Surgeon Donor Survival (mo) Alive/Dead
1/24/1959 Peter Bent Brigham Hospital, Boston J.E. Murray Fraternal twin >50 Alive
6/29/1959 Necker Hospital—University of Paris J. Hamburger Fraternal twin >45 Alive
6/22/1960 Centre Medico-Chirugical Foch, Seine R. Kuss Unrelated 18 Dead
12/19/1960 Necker Hospital—University of Paris J. Hamburger Mother 12 Dead
3/12/1961 Centre Medico-Chirugical Foch, Seine R. Kuss Unrelated 18 Dead
2/12/1962 Necker Hospital—University of Paris J. Hamburger Cousin >13 Alive
4/5/1962 Peter Bent Brigham Hospital, Boston J.E. Murray Unrelated 11 Alive
8 PART I General Considerations

Hume in Richmond,41 and Calne, who had moved to survival of a human organ allograft without host condi-
Boston for a fellowship with Murray,42,43 were using aza- tioning with total body irradiation. This positive element
thioprine in kidney transplants42 with survival results that in the report was tempered by the fact it was the only
would sometimes reach 100 days. recipient of the first 13 treated solely with drug immuno-
suppression that survived for more than 6 months.44-46
In the spring of 1962 the University of Colorado group
of Waddell and Starzl, working at the Denver Veterans
ANIMAL MODELS: TOWARD LIVER Administration hospital, obtained a supply of azathio-
TRANSPLANTATION BY KIDNEY prine and began developing experience with the drug.
TRANSPLANT EXPERIENCE Initially the plan had been to study azathioprine in a liver
transplant model, but it became clear quickly that the
Calne’s experiments showing transplant rejection could operation of liver replacement in dogs was too difficult
sometimes be substantially delayed with azathioprine and fraught with technical challenges to use it to evaluate
encouraged the Brigham Hospital program in Boston to an immunosuppressive drug. So the group decided to use
pursue human kidney transplant trials. When the trials of the simpler canine kidney model first as a precursor to
kidney transplant with azathioprine began in Boston in liver transplantation. The results from this transplant
1960-61, there were initially high expectations,44 and the model yielded similar results to other laboratories with
idea of actually transplanting livers seemed less remote. survival that sometimes approached 100 days. However,
In 1961 William R. Waddell left Massachusetts General two key observations came from these canine transplant
Hospital to become chair of surgery at the University of models that would affect future immunosuppressive man-
Colorado, where he was joined by Starzl, coming from agement strategies. The first observation was that the
Northwestern University in Chicago. Their goal at that allograft rejection that occurred after azathioprine mono-
point was to pursue development of liver transplantation, therapy could be reversed by delayed addition of large
especially considering the 3 years of experience Starzl had doses of prednisone.47 The second observation was that
gained at Northwestern University working with the pretreatment of the animals with azathioprine for 7 to 30
canine hepatic replacement models (Fig. 1-6). Unfortu- days before transplant doubled their mean survival, which
nately, the plans for liver transplantation were shelved to that point had been 36 days.48
when reports of the Boston clinical trial of kidney trans-
plantation described disappointing results. The report by
Murray et al,44 published in the Annals of Surgery, did HUMAN TRIALS: THE HUMAN KIDNEY
have one positive element, because it described a kidney TRANSPLANT TRIALS
allograft transplanted from an unrelated donor in April
196245 that was still functioning 120 days later using aza- Beginning in late 1962, the long-standing kidney trans-
thioprine immunosuppression. That kidney ultimately plant program at Brigham Hospital in Boston was joined
functioned for another 13 months after this report for a by two other centers in performing human kidney trans-
total of 17 months, and it was the first example of 1-year plantation: the group at the University of Colorado in
Denver comprising Starzl and Waddell and the group at
the Medical College of Virginia in Richmond led by Hume
(Fig. 1-7). The groups at Colorado and Virginia were in
Dr. Thomas E. Starzl close contact with each other, collaborating on ideas,49 and
both realized early that a combination of “azathioprine and
University of Pittsburgh steroids” was key to a successful outcome; however, they
Pittsburgh, PA
1981 – Present approached the strategy from different directions. The
University of Colorado group reserved steroids for when
University of Colorado
rejection occurred, which invariably happened with aza-
Denver, CO thioprine monotherapy. The Medical College of Virginia
1962 – 1980 group used reduced-dose steroids from the time of the
transplant as part of a dual drug combination.
Northwestern University The University of Colorado group began human kid-
Chicago, IL ney transplants in 1962 using a protocol that gave daily
1959 – 1961 doses of azathioprine 1 to 2 weeks before transplant, as
First Kidney Transplant 1962 well as continuing it after, and added high doses of pred-
First Liver Transplant 1963 nisone to treat any rejection. The successful results of the
first 10 kidney cases using this protocol were described in
the report “The Reversal of Rejection in Human Renal
FIGURE 1-6 n Thomas Starzl started his career at Northwestern
University, where he performed canine hepatic replacements for Homografts With Subsequent Development of Homo-
studying metabolic interrelationships of the liver with the pan- graft Tolerance.”50 The term tolerance referred to the
creas and intestine. When he moved to the University of Colo- time-related decline of need for maintenance immuno-
rado in 1962, those canine models laid the groundwork for suppression. Based on their results using this protocol,
developing human liver transplantation. He performed the first
human liver transplant in 1963. In 1981 he moved to the Univer-
Starzl and the University of Colorado group concluded
sity of Pittsburgh, making it the largest liver transplant program that renal transplantation had reached the level of a bona
in the world. fide (albeit still flawed) clinical service.
 1 The History of Liver Transplantation 9

In 1963 a small conference organized by the Before the 1963 National Research Council confer-
National Research Council ultimately became a land- ence there were only the three active kidney transplant
mark event in transplantation. Twenty-five of the lead- centers in the United States (Brigham Hospital, Univer-
ing transplant clinicians and scientists from around the sity of Colorado, and Medical College of Virginia).
world assembled to review the current status of human Within a year of the conference, and as word of the effec-
kidney transplantation.51 The results were very dis- tiveness of this new immunosuppression protocol spread,
couraging because less than 10% of the several hun- 50 new transplant programs began in hospitals through-
dred human allograft recipients had survived more out the United States, with a similar proliferation of
than 3 months.52 Of those treated with total body irra- transplant centers across Europe.49 Some of the benefits
diation for immunosuppression, only 6 patients had of kidney transplantation proved to be truly long lasting
survival close to 1 year. The results of those with drug- in some cases, because eight of the recipients from the
based immunosuppression were equally poor, as Mur- University of Colorado program from 1962 to 1963 still
ray reported that of his first 10 patients treated with had their kidney transplants 40 years later (making them
6-MP or azathioprine, only the one survived a year, the longest-surviving organ allograft recipients in the
whereas the others died within 6 months. Some par- world) and some of them have lasted 50 years.24
ticipants at the conference began to question whether
human transplantation could still be justified. Ulti-
mately the Colorado group described their success
with their immunosuppressive protocol of using aza-
thioprine and adding large doses of prednisone with
any rejection, which allowed a 1-year survival rate that
exceeded 70%.51 Because the Colorado group, which
had been a late invite to the meeting, reported more
surviving recipients than the rest of the world’s other
centers combined, the audience was incredulous, and it
provoked intense discussions. However, the fact that
Starzl brought with him the wall charts (on the advice
of Goodwin, who was aware of the results) that detailed
the daily progress, urine output, and laboratory work
of each patient, quelled the debate (Fig. 1-8). As Clyde
Barker of the University of Pennsylvania described the
events: “The gloom was dispelled by only one presen-
tation given by Tom Starzl, a virtually unknown new-
comer to the field, who was invited to the conference as FIGURE 1-8 n A segment of a typical kidney transplant wall chart
from the University of Colorado program, 1968. The wall chart
an afterthought…. The outlook for renal transplanta- was designed by T.E. Starzl, and the original version was hand
tion was completely changed by Starzl’s report.”51 drawn. Note the antilymphocyte globulin (ALG), Imuran, predni-
sone (Pred.), and x-ray dosing.

Dr. Francis D. Moore Dr. David M. Hume Dr. Joseph E. Murray

Brigham Hospital Medical College of Virginia Brigham Hospital
Boston, MA Richmond, VA Boston, MA

FIGURE 1-7 n Francis D. Moore, Joseph E. Murray, and David Hume were an integral part of the Peter Bent Brigham Hospital kidney
team in Boston that performed the first human kidney transplant in 1954. Hume moved to the Medical College of Virginia in Rich-
mond in 1956 to become the chairman of the Department of Surgery, where he initiated kidney transplant. In late 1962 the Brigham
Hospital, Medical College of Virginia, and the University of Colorado were the three programs performing kidney transplants in the
United States.
10 PART I General Considerations

HUMAN TRIALS: THE HUMAN LIVER and 8 hours, respectively, and neither recipient had any
TRANSPLANT TRIALS OF 1963 significant ischemic damage as evidenced by modest
increases in the liver enzyme levels after transplant.
Although the follow-up evaluations of the kidney For the operative procedure the various anastomoses
transplant trials were still short, the successful human were performed in the same way as in the dog experi-
kidney transplant experience at the Colorado program ments except for the biliary tract reconstruction. (The
encouraged the decision to go forward with the expo- complete operation was drawn in 1963 [Fig. 1-11], and
nentially more difficult initiative of liver transplanta- that picture could still be used today to depict a human
tion (Fig. 1-9). The first attempted human liver liver transplantation.) The immunosuppression proto-
transplant was on March 1, 1963, in a 3-year-old boy col for the recipients in the University of Colorado
with biliary atresia named Bennie Solis. Bennie had group’s liver transplantation trials derived from that
been operated on numerous times previously and had center’s experience in the human kidney transplant tri-
deteriorated to the point of being unconscious and als, with azathioprine administered both before and
ventilated.53 Unfortunately, Bennie bled to death dur- after transplantation, adding a high-dose course of
ing the actual transplant operation, because of the prednisone with the onset of rejection.
many high-pressure venous collaterals that had formed Although both procedures seemed satisfactory,
and an uncontrollable coagulopathy. This result these recipients—the second and third recipients of
occurred despite the fact that the operative team had the trial, died after 22 and 7.5 days, respectively. Both
performed more than 200 similar transplant operations patients died in part because of pulmonary emboli,
in animal models. The complexity and difficulty was so although interestingly, both were also found to have
extreme, it took the team several hours just to make the extrahepatic micrometastasis56 of their cancers at
incision and enter the abdomen, because of the signifi- autopsy, although with no rejection of the allograft.
cant collateralized adhesions. The strategy of controlling the coagulation using
Two more liver transplantations were performed transfusion of blood products and ε-aminocaproic acid
over the next 4 months in two adults, one transplanted for fibrinolysis, which was adopted following the
May 5, 1963, for a hepatoma, and the second trans- uncontrolled coagulopathy of the first transplant, had
planted June 3, 1963, for a cholangiocarcinoma. The unintentionally backfired. During the implantation of
donor procurement for these transplants had success- the livers, passive venovenous bypass with plastic
ful allograft preservation accomplished by transfemo-
ral infusion of a chilled perfusate into the aorta of the
non–heart-beating donors after cross-clamping the
aorta at the diaphragm (Fig. 1-10)—in much the same
way as the first stage of the multiple organ procure-
ment operation still performed today.54,55 The cold
ischemia time for the two procurements was 2.5 hours

Clam
p on th
orac
er i
Aorta Aort c
Liv

IVC a
Hepatic a.

Inferior
Glucose-primed mesenteric a.
pump oxygenator
and
heat exchanger

rta
in
to Ao

nt
oI
I

VC

FIGURE 1-10 n Extracorporeal perfusion of the deceased donors

reported in 1963. “The venous drainage was from the inferior
vena cava and the arterial inflow was through the aorta after
insertion of the catheters through the femoral vessels. Note
clamp on thoracic aorta to perfuse the lower half of the corpse
FIGURE 1-9 n Thomas E. Starzl at the University of Colorado in selectively. A glucose-primed pump oxygenator was used with
1963 performing one of the first liver transplants from the initial a heat exchanger.” a., Artery; IVC, inferior vena cava. (From Starzl
human liver trials at the Denver Veterans Administration TE, Marchioro TL, Von Kaulla KN, et al. Homotransplantation of the
hospital. liver in humans. Surg Gynecol Obstet. 1963;117:659-676.)
 1 The History of Liver Transplantation 11

tubing was used, similar to the technique used in the shown to be expendable in dogs submitted to common
canine model. However, in the humans who had been bile duct ligation several weeks in advance of trans-
given coagulation-promoting therapy, clots formed in plantation—an animal model of cirrhosis and portal
the bypass tubing and passed to the lungs, causing hypertension—and the venous collaterals that devel-
abscesses and lung damage that contributed to their oped enabled transplantation without venovenous
deaths (and to the next two recipients to follow). Ironi- bypass.60
cally, the use of the venovenous bypass to decompress
the venous system—something that was so crucial to
survival in the canine experiments—was not necessary HUMAN TRIALS: THE LIVER
for most human recipients. (A motor-driven venove- TRANSPLANT MORATORIUM
nous bypass system introduced in Pittsburgh in the
1980s57-59 and later use of percutaneous catheters have During the last half of 1963, two more liver transplanta-
made the procedure easier, but in many centers bypass tions were performed by Starzl’s group at the University
is only used selectively, if at all, and never in infants or of Colorado,7 and one each at the Brigham Hospital in
small children). Ultimately, venous decompression was Boston by Moore61 and at the Hospital St Antoine in
Paris by Jean Demirleau62,63 (Table 1-3). The transplant
in Paris was the first liver transplant in Europe, and used
IVC a 71-year-old donor into a 75-year-old recipient, making
gm this also the first transplant using what would be today
ra
ph L + r. hepatic v.
called a “marginal donor.”63 The operation lasted 4
a
Di

hours, but the patient died 3 hours after transplant from

uncontrollable fibrinolysis.
After the deaths of these seven patients in three dif-
ed)

ferent centers, there was great pessimism worldwide

mov

that the operation was too difficult to be practical, that

r (re

the methods of organ preservation were inadequate for

ladde

Aorta an organ so sensitive to ischemic damage, and that the

Celiac axis available immunosuppression options were too primi-
Gall b

Hepatic a. tive to allow success. This sentiment was reinforced by

Gastro- the fact that long-term survival following liver trans-
IVC duodenal a. plantation had not yet even been achieved in the experi-
Portal v. mental animal models. Clinical activity in liver
transplantation ceased for 3.5 years between January
in

ct
be

du 1964 and the summer of 1967. The worldwide morato-

tu

on rium was voluntary, but the decision to stop was rein-

T-

m
o m forced by widespread criticism that transplantation was
C Pancreas
too formidable to be practical. During the moratorium
Duodenum
on liver transplantation, the field did not stay still; prob-
FIGURE 1-11 n The operation carried out in the first two patients lems that contributed to the failures of the transplants of
who survived liver replacement on May 5 and June 3, 1963. The
patients lived for 22 and 7.5 days. a., Artery; IVC, inferior vena
1963 were addressed, and advances were made across
cava; L, left; r., right; v., vein. (From Starzl TE. Experience in the field, in immunosuppression, organ preservation,
hepatic transplantation. Philadelphia, PA: Saunders; 1969:138.) and operative techniques.

TABLE 1-3 The First Seven Human Liver Recipients

Survival
Date Age Program Surgeon Liver Disease (Days) Cause of Death
3/1/1963 3 University of Colorado, Denver T.E. Starzl Biliary atresia 0 Intraoperative
bleeding
5/5/1963 48 University of Colorado, Denver T.E. Starzl HCC 22 Pulmonary emboli,
sepsis
6/3/1963 68 University of Colorado, Denver T.E. Starzl Cholangiocarcinoma 7 Pulmonary emboli
7/10/1963 52 University of Colorado, Denver T.E. Starzl HCC 6 Pulononary emboli,
liver failure
9/16/1963 58 Brigham Hospital, Boston F.D. Moore Colon metastasis 11 Pneumonitis, liver
abscess/failure
10/4/1963 29 University of Colorado, Denver T.E. Starzl HCC 23 Pulmonary emboli,
sepsis
1/?/1964 75 Hospital St Antoine, Paris J. Demirleau Colon metastasis 0 Intraoperative
bleeding

HCC, Hepatocellular carcinoma.

12 PART I General Considerations

organ preservation was used from 1962 to 1969 before

IMMUNOSUPPRESSION: the acceptance of brain death and was the primary mode
ANTILYMPHOCYTE GLOBULIN used in both the initial liver trials of 1963 and the later
trials of 1967.69 Of note, the preliminary stages of this
A constant objective during the liver transplant morato- approach provided the basis for subsequent in situ tech-
rium was to improve immunosuppression regimens. niques that are used today.
With regard to human kidney transplant trials, despite After the failure from the trials of 1963 and during the
achieving consistent success with 1-year survival of moratorium following, the group at University of Colo-
70%, there was disappointment that the 30% mortality rado worked to improve the pitfalls of organ preservation
could not be improved upon,64 in spite of the increased that remained given that it was necessary to obtain livers
experience with kidney transplant techniques as well as from non–heart beating donors. To help surmount this
refinements in the azathioprine-prednisone protocol difficulty, the University of Colorado group developed an
and the application of histocompatibility matching. The ex vivo perfusion system in 1966 and 1967 that permitted
events leading to the typical patient death or graft loss reliable preservation in experiments with canine livers for
were predictable—the continuing function of the trans- as long as a day. This system combined the use of hypo-
plant kidney was dependent on toxic doses of predni- thermia, hyperbaric oxygenation, and low-flow perfusion
sone.65,66 For some patients, if the clinicians reduced the with fresh diluted blood.70
prednisone, the graft failed and had to be removed, but
if the prednisone dose was not removed, the graft could
be saved, but often at the cost of a lethal infection. ANIMAL MODELS: DEMONSTRATION OF
Between 1963 and 1966, antilymphocyte globulin HEPATIC TOLEROGENICITY
(ALG) was prepared from antilymphocyte serum obtained
from horses immunized against dog for preclinical canine Despite the failures of the human liver clinical trials of
studies, or against human lymphoid cells for later human 1963, during the liver moratorium the feasibility and
trials.67 In the preclinical canine studies, the efficacy of potential of liver transplantation was best reflected in the
dog-specific ALG was demonstrated in kidney transplant growing kennel population of long-surviving canine liver
models when it was given either 5 to 30 days before trans- recipients (Fig. 1-12), none of which was treated with
plant, at the time of transplant, or from 20 to 30 days more than a 4-month course of azathioprine71 or a few
after transplant.65 doses of ALG.64 In presenting the results of 143 canine
After extensive and successful preclinical canine stud- liver replacements to the Society of University Surgeons
ies, human-specific ALG was introduced clinically in in February 1965, it was emphasized that “Although the
human kidney recipients in a trial at the University of early recovery after liver homotransplantations has many
Colorado in June 1966.64-68 With a 1- to 4-month course hazards … the frequency and rapidity with which dogs
of ALG added as an adjuvant to the basic azathioprine could be withdrawn from immunosuppression without an
and prednisone protocol to create a “triple-drug cock- ensuing fatal rejection is remarkable… The consistency
tail,” the quantities of both azathioprine and especially of this state of host-graft nonreactivity and the rapidity
the prednisone were reduced and the function of the with which it seemed to develop exceeds that reported
graft was better maintained Ultimately, the mortality in after renal homotransplantations.”71
these kidney recipients was further decreased, approach- A year later the French surgeon Henri Garnier along
ing 10% using the triple-drug cocktail.64 with Gaston Cordier reported that a significant percentage
of untreated outbred pig liver recipients did not reject their
allografts.72 These observations were promptly confirmed
ORGAN PRESERVATION:
EXTRACORPOREAL HYPOTHERMIC
PERFUSION AND EX VIVO PERFUSION
The techniques of graft procurement and preservation
first developed for the liver grafts led to advances that
could be applied to other whole organs. The first
advancement was core cooling by infusion of chilled lac-
tated Ringer solution into the portal vein (this technique
was modified for use in clinical kidney transplants and
other organs). The first technique of in situ cooling was
by extracorporeal hypothermic perfusion. The catheters
were inserted via the femoral vessels into the aorta and
vena cava as soon as possible after death. A heat exchanger
was used to control the temperature.69 The thoracic
aorta was cross-clamped to limit the perfusion to the
FIGURE 1-12 n Canine recipient of an orthotopic liver homograft,
lower part of the body. The organs were then quickly 5 years later. The operation was on March 23, 1964. The dog was
resected in a bloodless field and then the tissue was dis- treated for only 120 days with azathioprine and died of old age
sected in the cold on the back table. This method of 13 years after transplantation.
 1 The History of Liver Transplantation 13

by Calne at the University of Cambridge program,73 John transplant trials, the young girl survived for more than a
Terblanche and J.H. Peacock at the University of Bristol, year before ultimately succumbing to metastatic recur-
England,74 and Starzl at the University of Colorado.75 rence 400 days after her transplant. The child’s vivacious
Calne and his colleagues at the University of Cambridge and charming personality lead Starzl to remark that Julie
further demonstrated that the tolerance self-induced by “became a metaphor for courage and human progress,”53
the liver extended to other tissues and organs from the and her successful transplant soon led to several more
liver donor, but not from third-party pigs.76 transplants that summer. Despite the advances, however,
the 1-year survival rate of these transplants remained
below 50%, and although it was a significant improve-
HUMAN TRIALS: THE HUMAN LIVER ment, the high mortality rate would lead to liver transplan-
TRANSPLANT TRIALS RESUME IN 1967 tation remaining controversial for another decade. Yet, in
spite of the controversy, the University of Colorado pro-
After the significant advances were made with immuno- gram was soon joined by similarly visioned clinicians at
suppression regarding ALG, and with the improvements other programs, aimed at advancing the field of liver
in organ preservation, once again the idea of liver trans- transplantation.
plantation became viable, and the liver program at the In February 1968 the liver transplant program at the
University of Colorado was reopened in July 1967, end- University of Colorado was bolstered by the opening of
ing a 4-year self-imposed moratorium. The program was Calne’s clinical program at the University of Cambridge,
reinforced by the addition of a powerful colleague, Carl England.22 On May 2, 1968, Calne (with Moore, visiting
Gustav Groth, a 2-year National Institutes of Health unexpectedly at Cambridge, acting as first assistant)78
(NIH) fellow and Fulbright Fellow from Stockholm (Fig. attempted the program’s first transplant (Fig. 1-14).
1-13). With a PhD in rheology (the study of the flow of Although the first patient transplanted by the program
matter), Groth’s knowledge of blood flow and the issues exsanguinated in a fashion similar to the experience at the
of blood coagulation proved vital to helping the Univer- University of Colorado, this was followed by several suc-
sity of Colorado group overcome the clotting issues that cessful liver transplants, aided by a fruitful collaboration
had plagued earlier transplants and had led to several with the hepatologist Roger Williams at King’s College
fatalities.77 Groth became a key member of both the Hospital in London, in what became known as the Cam-
donor and recipient teams at the University of bridge-King’s Program.78,79 By 1969 a total of 33 human
Colorado. liver transplants had been performed throughout the world,
With this hurdle overcome, the team was ready to including 25 performed at the University of Colorado by
attempt the operation in the summer of 1967, and Starzl the Starzl group and 4 performed at Cambridge-King’s
performed the first successful liver transplant in 1967 on Program by the Calne group. The importance of having
an 18-month-old child named Julie Rodriguez, who was another contemporary in the field was crucial for its
diagnosed with hepatoblastoma. With the triple-drug
cocktail16 that had been so successful in the kidney

Sir Roy Y. Calne

University of Cambridge
Cambridge, England
1965 – Present

St Mary’s Hospital
Westiminster Hospital
London, England
1962 – 1965

Brigham Hospital
Boston, MA
1960 – 1961

First Liver Transplant 1968

Developed: 6– MP,
azathioprine & cyclosporin

FIGURE 1-14 n Roy Calne began with studying immunosuppres-

sive drugs in canine kidney models. In 1960 he moved to Boston
to work with Joseph Murray and collaborated with George Hitch-
ing and Gertrude Elion to develop 6-mercaptopurine (6-MP) and
later azathioprine for use in transplantation. Returning to England
in 1962, Calne practiced first in London and then moved to the
University of Cambridge in 1965. He began performing liver trans-
FIGURE 1-13 n The first three human recipients to have pro- plantation at Cambridge in 1968, and together with Thomas E.
longed survival after liver replacements in July and August Starzl he helped define the field. In 1979 Calne initiated the cyclo-
1967. The adult, Carl Groth, was then a National Institutes of sporine clinical trials in liver transplantation that would change
Health–supported fellow from Stockholm, Sweden. the face of transplantation. He was knighted in 1981.
14 PART I General Considerations

Dr. Rudolf Pichlmayr Dr. Henri Bismuth Dr. Ruud A. Krom

University of Hannover Hôpital Paul Brousse University of Groningen
Hannover, Germany Villejuif, France Groningen, Netherlands
First Liver Transplant 1972 First Liver Transplant 1974 First Liver Transplant 1979

FIGURE 1-15 n Rudolf Pichlmayr in Hannover, Henri Bismuth in Paris, and later Ruud Krom in Groningen were the three other pro-
grams along with the University of Colorado and the Cambridge-King’s program that were actively performing liver transplants in the
1970s and early 1980s. These three surgeons were instrumental in helping to develop the field through their collaborations with
Thomas E. Starzl and Roy Calne.

advancement, as described by Starzl: “The fate of liver • The incidence of bile duct complications was reduced
transplantation would depend on an unspoken trans-­ to 30 % with the use of a choledochocholedochos-
Atlantic alliance between Cambridge and Denver without tomy with a T-tube stent.81 In time, this would be fur-
which further efforts could not have continued, much less ther refined and T tubes were no longer necessary.
succeeded, on either side of the ocean. These mutually • The systematic use of pump-driven venovenous
supportive moral and scientific bonds pulled liver trans- bypasses greatly diminished intraoperative bleed-
plantation into the mainstream of medical practice.” By ing; however, improvements in anesthesia and
1969 enough successes from the experience of these 33 intraoperative fluid management have made bypass
transplants allowed publication of the first textbook of liver a selective option.57,58
transplantation, Experience in Hepatic Transplantation.23 • The use of arterial grafts allowed arterialization of
By the early 1970s the two active liver transplant pro- the liver in cases of complex vasculature. The use of
grams of the University of Colorado and Cambridge-King’s venous grafts was introduced in the 1970s82 and
were joined by three other programs (Fig. 1-15) that would eliminated extensive thrombosis of the portal vein
also make important contributions to liver transplantation and superior mesenteric vein as a contraindication
over the next decade: the University of Hannover led by to transplant.83
Rudolf Pichlmayr performed their first liver transplant in • The piggyback operation (Fig. 1-16) that keeps
1972; the group from Hôpital Paul Brousse in Villejuif, intact the recipient retrohepatic vena cava was first
France, led by Henri Bismuth performed their first trans- used in 1968 at both the University of Cambridge
plant in 1974; and the group in Groningen led by Ruud program22 and the University of Colorado pro-
Krom, which followed with their first transplant in 1979. gram23 for pediatric recipients. The adult proce-
(Of note, that first patient from Groningen is still alive after dure was popularized by Andreas Tzakis at the
35 years.) Each of these programs reported a similar phe- University of Miami program.21
nomenon—the nearly miraculous benefits of liver trans- • The shortage of appropriate-sized donors for very
plantation when it was successful, but with the caveat that small pediatric recipients was greatly ameliorated
the mortality rate was too high to allow its practical use. by the use of partial liver segments.84,85
Nonetheless, much of the framework of liver transplanta- • Management of coagulopathy was facilitated by the
tion in place today was developed through the transatlantic thromboelastogram to follow minute-by-minute
alliance of these five mutually supportive centers during the clotting changes in the operating room. With bet-
frustrating period between 1969 and 1979.49,80 ter control of bleeding, the scarring from previous
surgery or prior portosystemic shunts were removed
as adverse factors in transplant.86
HUMAN TRIALS: ADVANCEMENTS TO
THE RECIPIENT OPERATION
ORGAN PRESERVATION: IN SITU
Although the overall procedure for a liver transplant today is PERFUSION
remarkably similar to the operation performed in 1967,
almost all of the elements of the initial transplant procedure The in situ perfusion technique was incorporated start-
have undergone refinements over the last 40 years. Some ing in 1970 and gained more exposure following the
examples of these refinements include the following: passage of brain death laws that allowed for controlled
 1 The History of Liver Transplantation 15

In 1976 Borel presented his finding in a lecture at the

spring meeting of the British Society for Immunology in
London,87 which was of major significance to the devel-
opment of cyclosporine because it stimulated the interest
of many clinicians, particularly Calne of the Cambridge-
Infrahepatic King’s program and his junior associate David White, an
Cava immunologist. White and Calne reviewed a sample of
ligated cyclosporine and began their own clinical studies using a
cut rat transplant model and confirmed it to be a powerful
immunosuppressant and one that could be administered
orally. However, the enthusiasm was not shared by all,
Ao
and Sandoz was not convinced of the commercial poten-
IVC
tial of cyclosporine given its small market. The company
proposed discontinuing the project, but Calne and White
Portal v. (g) traveled to Basel to make the case to the company direc-
tors, and the company ultimately relented.88
Portal v. (r)
During the 12 years spanning the period from the
FIGURE 1-16 n Transplantation of a liver piggybacked onto an restart of liver transplantation in 1967 until the discovery
inferior vena cava (IVC), which is preserved through its length. of cyclosporine, the 1-year survival for liver transplanta-
Note that the suprahepatic vena cava of the homograft is anas-
tomosed to the anterior wall of the recipient vena cava. The ret- tion remained stalled at an upper limit of 35%, despite
rohepatic vena cava of the homograft is sutured or ligated, continual attempts to improve it. This frustration ended
leaving a blind sac into which empty numerous hepatic veins. when cyclosporine became available in 1979,89 and it was
Ao, Aorta; g, graft; r, recipient; v., vein. (From Tzakis A, Todo S, first used initially by the Cambridge-King's group as a
Starzl TE. Orthotopic liver transplantation with preservation of the
inferior vena cava. Ann Surg. 1989;210:649-652.)
monotherapy drug. The improvements in transplant out-
comes were sudden, and by 1982 the Cambridge-King's
group passed the 50% 1-year survival mark for liver
organ procurement. The in situ perfusion of organs transplant, leading to several other transplant programs
developed out of the beginning stages of the hypother- opening in England and across Europe. The results of
mic and core cooling methods. Eventually in situ cold cyclosporine were taken up by Starzl at the University of
infusion techniques were perfected that allowed the Colorado, but as with past immunosuppression cocktails,
removal of all thoracic and abdominal organs, including Starzl combined cyclosporine with prednisone or ALG as
the liver, without jeopardizing any of the individual a double-drug combination.90 Of the first 12 liver recipi-
organs.54 With in situ cooling for multiple organ pro- ents treated with cyclosporine and prednisone in the first
curement, limited dissection of the aorta and great 8 months of 1980,91 11 (92%) lived for more than a year
splanchnic veins is performed, cannulating both. After and 7 of them were still alive over 12 years later. At last,
placing an aortic cross-clamp above the celiac axis, cold with the use of cyclosporine, liver transplantation was
infusates are run through these cannulas and they are able to achieve the success rates that could allow main-
used to chill the organs in situ. Modifications of this stream support.
procedure were made for unstable donors and donation
after cardiac death donors. By 1987 the techniques of
multiple organ procurement were interchangeable REGULATORY DEVELOPMENT:
among the various centers worldwide. NATIONAL INSTITUTES OF HEALTH
CONSENSUS COMMITTEE AND “THE
IMMUNOSUPPRESSION: THE NEW AGE STAMPEDE”
OF CYCLOSPORINE
In December 1981 the promising developments regard-
The immunosuppressant cyclosporine would revolution- ing liver transplantation with cyclosporine were reported
ize liver transplantation, and yet it came close to not com- to C. Everett Koop, who was the surgeon-in-chief at
ing into production at all. Cyclosporine was introduced Children’s Hospital of Philadelphia (CHOP). Koop had
by the company Sandoz in Basel, Switzerland, coming helped establish the biliary atresia program at CHOP by
from their routine study of fungi from soil samples bringing the pioneering Japanese surgeon Morio Kasai to
brought in from around the world. Sandoz began screen- CHOP in 1959-1960 as a research fellow—and liver
ing soil samples in 1970 looking for the cytostatic activity transplantation represented a crucial therapeutic option
among the fungi that might indicate an antibacterial or for biliary atresia. But more importantly, less than 2
anticancer property. In late 1971 a fungal extract contain- months after hearing about these results, Koop was
ing cyclosporine was submitted to the Sandoz laboratory appointed U.S. Surgeon General. Koop initiated steps
for testing its cytotoxic activity,87 and it was Jean-Fran- leading to a Consensus Development Conference for
cois Borel who was tasked with characterizing cyclospo- liver transplantation at the NIH in June 1983. In addition
rine’s immunological properties. Borel showed to Starzl’s program, which had moved to the University
cyclosporine caused a marked reduction of antibody for- of Pittsburgh, the conference also included the four vet-
mation in mice. eran European centers (Cambridge-King’s, Paris,
16 PART I General Considerations

University of Hannover, University of Groningen). This

consensus committee concluded that liver transplanta- U.W. Solution Composition
tion had become a “clinical service” as opposed to an
Potassium 125 mmol/L
experimental procedure.92 Sodium 30 mmol/L
After the success brought about by cyclosporine and Magnesium 5 mmol/L
the impact of the NIH Consensus report, there was a Lactobionate 100 mmol/L
worldwide stampede to develop liver transplant centers. Phosphate 25 mmol/L
In 1989, only 6 years after the NIH report, a 17-page Sulphate 5 mmol/L
Raffinose 30 mmol/L
article in the New England Journal of Medicine, spread over Adenosine 5 mmol/L
two issues, began with the following opening statement: Allopurinol 1 mmol/L
“The conceptual appeal of liver transplantation is so great Glutathione 3 mmol/L
that the procedure may come to mind as a last resort for Insulin 100 units/L
Dexamethasone 8 mg/L
virtually every patient with lethal hepatic disease.”49 Hydroxyethyl starch 50 g/L
Bactrim 0.5 mL/L

ORGAN PRESERVATION: COLD STORAGE Dr. Folkert Belzer Osmolality 320 mmol/kg pH 7.4
University of Wisconsin
Madison, WI
Another major advancement for liver transplantation was
the development of cold storage with preservation solu- FIGURE 1-17 n Folkert Belzer along with James H. Southard
tions. Working with kidney grafts, the idea of static cold developed University of Wisconsin (U.W.) preservation solution
storage was first proposed in 1969 by Geoffrey Collins as a way to avoid the cold-induced cellular injury that limited
from UCLA, working in the laboratory of Paul Terasaki. Euro-Collins solutions. After first developing the solution in
1979, they patiently made adjustments to the formula, improv-
He proposed cold storage after flushing out the kidneys ing the solution, so that in 1987 it was suitable for use in liver
with a simple electrolyte solution containing a high con- transplantation. This improved preservation solution allowed
centration of potassium designed to mimic the intracel- donor procurement from longer distances.
lular environment and also a high concentration of
glucose to increase osmolarity and minimize cell swell-
ing.93 After the kidney was flushed, the organ was placed appeared excessively toxic. The discrepancy likely was
in a sterile bag and kept on ice without perfusion. This explained by an inability to test levels and an unclear
fluid was further modified by removing magnesium and understanding of the drug pharmacokinetics.96 The pro-
substituting mannitol for glucose, and this modified Col- gram at the University of Pittsburgh was licensed to study
lins solution became known as Euro-Collins. Because of tacrolimus, initially restricting it to patients with chronic
the simplicity of the method and the success of Euro- rejection or having severe side effects from cyclospo-
Collins solution, cold storage of kidneys was adopted by rine.97 In the first trial, tacrolimus was successful in sal-
many kidney centers worldwide,94 although it was not vaging 7 out of 10 chronically rejecting grafts. In January
suitable for preserving liver grafts for transplant. 1989 a phase I trial of 110 new patients treated with
With the idea of cold static storage now a practice, tacrolimus showed a 1-year survival of 93%.98
Folkert Belzer (Fig. 1-17) now at the University of Wis- A multicenter trial of 20 centers examining tacrolimus
consin, along with James H. Southard worked to improve initially suffered from toxicity from high starting doses,
upon the strategy, turning their attention to ways to pre- but the investigators were able to salvage the trial after
vent the cold-induced cellular injury that limited Euro- adjusting the trial based on the learning curve of the drug
Collins solution. They experimented with different dosing. A randomized trial at the University of Pittsburgh
preservation solutions and perfusion solutions to create was notable in that 47 of 75 patients randomized to the
the initial University of Wisconsin (UW) solution in cyclosporine control arm were switched to the tacrolimus
1979 and then patiently made adjustments on more than study arm to salvage their rejection, at the recommenda-
a dozen different ingredients,27-29 improving the solution tion of the multi-institutional Patient’s Rights Commit-
so that in 1987 it was first employed successfully in liver tee given the evidence of the superiority of tacrolimus.97
transplantation. This advance would change the whole These study results led to the substitution of tacrolimus
strategy underlying liver transplantation. for cyclosporine as the benchmark immunosuppression
(Fig. 1-18). The Food and Drug Administration fol-
lowed, with fast track approval of tacrolimus for use in
IMMUNOSUPPRESSION: FURTHER liver transplantation in November 1993.95,97
ADVANCEMENTS USING TACROLIMUS
Following Sandoz’s commercial success with cyclospo- ORGAN SUPPLY: MARGINAL DONORS
rine, the Fujisawa Pharmaceutical company began testing
microorganisms and fungi from the soil and identified the As early as 1987, Leonard Makowka and his colleagues
macrolide FK506 in 1984 as a potential immunosuppres- at the University of Pittsburgh100 identified the impend-
sant. The first experimental reports appeared in 1987, ing organ shortage and reported the feasibility of sys-
and to investigators at the University of Pittsburgh,95 the tematically using livers from older donors, donors with
drug appeared very effective and free of many side biochemical or histopathological evidence of liver injury,
effects96; however, to investigators in England, the drug and those whose terminal course was characterized by
 1 The History of Liver Transplantation 17

100 involve dividing the liver into two segments, making

more efficient use of deceased donor liver allografts by
sharing one between two recipients. The first ex situ
80
split-liver transplant was reported by Pichlmayr103 from
Patient survival (%)

the University of Hannover in 1988, and similar proce-

60 dures were reported very soon after in Paris by Bis-
AZA (n  168) muth's team84 and at the University of Chicago by
CYA-EC (n  623) Christopher Broelsch.104,105 The first in situ liver trans-
40 CYA-UW (n  1217)
FK (n  1391)
plant was performed by Xavier Rogiers at the University
of Hamburg in 1995.106,107 The in situ technique used
20 the lessons learned from living donor liver transplanta-
tion to create the two separate segments that could be
used as liver allografts.107
0 Initially the results were inferior to those obtained
0 1 2 3 4 5 from whole livers, but after a learning curve and adopt-
Time after transplantation (yr) ing lessons from living donor transplantation, the
FIGURE 1-18 n Stepwise improvements in patient survival after results with livers split between adult and pediatric
liver replacement. These were associated with the advent of recipients have been comparable to standard deceased
increasingly potent immunosuppressive drugs. Most of the differ-
ence between the CYA-EC and CYA-UW lines was because of the
donor transplantation. There are two main types of
availability of FK for the rescue of cyclosporine failures. The data split livers. The first is the classic split into an extended
shown here were presented to the American Surgical Association right graft and a left lateral segment suitable for creat-
in April 1994. AZA, Azathioprine; CYA-EC, cyclosporine before the ing grafts for pediatric patients. The second type
availability of University of Wisconsin solution; CYA-UW, cyclo- results in a right and left segment that can be suitable
sporine after the availability of University of Wisconsin solution;
FK, tacrolimus. for two adults.107
The current role for split livers is controversial.
Although the evidence shows the outcomes are similar to
those of whole livers, the current regulatory environment
management errors, physiological abnormalities, or the does not reward the efforts and expenses incurred by cen-
administration of potentially damaging pharmacological ters that pursue these option to bring it to the
agents. Criticized at first, this form of expanding the mainstream.
donor pool became widely accepted once the magnitude
of the supply problem was fully appreciated. The use of
marginal donors has become so mainstream that what ORGAN SUPPLY: LIVING DONOR
was once considered marginal is now more often than TRANSPLANTATION
not considered standard.
Several efforts, many often contentious, have been Living donor liver transplantation evolved from the
made to define what constitutes a marginal donor, and reduced liver graft procedures done in deceased donors
how to decide who gets the liver.101 The Donor Risk and involves resecting liver segments (ranging in size
Index was defined by Sandy Feng of the University of from a left lateral segment to an extended right lobe seg-
California, San Francisco, along with colleagues from ment) from volunteer adult donors and transplanting
the University of Michigan102 in 2006. This group used them into a pediatric recipient. The first successful living
powerful statistical techniques and the data pooled donor liver transplant, from an adult to a pediatric recipi-
nationally from large clinical trials and databases to ent, was performed by Russell W. Strong and Stephen V.
identify significant donor parameters. An index was cre- Lynch of the University of Queensland in Brisbane, Aus-
ated that could quantify the risk of a particular donor tralia, in July 1989.108 The living donor transplant opera-
based on these known pretransplant parameters and tion for pediatric recipients was subsequently popularized
quickly provide that risk to the transplant surgeon in by Broelsch and associates from the University of Chi-
real time.102 cago, who reported their experience of living donation
As the organ supply issues become greater, and as the along with their experience of split livers and reduced-
technical capabilities of transplantation and posttrans- size deceased donors at the 1990 American Surgical Asso-
plant management continue to be refined, the question as ciation conference.105
to what defines a marginal donor will invariably be For adult-to-adult living donor transplantation, to
adjusted further. obtain an adequate liver mass, the size of the transected
liver segment was first increased from a left lateral seg-
ment, to a full left lobe, and then to the right lobe opera-
ORGAN SUPPLY: SPLIT-LIVER tion, which is the most common procedure today. This
PROCEDURES first right lobe living donor transplant was carried out by
the program at Kyoto University in Japan,109 when unex-
Split-liver transplantation evolved from the advance- pected anatomical findings were encountered in the
ments of hepatobiliary surgery that have improved donor. The first series of right lobe transplantation in the
parenchymal transection and an improved understand- United States was performed by the team of Igal Kam
ing of liver segmental anatomy. Split-liver procedures from the University of Colorado in 1997.109 Shortly
18 PART I General Considerations

thereafter, several other centers across the United States 1992 and January 1993 using the more phylogenetically
initiated adult-to-adult living donor transplants. Since distant baboon livers.115 The recipients were patients
this time, more than 3500 right lobe transplantations111 with human immunodeficiency virus (HIV) infection and
have been performed in more than 60 U.S. centers, with advanced hepatitis B, specifically chosen because animal
patient and graft survival equivalent to that of whole- livers are refractory to infection by either virus, and they
organ deceased donor transplantation or the various survived for 70 days and 26 days, respectively. In these
kinds of partial liver transplantation, including the adult- baboon xenotransplants, a four-drug immunosuppression
to-child living donor transplant. cocktail was used, and neither cell-mediated nor humoral
Despite its utility, living donor liver transplantation rejection was implicated as the cause of death in the
has been used with caution by many transplant sur- recipients. However, there was evidence of continuous
geons because of concerns of donor mortality. Living complement activation in both, and neither xenograft
donor liver transplant donor deaths have occurred at functioned optimally, with both developing intrahepatic
some of the largest and most experienced living donor cholestasis within the first postoperative week. Because of
liver programs in the United States. These deaths the heavy immunosuppression needed, both patients
occurred under a media microscope that never existed developed infections that led to their deaths, and the first
during the early liver transplant trials of the 1960s, and patient also had a fatal brain hemorrhage at 70 days.115 It
the intense media exposure magnified each event expo- was suspected that synthetic products created from the
nentially. A review of living donor liver transplantation baboon liver might have been incompatible with the
in the United States showed the incidence of early human metabolic environment. Further trials of xeno-
mortality in donors was 0.2%112 with seven liver donors transplantation involving chimpanzees and baboons have
having died in the United States by 2013, during either been avoided because of the anthropometric qualities of
the operative procurement or in the immediate post- the donor and the concerns that these animals pose a high
operative period. risk for zoonotic infections that might enter the human
Although much attention has focused on living population, given the evidence of human diseases that
donation in the United States, most of the later devel- originated from nonhuman primates such as HIV-1 and
opment in the field has occurred in programs through- HIV-2.116
out Asia, largely because of need related to a lack of It has been hoped that lower mammalian donors such
organ supply from deceased donors. Living donor as pigs may be suitable. Studies using the genetic knock-
transplantation flourished early on in Japan, leading to out of clone pigs missing the α1,3-galactosyltransferease
the creation of several very large programs in Fukuoka, gene,117 which is required for the 1,3-galactose sugar
Kyoto, and Tokyo. The greatest success has been in chains that induce human preformed antibodies, show it
Korea, particularly the program of Sung-Gyu Lee at avoided the hyperrejection from the immediate innate
the Asan Medical Center in Seoul, South Korea, which immune response. The first porcine-to-human xeno-
alone performs more living donor liver transplants transplantation was performed by Makowka at the
each year than all of the centers in the United States Cedars-Sinai program in Los Angeles in October 1992.
combined. It was intended as a bridge for a human liver in a patient
with acute liver failure, but the patient died of cerebral
swelling 32 hours after transplant, and 2 hours before
ORGAN SUPPLY: the human transplant was to begin.
XENOTRANSPLANTATION Later trials of porcine-to-human xenotransplantation
have focused on using them ex vivo, as extracorporeal
Xenotransplantation is the transplantation of living tis- support instead of implanting the liver, to bridge sick
sue or organs from one species to another. It has long patients until a human liver becomes available. Marlon
been hoped to be a solution for the supply issues facing Levy at the Baylor University Medical Center in Dallas
liver transplantation. At the same time, xenotransplan- reported the first successful ex vivo porcine xenoperfu-
tation is associated with a number of concerns, includ- sions used in this fashion.118 Nonetheless, concerns of
ing immunological problems and xenogeneic infections, xenogeneic infections have developed out of this situa-
as well as ethical, legal, and social concerns. Regardless tion, because pigs carry an endogenous retrovirus called
of these issues, it is not an area that has had great porcine endogenous retrovirus that is capable of infecting
success human cell lines.113 There have been no reports of por-
The first clinical attempts in xenotransplantation of cine-to-human transmission of porcine endogenous ret-
livers involved chimpanzees between 1966 and 1973.113 rovirus from these ex vivo porcine systems.
There were three attempted transplants of chimpanzee
livers into three children, and all were unsuccessful
with all dying within 14 days of transplant.114 Of inter-
est, the clinical course and histopathological examina-
REGULATORY DEVELOPMENT:
tion of the xenograft livers on autopsy were NATIONAL ORGAN TRANSPLANT ACT
indistinguishable from allotransplantation transplants OF 1984 AND BEYOND
at that time.
With the development of improved immunosuppres- The rapid developments in organ transplantation follow-
sion, two more xenotransplants were attempted by Starzl ing the introduction of cyclosporine, as well as the report
at the University of Pittsburgh program between June from the NIH consensus committee, led to many issues
 1 The History of Liver Transplantation 19

NATIONAL ORGAN TRANSPLANT ACT REGULATORY DEVELOPMENT:

EQUITABLE ORGAN ALLOCATION AND
THE MELD SCORE
HEARING
BEFORE THE As liver transplantation moved from being experimen-
SUBCOMMITTEE ON HEALTH tal to a “clinical service, and as it became more success-
OF THE ful, the increased demand was met with shortages of
COMMITTE ON WAYS AND MEANS organ supply. To help manage this supply-demand
HOUSE OF REPRESENTATIVES mismatch, the transplant field in the United States in
NINETY-EIGHTH CONGRESS
SECOND SESSION
2002 began using the Model for End-Stage Liver Dis-
ON ease (MELD) score, based on an equation using three
H.R. 4080 laboratory-based parameters, to prioritize equitable
TO AMEND THE PUBLIC HEALTH SERVICE ACT TO AUTHORIZE organ allocation. The MELD score was implemented
FINANCIAL ASSISTANCE FOR ORGAN PROCUREMENT in response to the OPTN Final Rule, a mandate to
ORGANIZATIONS, AND FOR OTHER PURPOSES deemphasize waiting time and focus on disease severity
and waiting list mortality.122 Compared to the prior
FEBRUARY 9, 1984
system that used the Child-Turcotte-Pugh score and
Serial 98–64 location of the patient (i.e., home, hospital, intensive
care unit) to allocate organs, the MELD system was
Printed for the use of the Committee on Ways and Means thought to be more standard and equitable, more dif-
ficult to manipulate, less dependent on waiting list, and
FIGURE 1-19 n The National Organ Transplant Act was sponsored instead focusing on the idea of the “sickest first.”
by Representative Al Gore and Senator Orrin Hatch and was Exception points were provided in certain situation
approved on October 19, 1984. The act was important in codify- such as for hepatocellular carcinomas that met the
ing guidelines regarding transplantation, including prohibiting
the sale of human organs. Many of the administrative bodies
Milan criteria.
and tools used today, including the Organ Procurement and The system is not perfect, and its weaknesses have
Transplantation Network, organ procurement organizations, the been widely recognized, including a lack of specificity for
United Network for Organ Sharing, and the Scientific Registry of different liver diseases and particular biases associated
Transplant Recipients, were laid out in the act. with each laboratory parameter. Nonetheless, the MELD
score has set a standard and has allowed for the idea of a
that needed regulation and oversight. Before the passage newer system that reflects these weaknesses to one day be
of the National Organ Transplant Act (NOTA), there incorporated.
was not a clear understanding of property rights for trans-
plant and there were concerns of a developing commer-
cial marketplace for organs.
The NOTA was sponsored by Representative Al
ORGAN PRESERVATION:
Gore and Senator Orrin Hatch (Fig. 1-19), and it was EXTRACORPOREAL MACHINE
approved on October 19, 1984.119 The act provided for PERFUSION SYSTEMS
the establishment of the Task Force on Organ Trans-
plantation, and it outlawed the sale of human organs. Extracorporeal machine perfusion systems are an exam-
Many of the administrative bodies in place today were ple of history repeating itself in the modern day.123
outlined in the act. One mandate was the formation of Machine organ perfusion was part of the first studies of
the Organ Procurement and Transplantation Network organ transplant, before the development of better pres-
(OPTN),120 which would establish and oversee organ ervation solution that allowed cold storage at 4° C.
procurement organizations (OPOs). Another mandate Unfortunately, the organs from marginal donors that
was the development of the Scientific Registry of make up so many of the transplants in today’s transplant
Transplant Recipients (SRTR) with which patient and centers are more susceptible to damage from cold stor-
graft survival could be assessed from center to age. The successful development of hypothermic pulsa-
center.121 tile machine perfusion for kidney allografts, as well as
Following passage of the NOTA, the Department of interest in expanding the use of marginal donors, has led
Health and Human Services awarded the contract to to efforts to create a similar system for livers. James Guar-
administer the OPTN and the OPOs to a private non- rera and colleagues from Columbia University, New
profit organization, the United Network for Organ Shar- York, devised a hypothermic machine perfusion system
ing (UNOS). The SRTR was created in 1987 to support for liver (Fig. 1-20), and the initial trials reported in 2010
ongoing evaluation of the scientific and clinical status of have shown benefit. These machine perfusion systems
solid organ transplant. The SRTR contract was trans- also allow delivery of metabolic substrates and therapeu-
ferred to the University of Michigan–based Arbor tic agents to the allograft and make assessments that can
Research Collaborative for Health in 2000. In 2010 the predict graft function.123,124 The main limitation is devis-
University of Minnesota–based Minneapolis Medical ing a portable system that can accommodate the size and
Research Foundation was awarded the contract for the perfusion demands of a liver. Another machine perfusion
SRTR. strategy involves a normothermic perfusion system that
20 PART I General Considerations

The history of liver transplantation is a complicated

story to tell—but it's a really good one.

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for the prediction of outcome in clinical liver transplantation. 2009;250:1-6.
Transplant Proc. 1987;19:2378-2382. 127. Vogel T, Brockman JG, Friend PJ. Ex-vivo normothermic liver
101. Busuttil RW, Tanaka K. The utility of marginal donors in liver perfusion: an update. Curr Opin Organ Transplant.
transplantation. Liver Transpl. 2003;9:651-663. 2010;15:167-172.
102. Feng S, Goodrich NP, Bragg-Gresham JL, et al. Characteristics 128. Moore FD, Wheeler HB, Demissianos HV, et al. Experimental
associated with liver graft failure: the concept of a donor risk whole organ transplantation of the liver and of the spleen. Ann
index. Am J Transplant. 2006;6:783-790. Surg. 1960;152:374-387.
103. Pichlmayr R, Ringe B, Gubernatis G, et al. Transplantation einer 129. Marchioro TL, Huntley RT, Waddell WR, et al. Extracorporeal
spenderleber auf Zwis Empfanger (Split liver transplantation) perfusion for obtaining postmortem homografts. Surgery.
Eine neue Methode in der Weitzentwicklung der Lebesegment 1963;54:900-911.
transplantation. Langenbecks Arch Surg. 1989;373:127-130. 130. Definition of irreversible coma. Report of the ad hoc committee
104. Broelsch CE, Emond JC, Whitington PF, et al. Application of of the Harvard Medical School to examine the definition of brain
reduced-size liver transplants as split grafts, auxiliary orthotopic death. JAMA. 1968;205:337.
grafts, and living related segmental transplants. Ann Surg. 131. Starzl TE, Gordon RD, Tzakis A, et al. Equitable allocation of
1990;212:368-375. extrarenal organs: With special reference to the liver. Transplant
105. Emond JC, Whitington PF, Thistlethwaite JR, et al. Transplan- Proc. 1988;20:131-138.
tation of two patients with one liver. Analysis of a preliminary 132. Wiesner R, Edwards E, Freeman R, et al. Model for end-stage
experience with ‘split-liver’ grafting. Ann Surg. 1990;212:14-22. liver disease (MELD) and allocation of donor livers. Gastroenterol-
106. Rogiers X, Malago M, Gawad K, et al. In situ splitting of cadav- ogy. 2003;124:91-96.
eric livers. The ultimate expansion of a limited donor pool. Ann
Surg. 1996;224:331-339.
107. Gundlach M, Broering D, Topp S, et al. Split-cava technique: Liver
splitting for two adult recipients. Liver Transpl. 2000;6:703-706.
108. Strong RW, Lynch SV, Ong TH, et al. Successful liver transplan-
tation from a living donor to her son. N Engl J Med.
1990;322:1505-1507.
 CHAPTER 2

Surgical Anatomy of the Liver

John F. Renz • Milan Kinkhabwala

CHAPTER OUTLINE

EMBRYOLOGY Left Lobe Arterial Anatomy

Left Lobe Ductal Anatomy
TOPOGRAPHICAL ANATOMY
Left Lobe Hepatic Venous Anatomy
LOBAR ANATOMY Hemiliver Allografts
MODERN SEGMENTAL ANATOMY Arterial Anatomy and Reduced-Size Grafts
Portal Venous Anatomy and Reduced-Size
APPLIED SURGICAL ANATOMY
Grafts
Anatomy of the Hepatic Hilum
Hepatic Venous Anatomy and Reduced-Size
Couinaud Segment II/III Allograft Grafts

The increasing organ shortage observed since the previ- undergo further differentiation into an intrahepatic
ous edition of Transplantation of the Liver mandates expert component containing hepatic chords and portal sinu-
knowledge of partial allograft transplantation by the prac- soids, a cranial component delivering blood from the
ticing clinician. The maturation of hepatobiliary surgery embryonic liver to the heart, and a caudal component
has expanded the role and safety of major hepatic resec- carrying blood from the yolk sac to the liver. Later endo-
tion,1 permitting the expanded application of partial-liver dermal cell proliferation yields hepatic cords and biliary
allografts derived from living or deceased donors to adults epithelia that coalesce to create sinusoids, whereas
and children.2,3 In this past decade, partial-liver allografts hemopoietic tissue, Kupffer cells, and interstitial con-
have become the most common allograft for pediatric nective tissue originate from the splanchnic mesenchyme
patients with superior results observed in infants,4 while of the septum transversum.12
the application of partial-liver allografts to adults from The hepatic veins originate from the vitelline venous
living and deceased donors has expanded.5-8 Fundamental system. The cranial component of the left vitelline vein
to the successful outcome of major hepatic resection or initially involutes, shunting all returning blood to the
partial-liver transplantation is the avoidance of technical heart through the cranial component of the right vitelline
complications. This requires maximizing functional vein, known as the embryonic common hepatic vein. The
hepatic mass while minimizing iatrogenic injury. Cur- common hepatic vein functions as an early single outflow
rently several nomenclature systems are used within the source from the liver to the heart and persists as the later
literature,9,10 which can be a source of confusion. In this right hepatic vein. The vitelline venous system of the left
context a concise anatomical review with direct applica- side of the liver later reconstitutes channels that mature
tion to clinical transplant surgery is particularly relevant. into left and middle hepatic veins to augment venous
return from the liver to the heart and define the perma-
nent anatomical arrangement. Vitelline venous system
EMBRYOLOGY development is manifested by the surgical findings of a
distinct right hepatic vein emptying directly into the vena
The hepatic diverticulum, a ventral outpouching of the cava as compared with the middle and left hepatic veins
distal foregut observed early in the fourth week of gesta- that typically empty via a common channel.13,14
tion (3-mm embryo), is the origin of the hepatobiliary The development of the extrahepatic main portal vein
system. This outgrowth of proliferating endodermal is one of the most complex processes observed in embry-
cells infiltrates the embryonal ventral mesentery and ology.9,13,14 Origination of the extrahepatic main portal
extends into the septum transversum to form the early vein begins with fusion of left and right vitelline venous
liver primordium.11,12 The rapidly proliferating primor- elements returning blood from the gut–yolk sac complex.
dium expands into the left and right vitelline veins The objectives are to create a single inflow source to the
(omphalomesenteric veins) to stimulate extensive remod- liver from the bilateral vitelline veins while preserving
eling into separate liver chords and portal sinusoids from the anatomical relationship of the main portal vein to
the primordium mass,9,11,13creating separate right and the developing duodenum. As the yolk sac regresses, the
left intrahepatic portal circulations.9 The vitelline veins omphalic portions of the vitelline veins disappear while

23
24 PART I General Considerations

the mesenteric branches proliferate, increasing in length

and complexity to serve the intestinal tract.15 Between
the fourth and sixth weeks (4.5- to 9-mm embryo), caudal
elements of both vitelline veins unite through intrave-
nous channels and undergo segmental involution to form Right Left
a composite, S-shaped vessel, located posterior to the lobe lobe
first portion of the duodenum, that drains both vitelline
venous beds as a single vessel to the liver.9,13,14
The intrahepatic left portal vein is also a composite
vessel originating from a communication between the
vitelline veins and a segment of the left umbilical vein.14 A
The umbilical veins are originally paired; however, the
Quadrate
left umbilical vein is invaded by hepatic tissue and hyper- Left
lobe
trophies, whereas the right atrophies before contact with lobe
the liver. Umbilical blood initially flows through a mesh- Right
work of intrahepatic sinusoids, but as volume increases, lobe
these sinusoids coalesce to receive the proximal portion
of the developing left portal vein and form a single vessel
shunting blood through the liver, the ductus venosus.14,15
The ductus venosus receives branches from the liver
before joining the hepatic veins to drain into the inferior Bare Caudate
vena cava.13 After birth the ductus venosus closes to form B area lobe
the ligamentum venosum. FIGURE 2-1 n Topographical anatomy of the liver. The landmarks
The biliary and arterial systems develop later, along defining topographical anatomy include the falciform ligament,
the latticework provided by the established portal venous umbilical fissure, gallbladder fossa, and transverse hilar fissure.
system. The right biliary and arterial branches follow the These delineate four hepatic lobes: left, right, quadrate, and cau-
portal system exactly, whereas the left biliary and arterial date (spigelian). A, Anterior view. B, Posterior view.
systems divide into equal-size branches on either side of
the intrahepatic portion of the umbilical vein.9
The embryonal liver develops rapidly to occupy most dominated through the late nineteenth century but is
of the abdominal cavity. By 9 weeks’ gestation, the liver currently only of historical interest. The principal land-
accounts for approximately 10% of the embryo’s total marks defining topographical anatomy include the falci-
weight with relatively equal hepatic mass on each side of form ligament, umbilical fissure, gallbladder fossa, and
the falciform ligament. The initial equality in volume transverse hilar fissure.18,20 These landmarks delineate
between topographical lobes is lost by 12 weeks as the four lobes (Fig. 2-1): left (medial to falciform), right (lat-
topographical right lobe hypertrophies to spawn the cau- eral to falciform), quadrate, and caudate (spigelian).21
date lobe (initially recognizable at 6 weeks) and become The liver is supported in position through peritoneal
the dominant hepatic mass.11,12 reflections continuous with Glisson’s capsule that attach
The ventral mesentery forms the gastrohepatic liga- to the duodenum, stomach, diaphragm, and anterior
ment16 and the fibrous visceral peritoneum of the liver. abdominal wall. These peritoneal reflections include the
This was first described by Glisson in 1659,17 as a perito- falciform ligament, right and left triangular ligaments,
neal sheath that envelops the organ, except for a “bare and right and left coronary ligaments, as well as the lesser
area” on the superoposterior surface of the right lobe omentum. The falciform ligament extends from the liga-
where the organ is in direct contact with the inferior vena mentum teres superiorly along the anterior liver surface
cava, diaphragm, and superior aspect of the right adrenal in continuity with both the diaphragm and anterior
gland. Glisson’s capsule involutes into the parenchyma as abdominal wall above the umbilicus.18 The ligamentum
intrahepatic septa or trabeculae that support vascular teres is a remnant of the vestigial umbilical vein. Nor-
structures and serve as surgical landmarks.18,19 mally obliterated, it may recanalize in disease conditions
Functional milestones in embryonic development like cirrhosis, decompressing the portal circulation
include intrahepatic hematopoiesis during the sixth week, through collaterals of the periumbilical superficial venous
hepatocyte bile formation at the twelfth week, and excre- plexus. This shunts portal blood to the systemic circula-
tion of bile into the duodenum by the sixteenth week.11 tion through superficial venous plexuses, producing the
The third trimester marks the cessation of hematopoiesis characteristic “caput medusa.” As the falciform ligament
with a concomitant decrease in liver growth to account continues toward the diaphragm, the peritoneal sheets
for approximately 5% of the newborn’s body weight.12,18 composing the ligament separate to adopt a triangular
shape that broadly covers the entry of the hepatic veins
into the suprahepatic vena cava.19
TOPOGRAPHICAL ANATOMY At the level of the suprahepatic vena cava, the perito-
neal reflections progress laterally to become the anterior
Topographical anatomy of the liver dates to early Baby- layers of the left and right coronary ligaments. The coro-
lon (3000-2000 bc), where the liver was described accord- nary ligaments anchor the superior surface of the liver
ing to external landmarks. This anatomical system through anterior and posterior reflections to the
 2 Surgical Anatomy of the Liver 25

diaphragm. As the right and left coronary ligaments

extend laterally, each unites with the posterior reflections
to form the respective right and left triangular ligaments.
The right coronary ligament may continue and fuse to VIII II
the superior pole of the right kidney to form the hepa- I
VII
torenal ligament.18 III
IV
The lesser omentum is a continuous fold of perito-
neum arising from the posterior reflection of the left tri-
angular ligament. The lesser omentum extends from the V
liver onto the lesser curvature of the stomach and first
2 cm of the duodenum to form the gastrohepatic and
hepatoduodenal ligaments, respectively. The hepatoduo- FIGURE 2-2 n Segmental liver anatomy. The segmental anatomy
denal ligament forms the anterior border of the epiploic of the liver as described by Couinaud. Each anatomical segment
foramen of Winslow and contains the porta hepatis. (Roman numeral) receives a unique portal pedicle (light gray)
consisting of a portal venous branch, hepatic arterial inflow, and
bile duct. Venous drainage occurs via a major hepatic venous
outflow branch (dark gray).
LOBAR ANATOMY
Galen (130-201 ad) postulated the hepatic arterial and anatomical classification) when applying the term lobe or
portal venous systems terminated as minute connec- lobectomy. A more appropriate scheme is to refer to
tions that reconstituted into hepatic veins draining to Cantlie’s anatomical lobes as hemilivers, thus describing
the inferior vena cava.21 Galen’s concept of separate a right or left hepatectomy.
arterial and portal venous systems reconstituting into The anatomical system of Cantlie was later expanded
hepatic veins resurfaced in 1888, when Hugo Rex stud- by the North American anatomists Healey and Schroy,26
ied hepatic corrosion casts from mammals.22 Rex con- who based their nomenclature on biliary anatomy,
cluded that the right and left branches of the portal vein rather than on Cantlie’s description of portal venous
functioned as unique vascular systems, dividing the liver anatomy, while retaining the term lobe. The right lobe
into separate halves. In 1897 James Cantlie extended was divided into anterior and posterior segments by a
these findings to humans, proposing a functional divi- right segmental fissure, whereas the left lobe was
sion of the liver into two lobes (“Cantlie’s line”) of rela- divided into medial and lateral segments by a left seg-
tively equal size based on the branching of the portal mental fissure.9 The left segmental fissure corresponds
vein (and followed by the hepatic ducts).23 Cantlie’s line to the falciform ligament, whereas the segmental “fis-
has no visible surface topography but rather is a virtual sure” that divides anterior and posterior sectors of the
plane that bisects the gallbladder fossa and the suprahe- right lobe is not easily discerned by surface landmarks,
patic vena cava. This plane roughly overlies the course though one can infer its location based on the plane of
of the middle hepatic vein and can be demonstrated in insertion of the extrahepatic right portal pedicle.
clinical practice by devascularization of the hemiliver Healey and Schroy’s classification scheme led to the
(right or left). descriptive but imprecise term hepatic trisegmentectomy
Cantlie’s description of functional anatomy shifted the for extended right hepatectomy, and the often used
entire quadrate lobe (topographical term), as well as a term left lateral segment for the topographical portion of
large component of the caudate lobe (topographical the liver containing modern segments II and III.27
term), into the anatomical boundaries of the left lobe
rather than the right. This classification system, founded
on intrahepatic functional anatomy rather than surface MODERN SEGMENTAL ANATOMY
topographical landmarks, was the underpinning of a
modern surgical revolution in anatomically based hepatic The most sophisticated classification of intrahepatic
resections.24 Tiffany25 reported the first liver resection anatomy is by Couinaud,28 who in 1954 founded his ana-
performed in the United States in 1890 (although the tomical description on the portal venous system. Portal
accuracy of this publication is widely disputed), and Pro- vein distribution within the liver was subdivided into
fessor William Keen of Jefferson Medical College confi- eight “segments.” Individual segments each receive a
dently and somewhat prematurely proclaimed to “portal pedicle” consisting of a portal venous branch,
members of the Pennsylvania State Medical Society on hepatic arterial branch, and a bile duct radicle with seg-
May 17, 1899, “after my experience with these three cases mental drainage through a dedicated hepatic venous
[liver resections], I should hardly hesitate to attack almost branch. The eight functional segments embrace the
any hepatic tumor without regard to its size.”21 hepatic veins that provide outflow to the inferior vena
Cantlie’s reference to hepatic lobes created two defini- cava (Fig. 2-2).
tions for the same term and was the source of continuing The hepatic veins travel in planes termed fissures or
confusion.9 Europeans continued to describe hepatic scissurae, dividing the liver into four sectors (see Fig. 2-1).
lobes based on topographical anatomy, whereas North The left portal fissure contains the left hepatic vein, the
American surgeons adopted lobectomy as the hemiliver main portal fissure contains the middle hepatic vein (in
defined by Cantlie. One must be certain as to the refer- the plane of Cantlie), and the lateral-most (right) portal
ence system in use (topographical anatomy or Cantlie’s fissure contains the right hepatic vein. Three of the four
26 PART I General Considerations

sectors contain smaller fissures that subdivide each into

two segments to form a total of seven segments. Only the
caudate lobe (segment I) is a functionally autonomous
segment supplied by both the left and right branches of VII VIII II
the portal vein and hepatic artery with drainage directly
into the inferior vena cava.28 Clinically this relationship is
well demonstrated in patients with Budd-Chiari disease VI V IV III
who compensate for major hepatic vein outflow
obstruction by development of alternative outflow tracts
via veins draining directly from segment I into the
retrohepatic vena cava. A B
Biliary drainage of segment I occurs via small anterior FIGURE 2-3 n Surgical division of the liver along Cantlie’s line
radicles draining directly into the posterior surface of the (dashed line A) yields a left hemiliver (segments I to IV or II to IV)
biliary confluence. A well-defined segment 1 duct consis- and right hemiliver (segments V to VIII) allograft that can be
used in adult-to-adult living donor and split-liver transplantation
tently drains into the proximal left hepatic duct between between two adults. Division along the falciform ligament
the hepatic duct bifurcation and the umbilical fissure. It is (dashed line B) yields a segment II/III allograft, also termed a left
important to recognize and control this duct during lateral segment allograft or topographical left lobe, and remnant
resectional surgery and for partial liver allografts involv- segments I, IV to VIII allograft, also termed a right trisegment
ing the left lobe. Segments II and III correspond to the allograft or topographical right lobe.
posterior and anterior segments of the topographical left
lobe, respectively. Segment IV, the largest segment and was realized in clinical practice during the 1980s. The
the only one derived from an undivided hepatic sector, successful application of partial-liver allografts mandates
extends from the left portal fissure to the main portal fis- detailed anatomical considerations because these proce-
sure (Cantlie’s line) and includes the entire volume of the dures predispose to unique surgical complications. Fun-
quadrate lobe. damental to the application of these techniques is an
The right portal fissure divides the right lobe into an understanding of intrahepatic vascular and biliary anat-
anteromedial sector and a posterolateral sector, each of omy. Although the incidence of vascular complications
which is subdivided into anterior and posterior seg- has declined with the widespread application of micro-
ments. The two anterior segments of the right lobe surgical techniques,29-34 a relatively high incidence of
include segment V (inferiorly adjacent to the gallbladder biliary complications persists.3,7,35
fossa) and segment VIII (superiorly). The two posterior Four distinct allografts have been used routinely in
segments of the right lobe include segment VI (inferi- partial-liver transplantation (see Fig. 2-3). These include
orly, adjacent to the right kidney), and segment VII the right hemiliver (Couinaud segments V to VIII), the
(superiorly). The posterior segments VI/VII are located left hemiliver (Couinaud segments II to IV), the topo-
posterior to the peritoneal reflection and are therefore graphical left lobe (Couinaud segments II to III), and the
retroperitoneal structures that are not visible at lapa- topographical right lobe (Couinaud segments IV to VIII).
rotomy without mobilizing the right lobe of the liver
(see Fig. 2-2).28 Anatomy of the Hepatic Hilum
The recognition of the segmental anatomy of the
liver was a significant advancement for hepatic surgery. All partial-liver allograft preparation includes a hilar dis-
In 1982 Bismuth24 integrated Couinaud’s classification section. The objective is to specifically isolate vascular
scheme into a formal anatomical approach to hepatec- and biliary supply with minimal disruption to surround-
tomy that has been widely adopted by hepatobiliary sur- ing structures. Figure 2-4 depicts the anatomical rela-
geons to standardize techniques and nomenclature. tion of the proper hepatic artery, common hepatic duct,
Rather than perform atypical resections based on the and portal vein. The conventional anatomical relation-
size or location of a lesion, hepatic resections could be ship of the hilum is a posterior portal vein, anteromedial
performed along functional planes that would minimize proper hepatic artery, and anterolateral common bile
intraoperative blood loss and postoperative necrosis of duct. Following bifurcation of the proper hepatic artery,
devitalized tissue, in addition to potentially improving the right hepatic artery typically courses posterior to the
oncological control of malignancy after resection. This common hepatic duct (see Fig. 2-4). Arterial variations
classification has revolutionized hepatic surgery by pro- within the hilum are common,36,37 particularly in the
viding a foundation for the development of highly selec- setting of superior mesenteric artery–derived arterial
tive anatomical resections as well as innovations in supply. In classic descriptions the proper hepatic artery
transplantation using surgically created partial-liver originates distal to the gastroduodenal artery and
allografts. receives aortic inflow from the celiac trunk. When arte-
rial inflow to the liver originates from the superior mes-
enteric artery rather than the celiac artery, anatomy is
APPLIED SURGICAL ANATOMY termed replaced. Thus the entire proper hepatic artery
may be replaced, or the right hepatic artery may inde-
Couinaud’s anatomical classification permitted the theo- pendently originate from the superior mesenteric, rather
retical construction of partial-liver allografts based on the than the proper hepatic, to be replaced. Replaced arte-
known regenerative capacity of the liver (Fig. 2-3), which rial anatomy is readily identifiable preoperatively by
 2 Surgical Anatomy of the Liver 27

PHA
IV
PV RHA

CHD CBD

LHA

FIGURE 2-4 n Intraoperative hilar dissection. The three principal

elements of the porta hepatis—the common hepatic duct (CHD),
the portal vein (PV), and the proper hepatic artery (PHA)—are
FIGURE 2-6 n Segment IV arterial branches originating from the
demonstrated in this intraoperative photograph. The anterolat-
left hepatic artery (LHA).
eral CHD is retracted (lower vessel loop) just before the origin of
the cystic duct signaling the beginning of the common bile duct
(CBD). The bifurcation of the anteromedial PHA to form the right with isolation of the left hepatic artery and left portal
hepatic artery (RHA) is retracted medial (upper vessel loop). The vein. The left hepatic vein is isolated and encircled with a
RHA (center) is immediately anterior to the PV and courses pos-
terior to the CHD in celiac-derived hepatic arterial supply. vessel loop. With vascular control achieved, parenchymal
transection typically occurs within 1 cm to the right of
the falciform ligament and progresses to within 1 cm of
the left hepatic duct in the umbilical fissure.7,42
At its origin the left hepatic artery enters the base of
the umbilical fissure anteromedial to the left portal vein.
RHA The left portal vein travels for a variable distance in a
horizontal direction outside the liver along the inferior
aspect of segment IV before entering the base of the
CHD umbilical fissure, in a similar pathway as the left hepatic
duct. The left hepatic artery originates anteromedial and
inferior to the origin of the left portal vein but ascends to
be anterosuperior to the left portal vein by the point of
PV parenchyma entrance. Although extrahepatic, the left
hepatic artery sends a major and several minor branches
to segment IV. Accompanying the left hepatic artery is
the left portal vein with branches to segments I and IV
along its intrahepatic and extrahepatic course.

FIGURE 2-5 n Anatomy of the hilum. The main portal vein (PV) is Left Lobe Arterial Anatomy
dissected and encircled with a vessel loop. The cystic duct is
retracted with the forceps and the right hepatic artery (RHA) lies
Principal segment IV arterial branches may originate
above the common hepatic duct (CHD). Note that the course of proximal, near the origin of the left hepatic artery, or distal
the RHA anterior to the CHD is rare except in the setting of at the level of the umbilical fissure (Fig. 2-6). Further-
replaced arterial anatomy. more, principal segment IV arterial branches may origi-
nate independently, distal to the origin of the left hepatic
computed tomography, magnetic resonance arteriogra- artery, to create parallel arteries across segment IV
phy, or angiography and is clinically relevant to hepato- with superior branches servicing segment II (Fig. 2-7).42,43
biliary surgery and transplantation (Fig. 2-5). Segment IV penetrating arteries provide significant
inflow and should be preserved whenever possible. When
Couinaud Segment II/III Allograft allografts are split to produce an extended right lobe
graft (segment IV to VIII) and a smaller lateral segment
Division of the hepatic parenchyma at the falciform liga- graft (segment II/III), major segment IV arteries may
ment yields a segment II/III allograft, commonly referred require reconstruction to preserve viability of segment
to as a left lateral segment or topographical left lobe graft for IV after implantation.
pediatric recipients.38-40 The segment II/III allograft can Arterial supply to the left lobe (and by extension to
be further reduced to a “monosegment” allograft (seg- segment II/III allografts) may originate from the left gas-
ment III) for very small infants and neonates.41 tric artery (“replaced left hepatic artery”). Replaced left
Dissection of the portal triad in segment II/III donor arteries course transversely across the gastrohepatic liga-
hepatectomy originates at the base of the round ligament ment from the left gastric artery on the lesser curvature
28 PART I General Considerations

IV

LHA

RHA

A B
FIGURE 2-7 n Independent segment IV hepatic artery. A large segment IV artery, diameter greater than 1 mm, originates distal to the
origin of the left hepatic artery (LHA) and courses anterosuperior to the left portal vein to supply segments IV and II. A, Corrosion cast.
B, Intraoperative photograph. RHA, Right hepatic artery.

of the stomach to enter the inferior surface of segment III Schroy47 have described the union of segment II and seg-
just anterior to segment I (caudate lobe) in approximately ment III bile ducts within the umbilical fissure in 50%,
15% to 23% of deceased donors.36,37,44,45 This anatomi- lateral to the umbilical fissure in 42%, and medial to the
cal variant can be the principal arterial supply to the seg- fissure in 8% of autopsy specimens.
ment II/III allograft as a replaced vessel or augment The second most frequent anatomical pattern (30%) is
arterial supply to the allograft as an accessory vessel. creation of the segment II/III duct close to the umbilical
fissure followed by the union of two parallel ducts from
Left Lobe Ductal Anatomy segment IV to form the left hepatic duct (see Fig. 2-8, B).
Typically, one segment IV duct is on the umbilical por-
Arterial and biliary structures are located superior to the tion of the left portal vein and one is close to the union of
extrahepatic portion of the left portal vein with the orien- the right hepatic duct. Thus biliary radicles originating in
tation of the portal pedicle at the umbilical fissure pre- segment IV cross the umbilical fissure to drain the antero-
served as the structures penetrate the hepatic parenchyma. inferior component of segment III in approximately 30%
The left hepatic artery is anterosuperior to the left portal of specimens. Healey and Schroy47 reported a 20% inci-
vein, whereas the orientation of the left hepatic duct sys- dence of segment IV ducts crossing the umbilical fissure
tem, with respect to the left portal vein, is variable. The in a study of 100 autopsy specimens. Segment IV biliary
anatomical relationship of the left hepatic duct to the left radicles crossing the umbilical fissure are a potential
portal vein at the umbilical fissure is anterosuperior source of parenchymal leaks. Segment IV biliary radicles
(35%), superoposterior (35%), and midline on the left that cross the umbilical fissure are consistently located
portal vein (20%). Separate ducts from segments II and anterior to the left portal vein and the segment II/III duct
III that unite greater than 1 cm lateral to the umbilical (see Fig. 2-8, B). They are terminal in nature without a
fissure to form the left hepatic duct occur in approxi- distinct connection to the principal segment III duct;
mately 10% of study specimens.42,46 In this anatomical however, their significance in biliary drainage is trivial,
variant the segment II duct remains posterosuperior and they are readily amenable to suture ligation.
while the segment III and IV ducts course anterosuperior The third biliary pattern is a single segment III duct,
to join just before the hilum (Fig. 2-8, C). which receives a duct from segment IV and joins segment
The segment II and III ducts join to form a common II close to the hepatic hilum (see Fig. 2-8, C). This pat-
channel (the left lateral segment duct), which is typically tern was identified in 10% of specimens. In this anatomi-
formed within the umbilical fissure. The segment II/III cal variant there is absence of a distinct segment II/III
duct then receives biliary drainage from segment IV and duct.
segment I to form the main left hepatic duct. The anat- The least observed biliary pattern (5%) is defined by
omy of the segment II/III duct, as well as segment IV segment II and segment III ducts joining lateral to the
ducts that cross the plane of the umbilical fissure, is highly umbilical fissure to form a very short segment II/III duct
variable.42,46 The most commonly observed biliary pat- that immediately receives the segment IV duct to become
tern (55%) is the union of segment II and segment III the left hepatic duct (see Fig. 2-8, D). In our analysis a
ducts within 1 cm of the umbilical fissure (see Fig. 2-8, single segment II/III duct had formed within 1 cm lateral
A). For this variant the segment II/III duct receives a sin- to the umbilical fissure in 90% of specimens. Russell et al,
gle segment IV duct between the umbilical fissure and the 48 in a review of 838 cholangiograms and 15 liver autopsy

hilum to form the left hepatic duct. The union of seg- specimens, likewise described the union of segment II
ment II and segment III ducts was at the umbilical fissure and segment III bile ducts immediately lateral to the
in 5% of specimens, lateral to the umbilical fissure within plane of the falciform ligament in most specimens.
segment IV in 50% of specimens, and medial to the The union of segment II and segment III ducts occurs
umbilical fissure in 45% of specimens. Healey and within a connective tissue sheath to form a bile duct plate
 2 Surgical Anatomy of the Liver 29

55% II
I

III
II/III
A IV

III
30% II IV
II
I

III

IV
B IV

II III
10% IV
II
I

III

IV IV
C

II LHD
5% I

III

LHV
D IV
FIGURE 2-8 n Biliary variation within segments II and III. A to D, The four biliary variants of segments II and III. Each variant is depicted
as an illustration (left), in relation to the segment II/III allograft (center), and by actual photograph (right) within the panel. B, Segment
IV biliary radicles crossing the umbilical fissure to drain the anterior aspect of segment III. Segment IV radicles are located anterior to
the principal duct of segment III outside of the biliary connective tissue sheath and may be the source of posttransplantation biliary
leaks if not identified.
30 PART I General Considerations

Left hepatic vein Left hepatic vein Left hepatic vein

73% 14% 13%

LHV LHV
LHV

A B C
FIGURE 2-9 n A to C, Anatomical variation of the left hepatic vein (LHV) in schematic form with an accompanying corrosion cast.

that can be identified clinically (see Fig. 2-8). The connec- segments II and III will independently drain into the infe-
tive tissue plate at the origin of the segment II/III duct is rior vena cava. Recognition of separate segment II and
analogous to the hilar plate at the main biliary confluence. segment III hepatic veins is critical to maintaining ade-
An essential element to identification of biliary anatomy is quate venous outflow from the allograft and requires both
recognition of the bile duct plate as a connective tissue orifices to be incorporated on a common caval patch.42
interface that envelops the ducts and guides dissection.
Hemiliver Allografts
Left Lobe Hepatic Venous Anatomy For transplantation of two adults from one adult deceased
The anatomy of the left hepatic vein can be broadly donor or living donor liver transplantation between two
described by three distinct anatomical patterns (Fig. 2-9). adults, the liver is divided along Cantlie’s line to create two
The most common pattern, observed in 73% of speci- relatively equal-sized hemilivers (see Fig. 2-3). Left hemili-
mens, is the union of segment II and segment III veins to ver allografts of approximately 400-mL volume can be cre-
form a principal left hepatic vein at the superior umbilical ated with (segments I to IV) or without the caudate lobe
fissure (see Fig. 2-9, A). This pattern receives significant (segments II to IV) for recipients who are children, teenag-
tributaries draining the posterior aspect of segment IV as ers, and adults who typically weigh less than 60 kg. Right
it approaches the inferior vena cava. The second most hemiliver allografts (segments I, V to VIII, or V to VIII)
frequently observed pattern, observed in 14% of anatom- have a typical volume of approximately 800 to 1000 mL and
ical specimens, involves separate large veins, each drain- are generally suitable for candidates who weigh less than
ing an individual segment, that unite to form the left 80 kg.49-52 The applied surgical anatomy for these proce-
hepatic vein at the level of the inferior vena cava (see Fig. dures focuses on hilar anatomy at the bifurcation, as well as
2-9, B). In this pattern each venous channel receives trib- the relationship of the middle and right hepatic veins.
utaries from the posterior aspects of segment IV before
uniting just before the inferior vena cava. The third ana-
Arterial Anatomy and Reduced-Size Grafts
tomical pattern, identified in 13% of specimens, is a union
of segment II and segment III draining veins within the Bifurcation of the proper hepatic artery into the right and
parenchyma of the segment II/III allograft to form the left hepatic arteries occurs outside the hepatic paren-
left hepatic vein medial to the umbilical fissure. In this chyma, permitting direct isolation of each vessel. Classic
pattern the left hepatic vein is a large single vessel that descriptions emphasize distinction; however, the region
empties directly into the inferior vena cava without of the hilar plate and the junction of segments IV and V is
receiving significant tributaries from segment IV (see Fig. best understood as a network of vascular supply involving
2-9, C). The middle and left hepatic veins fuse to form a both left and right hepatic arteries. Following bifurcation
common channel before the vena cava; however, dissec- of the proper hepatic artery, the right hepatic artery
tion at or slightly within the parenchyma will delineate a courses posterior and lateral to the common hepatic duct
plane of separation between the venous structures. Rarely, to enter the right hemiliver directly. As described earlier,
 2 Surgical Anatomy of the Liver 31

LPV
LPV
RHA

RHA

A B

LPV

RHA
LPV

RHA

C D
FIGURE 2-10 n Right hepatic arterial supply to the left hemiliver. The anatomical relationship of the hilum is confirmed in each cast with
the common hepatic duct anterior to the right hepatic artery (RHA) and portal vein bifurcation. A, A 1-mm branch of the RHA (arrow)
extends anterior to the portal vein to supply segment IV. Note the trifurcated portal vein and posterior right hepatic duct to be dis-
cussed. B, A 2-mm branch of the RHA (arrow) crosses Cantlie’s line posterior to the left portal vein (LPV) to supply segments II, III, and
IV. C and D, The RHA sends small branches of less than 1 mm diameter (arrow) across Cantlie’s line to supply segment IV both ante-
rior (C) and posterior (D) to the LPV.

the left hepatic artery courses extrahepatic along the infe- hepatic artery lateral to the common hepatic duct is advo-
rior aspect of segment IV with the left hepatic duct before cated to minimize potential supraintestinal vein ischemia,
entering the parenchyma at the umbilical fissure. The as well as to minimize devascularization of the common
occurrence of a significant (>1 mm) arterial branch or hepatic duct. In split-liver transplantation this can be
branches derived from the right hepatic artery that cross achieved by preserving the donor celiac axis with the left
Cantlie’s line to supply segment IV was identified in 15% allograft rather than the right allograft. Accessory right
of specimens (Fig. 2-10). These branches may be extrapa- hepatic arteries, originating outside the liver from the
renchymal or intraparenchymal and pass anterior or pos- proper hepatic artery and traveling lateral for approxi-
terior to the left portal vein coursing along the inferior mately 2 cm before penetrating the right hemiliver to
aspect of segment IV. Segment IV receives the principal supply the inferior portions of segments V and VI, may be
supply of these branches; however, we have identified observed in approximately 5% of specimens (Fig. 2-11).
small branches to segments II and III (see Figs. 2-7, A, In 1963 Parke et al54 provided a detailed description of
and 2-10). Marcos53 has described the clinical occurrence the vascular supply of the common bile duct that has
of this anatomical variant in living donor liver transplan- become a landmark manuscript. The extrahepatic biliary
tation and has advocated a modified arterial dissection to tree (common hepatic and common bile ducts) has a lon-
preserve the vascular supply to segment IV, by dividing gitudinal epicholedochal plexus that is supplied by pan-
the right hepatic artery for the allograft distal to the ori- creaticoduodenal, gastroduodenal, cystic, and hepatic
gin of the supraintestinal vein. arteries.54 The left and right hepatic arteries contribute
The right hepatic artery also sends numerous small equally to the common hepatic duct bifurcation, under-
branches of less than 1 mm diameter across Cantlie’s line scoring the recommendation for the dissection strategy
that may supply segment IV as well as the common discussed earlier. For the same reason, dissection should
hepatic duct and hepatic duct bifurcation (see Fig. 2-10). be minimized in the tissue plane between the hepatic
These are surgically significant, and dissection in the tis- artery and common duct during recipient hepatectomy
sue plane defined by the bifurcation of the right and left before live donor allotransplantation to preserve the
hepatic arteries should be avoided during donor right or integrity of the native common duct as a potential con-
left hepatectomy.53 Limiting dissection of the right duit for biliary reconstruction.
32 PART I General Considerations

RHD
LHD
ARHA

FIGURE 2-11 n An accessory right hepatic artery (ARHA) origi- FIGURE 2-12 n Anatomy of the common hepatic duct bifurcation.
nates from the proper hepatic artery proximal to its bifurcation The common hepatic duct bifurcates at the hilar plate to form
and courses laterally to supply segments V and VI. the left hepatic duct (LHD) and right hepatic duct (RHD). The LHD
remains extrahepatic with the left portal pedicle, whereas the
RHD directly enters the hepatic parenchyma, dividing early into
Portal Venous Anatomy and Reduced-Size its secondary branches. Union of anterior and posterior
branches of the RHD occurs within 5 mm of the common hepatic
Grafts duct bifurcation in 33% of specimens.
The bifurcation of the main portal vein is superior and
posterior to the bifurcation of the proper hepatic artery
and immediately inferior to the hilar connective tissue right hepatic duct directly enters the hepatic parenchyma
plate. As it ascends, the main portal vein produces several and, similar to the portal vein, divides early into its sec-
minor branches to the hilum above the origin of the left ondary branches. Union of anterior and posterior
gastric vein, including a medial branch to the left portion branches of the right hepatic duct occurs within 5 mm of
of the caudate lobe and a lateral branch to the right cau- the common hepatic duct bifurcation in 33% of speci-
date lobe. As described earlier, the left portal vein remains mens and within 1.5 cm of the common hepatic duct
extrahepatic, whereas the right portal vein immediately bifurcation in 90% of specimens (Fig. 2-12).
enters the parenchyma along with the right hepatic artery A significant surgical variant found in approximately
and bile duct to form the main right portal pedicle. This 15% of specimens is the separate origination of the pos-
pedicle is easily visualized on sonography. The right por- terior branch of the right hepatic duct directly from the
tal vein classically branches within 3 cm of its origin into left hepatic duct (Fig. 2-13). In this variant the posterior
anterior and posterior divisions and occasionally pro- branch of the right hepatic duct originates approximately
duces a distinct segment VIII branch. A trifurcation may 1 cm beyond the hilar plate from the left hepatic duct and
also be encountered originating from the main portal crosses Cantlie’s line to drain segments VII and VIII.46
vein, with distinct anterior and posterior right portal divi- This branch cannot be ignored in right hemiliver grafts
sions visualized outside the liver (see Fig. 2-10, A). Typi- and requires a separate biliary reconstruction or ligation
cally the anterior right portal division services segments of both sides to avoid bile leakage in both recipient and
V and VI, whereas the posterior branch services segments donor . In left hemiliver grafts the duct should be gently
VII and VIII. Some hepatic surgeons have advocated probed to verify it does not lead to segment II (as detailed
intrahepatic ligation of the right portal pedicle during by Fig. 2-8, C) with connection to the left hepatic duct
right hepatic resection to completely avoid extrahepatic verified by gentle flushing of saline before ligation.
dissection. Faithful to Couinaud’s anatomical descrip-
tion,28 the biliary tree parallels hepatic portal venous Hepatic Venous Anatomy and Reduced-Size
anatomy within the right lobe and segment IV. At the Grafts
bifurcation the common hepatic duct is sheathed in con-
nective tissue to create a surgically identifiable hilar plate Paramount to the successful application of partial-liver
within the transverse fissure. In reconstructive biliary allografts is an appreciation of hepatic venous outflow for
surgery it is possible to expose the confluence of the right graft function. Though the principal three hepatic veins
and left hepatic ducts by dissecting anteriorly in the por- are fairly constant at the level of their junction with the
tal plate at the base of segment IV.19 Thus it is possible to suprahepatic inferior vena cava, there is sufficient vari-
access high bile duct cancers or biliary strictures above ability and overlap in their intrahepatic territories that
the confluence. careful presurgical assessment of the potential remnant
The bifurcation of the common hepatic duct is the and graft is essential to successful outcomes. The overlap
superior landmark of the hilum. The left hepatic duct, zones are primarily located in the middle vein territory:
like other components of the left portal pedicle, courses segment IV, V, and VIII. Left hemiliver allografts gener-
approximately 3 cm along the inferior border of segment ally include the entire segment IV and the entire middle
IV superior to the left portal vein and is available for high hepatic vein and consequently have reliable venous out-
anastomosis in the treatment of hilar obstruction. The flow through both the middle hepatic vein and left hepatic
 2 Surgical Anatomy of the Liver 33

PRHD
PRHD

A B

RPV
LPV PRHD LHD

RPV

C D
FIGURE 2-13 n A posterior right hepatic duct (PRHD) originates from the left hepatic duct (LHD) and crosses Cantlie’s line to enter the
right lobe (A and B) (see also Fig. 2-10, A). C, Dorsal view of PRHD branch as it courses to drain segments VII and VIII. Note the trifur-
cated portal vein (PV). D, Anatomical variant with two anterior right hepatic branches uniting at the bifurcation and a posterior hepatic
duct branch originating from the LHD.

vein. In cast studies, segment IV venous outflow was receives multiple trunks from the anterolateral right lobe
principally derived from the left hepatic vein in 9%, mid- and segment IV. This variant provides the principal
dle hepatic vein in 55%, and equally between left and venous outflow to segments V and VI in addition to
middle in 36% of specimens.46 drainage of segments VIII and IV (see Fig. 2-14, C).
Right hemiliver grafts have considerably greater risk Because right hemiliver grafts may not have sufficient
related to venous outflow deficiency of segments V and venous outflow without the middle hepatic vein, major
VIII if the middle hepatic vein is not included in the graft segment V and VIII branches must be preserved during
(as is typically the case at most Western centers). Figure the donor hepatectomy for possible reconstruction, par-
2-14 details the anatomy of the middle hepatic vein. The ticularly when the allograft is of marginal predicted size
most frequently observed anatomical pattern (70%) is or when the recipient is known to have significant portal
approximately equal venous drainage from segments IV, hypertension.
V, and VIII via large secondary branches uniting deep Figure 2-15 illustrates the right hepatic venous anatomy.
within the hepatic parenchyma (see Fig. 2-14, A). In 20% In approximately 90% of specimens (see Fig. 2-15, A, B,
of specimens, the middle hepatic vein is a single large ves- and D), the right hepatic vein courses throughout the right
sel receiving secondary branches from segments IV, V, hemiliver to provide venous drainage; however, as
and VIII throughout its course (see Fig. 2-14, B). A clini- demonstrated in Figure 2-15, C, there is a variant where
cally significant variant observed in 10% of specimens the right hepatic vein is very short and posterior, providing
consists of a broad middle hepatic vein vascular tree that limited venous drainage to segments VII and VIII with no
34 PART I General Considerations

Middle hepatic vein Middle hepatic vein

70% 10%

MHV

A
Middle hepatic vein
20%
MHV

MHV C

B
FIGURE 2-14 n A to C, Diagram of the anatomy of the middle hepatic vein (MHV) with a corresponding corrosion cast.

involvement of the anterolateral surface of the right single, short, posterior right hepatic vein that principally
hemiliver (segments V and VI). This anatomical variation drains segments VII and VIII (see Fig. 2-15, C).
occurs in conjunction with a broad anterior middle hepatic Identification of large, accessory hepatic veins from
vein that sweeps lateral as depicted in Figure 2-14, C. The segments V and VI during hepatectomy is a predictor of
drainage provided by these two variants (Fig. 2-16) neglects this anatomical venous pattern. Middle hepatic venous
the posterior aspect of segments V and VI that are serviced branches draining segments V and VIII55-57 as well as
by large accessory hepatic veins that drain directly into the accessory hepatic veins larger than 5 mm in diameter are
inferior vena cava (Fig. 2-17). Accessory hepatic veins with clinically significant and should be preserved through a
a diameter larger than 5 mm occur with an incidence of caval patch or individually for implantation into the
approximately 10% to 15%, particularly in the setting of a recipient vena cava.
 2 Surgical Anatomy of the Liver 35

Right hepatic vein

54%

RHV

Right hepatic vein

27%

RHV

B
FIGURE 2-15 n A to D, Diagram of the anatomy of the right hepatic vein (RHV) with a corresponding corrosion cast.
Continued
36 PART I General Considerations

Right hepatic vein

10% RHV

Right hepatic vein

6%

RHV

D
FIGURE 2-15, cont'd
 2 Surgical Anatomy of the Liver 37

MHV

RHV
I

II

III
A B

MHV
RHV

IVC

C
FIGURE 2-16 n Interaction of the right and left hepatic veins. A broad, anterior middle hepatic vein (MHV) sweeps lateral to provide the
principal drainage to the anterolateral aspect of the right hemiliver. This occurs in conjunction with a short, posterior right hepatic
vein (RHV) that principally drains segments VII and VIII. Notice the multiple venous arcades (B, numbered I, II, and III) that
interconnect the two venous systems. C, Intraoperative ultrasonography demonstrates the venous drainage of segment VIII by the
middle hepatic vein. IVC, Inferior vena cava.

ARHV
ARHV

IVC

A B
FIGURE 2-17 n Accessory right hepatic veins (ARHVs) originating from the posterior surface of the liver and draining directly into the
inferior vena cava (IVC) are demonstrated by a corrosion cast (A) and intraoperative photograph (B).
38 PART I General Considerations

Pearls and Pitfalls

• Successful application of partial-liver allografts mandates arteries. To minimize segment IV ischemia, identification
detailed understanding of intrahepatic anatomy. and exposure of the right hepatic artery lateral to the com-
• Review of the embryology and nomenclature systems de- mon hepatic duct during living donor liver transplanta-
scribed in this chapter provides a foundation for appreciat- tion of segment IV to VIII allografts is advocated. Lateral
ing the origin of anatomical variants and their relevance in exposure avoids devascularization of the bifurcation and
surgical procedures. preserves arterial supply to segment IV. In split-liver trans-
plantation this practice preserves the celiac axis with the
Hilar Anatomy left graft.
• Arterial variations with respect to orientation and destina- • At the bifurcation the common hepatic duct is sheathed in
tion are frequent in the presence of replaced anatomy. connective tissue to create an identifiable hilar plate within
• Trifurcation of the portal vein is often approachable with a the transverse fissure. It is possible to expose the confluence
high hilar dissection. of the right and left hepatic ducts by dissecting anteriorly
in the portal plate at the base of segment IV. This provides
Couinaud Segment II/III Allograft access to high bile duct cancers or biliary strictures above
• Dissection of the portal pedicle at the base of the round the confluence.
ligament isolates the left hepatic artery, left portal vein, and • A significant surgical variant is the separate origination of
left hepatic duct. Branches of the left portal vein servicing the posterior branch of the right hepatic duct directly from
the caudate lobe should be divided during the dissection. the left hepatic duct. The posterior branch of the right he-
• Parenchyma transection 1 cm lateral of the falciform liga- patic duct originates approximately 1 cm beyond the hilar
ment yields a single segment II/III duct in approximately plate from the left hepatic duct and crosses Cantlie’s line
90% of surgical specimens. to drain segments VII and VIII. This branch cannot be ig-
• Biliary radicles from segment IV may cross the umbilical nored in right hemiliver grafts and requires a separate bili-
fissure anterior to the segment II/III bile duct outside of ary anastomosis.
the biliary connective tissue sheath. These are terminal • Hepatic venous anatomy can be broadly categorized and
ducts that are amenable to suture ligation. is easily recognizable with preoperative imaging. The
• Segment IV penetrating arteries provide significant in- presence of an anterior, broadly sweeping lateral middle
flow, and particular attention should be devoted to their hepatic vein that services segments V and VI occurs with
preservation. a short, posteriorly located right hepatic vein. With this
anatomy, clinically significant accessory hepatic veins
Hemiliver Allografts drain the posterior surface of the liver directly to the infe-
• The hilar plate and junction of segments IV and V compose    rior vena cava.

a vascular network involving both left and right hepatic

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 CHAPTER 3

Molecular and Cellular Basis

of Liver Failure
Constance Mobley • Ali Zarrinpar

CHAPTER OUTLINE

DEFINITIONS CIRRHOSIS
ACUTE LIVER FAILURE Clinical Manifestations
Clinical Manifestations Etiology
Etiology Pathogenesis
Pathogenesis Myofibroblasts Mediate the Liver’s Response
to Injury
Liver Regeneration and Repair
Hepatic Stellate Cell Activation
Necrosis, Apoptosis, and Hepatic
Cell Death Fibrosis Results From a Complex Cascade
in Interconnected Signaling Events
Summary of the Pathogenesis of Acute
Liver Failure Summary of the Pathogenesis of Cirrhosis
PERSPECTIVES AND FUTURE DIRECTIONS

Liver failure is the inability of the liver to perform its normal distinct. Nonetheless, we separate these two ends of a
synthetic and metabolic function as part of normal physi- spectrum in this chapter for clarity. We briefly review
ology and arises from the loss of functional hepatic the molecular and cellular basis of acute liver failure and
parenchyma from either acute or chronic injury. More cirrhosis, focusing on recent advances in understanding
than 30 million people in the United States have liver the molecular signaling pathways that mediate liver
disease—1 in 10 Americans. Cirrhosis affects hundreds injury. Space limitations dictate that many important
of millions of patients worldwide.1 In the United States areas of research in this field are not addressed. Similarly,
the overall prevalence is estimated at 360 per 100,000 worthy contributions from many laboratories are not
population, or 900,000 total patients. Cirrhosis accounts cited. Accordingly, references to several recent reviews
for approximately 30,000 deaths per year, not including are provided for readers interested in a more detailed
another 10,000 deaths from liver cancer, which largely treatment.
arises in cirrhotic livers.2 Acute liver failure (ALF) affects
approximately 2000 to 4000 persons per year and carries
a high mortality rate of 60% to 80%.3 Overall, ALF DEFINITIONS
accounts for 6% of liver-related deaths and 7% of ortho-
topic liver transplants.4 Regardless of the cause of the Liver injury encountered in clinical practice is arbitrarily
hepatic failure, liver transplantation remains the only divided into fulminant, acute, acute-on-chronic, and
viable means for cure. However, in the United States chronic/cirrhosis, based on the symptoms and duration
nearly 16,000 patients with liver disease are listed and or persistence of liver injury. Fulminant hepatic failure
awaiting liver transplantation. In 2012, although over (FHF) is defined as the onset of hepatic encephalopathy
6200 liver transplants were performed, less than 40% of within 8 weeks of the first symptoms of liver disease, with
eligible candidates received this lifesaving operation.1 the absence of preexisting liver disease being critical to
Ideally, a better understanding of the molecular and cel- the diagnosis. Specific laboratory criteria demonstrating
lular mechanisms that underlie hepatic failure could yield severe hepatic dysfunction allow these patients to receive
alternative therapeutic interventions to treat or bridge the highest priority for organ allocation, given that their
patients to definitive therapy with transplantation. Thus life expectancy without a liver transplant is less than 7
an understanding of the mechanisms mediating liver days.1
injury is of biomedical and clinical relevance. Although Similar to FHF, ALF is a clinical syndrome character-
impaired hepatic function characterizes both acute liver ized by severe liver injury complicated by encephalopa-
failure and cirrhosis, the mechanisms underlying the thy. Essential for the diagnosis of ALF is the absence of
pathogenesis of these two disorders are, in general, clinically overt chronic liver disease and the presence of

40
 3 Molecular and Cellular Basis of Liver Failure 41

encephalopathy not caused by sedation or some other

TABLE 3-1 C
 linical Manifestations of Acute Liver
nonhepatic cause. ALF carries a high mortality rate with
Failure and Decompensated Cirrhosis
estimates ranging between 60% and 80%. Although a
recent systematic literature review showed a lack of a Acute Liver Decompensated
definitive consensus definition, generally most studies of Failure Cirrhosis
ALF include patients that develop encephalopathy within Fluid retention + +++
8 to 26 weeks of the onset of symptoms of hepatic syn- Portal hypertensive − +++
thetic dysfunction demonstrated by jaundice and bleeding
coagulopathy.6 Coagulopathy +++ ++
In addition, acute-on-chronic liver failure has been Jaundice ++ +++
described, although the precise pathophysiological pro- Hepatic +++ ++
cesses underlying this condition remain to be elucidated. encephalopathy
Generally it is recognized as an acute deterioration of liver Cerebral edema +++ −
function in patients with cirrhosis, either secondary to Infection +++ ++
superimposed liver injury or due to extrahepatic precipitat- Renal failure +++ ++
ing factors such as infection culminating in the end-organ Hepatocellular − ++
dysfunction.7 More specifically, the European Association carcinoma
for the Study of the Liver–American Association for the
−, Unusual; +, infrequent; ++, common; +++, characteristic of the
Study of Liver Diseases definition is an acute deterioration syndrome.
of preexisting, chronic liver disease, usually related to a
precipitating event and associated with increased mortality
at 3 months due to multisystem organ failure.6 or equal to 1.5, jaundice, and elevated serum aminotrans-
Although FHF, ALF, and acute-on-chronic liver fail- ferase levels. Other common clinical manifestations
ure are distinct physiologically, the molecular mecha- include loss of vascular tone with hypotension, renal fail-
nisms dictating their pathogenesis are overlapping, and ure, infection and/or sepsis, hypoglycemia, electrolyte
clinically liver transplantation remains the only definitive abnormalities, cardiac dysfunction, acute lung injury,
treatment for patients who fail to demonstrate recovery. gastrointestinal bleeding, and disseminated intravascular
Therefore, for the purposes of this chapter, we will group coagulation. Portal hypertensive bleeding and severe
them categorically into ALF and make mechanistic dis- fluid retention are distinctly unusual (Table 3-1). The
tinctions where research provides more specific elucida- syndrome of ALF is associated with high mortality, with
tion of their pathogenesis. most patients dying from cerebral edema and sepsis.
Chronic liver failure seen in cirrhosis can be defined as Some causes of ALF are associated with a better prog-
the end-stage consequence of fibrosis of the hepatic paren- nosis than are other causes. In general, the more rapid
chyma, resulting in nodule formation and altered hepatic onset forms of ALF have a higher incidence of cerebral
function. It is a pathological diagnosis characterized by the edema but an overall better prognosis, probably reflect-
presence of nodules of regenerating hepatocytes sur- ing the lack of liver architectural derangement and thus
rounded by exuberant extracellular matrix (ECM) in the more favorable conditions for hepatic regeneration. ALF
form of fibrotic bands.2 Hepatic function can be impaired due to acetaminophen overdose, hepatitis A, shock liver,
to a clinically significant degree when the structural abnor- or pregnancy-related disease showed a 50% or more
malities that distinguish cirrhosis are sufficiently advanced. transplant-free survival.8 In contrast, ALF caused by
This potentially life-threatening condition is the final idiosyncratic drug reactions, Wilson’s disease, and inde-
common pathway through which nearly all forms of terminate causes tends to carry a particularly poor
chronic liver disease cause morbidity and mortality. prognosis.9
The determination of the prognosis for ALF has
immense value. Irreversible ALF recognized early can be
ACUTE LIVER FAILURE treated so that life-threatening complications can be pre-
vented. In turn, patients with recoverable liver function
Clinical Manifestations would be spared unnecessary surgery. Several prognostic
indices have been developed. King’s College Hospital
ALF is a clinical syndrome resulting from rapid loss of criteria are the most widely used, and they include clinical
hepatocyte function. Hepatic encephalopathy is, by defi- and biochemical data routinely available in clinical prac-
nition, present to some degree in all patients with ALF. tice. However, no prognostic model to date has proved
Cerebral edema is a cardinal feature and may produce reliable in determining the prognosis for ALF, and ALF
uncal herniation, yielding brainstem compression and remains an unpredictable disease with high morbidity
death. ALF requires a multidisciplinary, collaborative and mortality.
effort among hepatologists, transplant surgeons, inten-
sive care physicians, nephrologists, and neurosurgeons.
Patients should be rapidly evaluated for cause and sever-
Etiology
ity of liver injury, and an urgent assessment should be ALF results from the abrupt loss of liver function second-
made regarding suitability for liver transplantation. Hall- ary to severe injury from a variety of causes that may be
marks of presentation include coagulopathy as evidenced grouped into several general categories (Table 3-2). The
by an elevated international normalized ratio greater than most common causes of ALF in the United States
42 PART I General Considerations

TABLE 3–2 Causes of Liver Failure

Acute Liver Failure Decompensated Cirrhosis
Drugs/toxins Acetaminophen, isoniazid Ethanol, methotrexate, excess vitamin A
Infections Hepatitis A, hepatitis B (±hepatitis Δ), Hepatitis B, hepatitis C, schistosomiasis
hepatitis E
Vascular Shock (i.e., acute ischemia), hepatic Congestive heart failure, hepatic vein
vein occlusion (Budd-Chiari syndrome) occlusion (Budd-Chiari syndrome)
Metabolic and genetic Wilson’s disease, Reye’s syndrome, Nonalcoholic steatohepatitis, hereditary
disorders tyrosinemia, pregnancy-associated hemochromatosis, α1-antitrypsin
(acute fatty liver/HELLP syndrome) deficiency, Wilson’s disease, tyrosinemia
Autoimmune Autoimmune hepatitis Autoimmune hepatitis, primary biliary
cirrhosis, primary sclerosing cholangitis
Biliary disorders Chronic obstruction of the biliary tract,
Byler's disease
Unknown Indeterminate acute liver failure Cryptogenic cirrhosis

HELLP, Hemolysis, elevated liver enzymes, and low platelet (count).

currently are drugs and toxins, in particular, acetamino- growth factor stimulation (epidermal growth factor
phen (APAP; 46%), ALF of indeterminate cause (14%), [EGF], heparin-binding EGF, transforming growth
hepatitis A and B viral infections (11%), autoimmune dis- factor-α [TGF-α], and hepatic growth factor [HGF]),
orders (5%), ischemia (4%), Wilson’s disease (2%), and a which together induce transcription of early genes in
cluster of other diverse metabolic, structural, and unde- hepatocytes (e.g., c-fos, c-jun, c-myc) and activate multiple
termined causes (14%).10 Most patients who develop an signaling pathways (mitogen-activated protein kinase
acute hepatitis episode recover spontaneously. Recovery [MAPK], signal transducer and activator of transcription
rate is higher if the triggering event is related to certain 3 [STAT3], phophatidylinositol-3 kinase [PI3K]/Akt,
causes (i.e., hepatitis A virus, transient hypoxia, and extracellular signal-regulated kinase [ERK1/2]) pro-
paracetamol intoxication, and mushroom poisoning).8 moting the G0/G1 transition and cell progression.15
Although acetaminophen hepatoxicity is the most com- Although the hepatocyte is often the focus of attention in
mon cause of ALF in the United States, viral causes are ALF, all of the various liver cell types (Table 3-3)
the predominant cause of ALF in developing countries.11 undoubtedly play important roles. Indeed, recent studies
The incidence of ALF from viral hepatitis A and B in the have shown the importance of macrophages, hepatic stel-
United States appears to be decreasing, perhaps in part late cells (HSCs), lymphocytes, natural killer T (NKT)
the result of an active vaccination program, and together cells, natural killer (NK) cells, and endothelial cells in
they now account for less than 10% of ALF cases per liver regeneration.13,16-18 Moreover, liver regeneration
year.12 These diverse metabolic, toxic, and inflammatory after PH may provide molecular insights into the self-
insults result in liver injury and disease. A common fea- renewal of mature cells, a property often ascribed exclu-
ture of these insults is activation of apoptotic cell death. sively to stem cells.
The subsequent sections of this chapter will discuss the The extent to which hepatic stem cells mediate liver
pathogenesis of liver failure, focusing on the experimen- regeneration remains under intense study. The liver pro-
tal evidence for cytotoxic pathway activation and molecu- genitor cell, or oval cell, is widely used to describe hepatic
lar mechanisms whereby insult is translated into damage, progenitors; however, there is no consensus on the phe-
and ultimately hepatobiliary disease. notypic or molecular traits of these cells. The rapid
reconstitution of liver mass following injury is usually
fulfilled by resident hepatocytes. However, in circum-
Pathogenesis stances that overwhelm hepatocyte regeneration, pro-
To develop more effective prognostic tools and treat- genitor cells reconstitute hepatic parenchyma, as
ments in ALF, it is necessary to elucidate the molecular determined in transplantation studies, and contribute to
pathways that dictate the pathological changes and ulti- the formation of bile ducts.19 Based on the available data,
mately influence outcome. Knowledge of the degree of it appears that oval cell activation reflects the effects of
ongoing hepatic regeneration would be a useful tool, inflammatory cytokines (IL-6, IL-18, interferon-γ, TNF)
given that recovery of patients with ALF is thought to and intracellular signaling pathways (e.g., Janus kinase
reflect the capacity of the liver for regeneration. The par- (JAK)/STAT, Sonic hedgehog), initiating a cascade of
tial hepatectomy (PH) model in rodents has been a main- events culminating in differentiation into biliary cells and
stay in studying hepatocyte proliferation and the hepatocytes.20,21 Further studies to delineate the molecu-
initiation of the downstream cascades resulting in liver lar mechanisms controlling differentiation of hepatic
regeneration.13,14 Our most current model based on PH progenitor cells are ongoing.
defines distinct phases of regeneration, each involving Full recovery from ALF is possible, and this suggests
cytokine pathway interactions (e.g., tumor necrosis that outcomes may be improved not only if hepatic regen-
factor-α [TNF-α], interleukin-6 [IL-6]) between hepato- eration is enhanced, but if cell death is curtailed. A common
cytes and nonparenchymal cells in conjunction with feature of liver injury is activation of apoptotic or necrotic
 3 Molecular and Cellular Basis of Liver Failure 43

TABLE 3-3 The Roles of the Major Cell Populations in the Healthy Liver
Approximate Fraction
Cell Type in the Healthy Liver (%) Roles in the Healthy Liver
Hepatocytes 60 Uptake, storage, metabolism, and release of carbohydrates, proteins, lipids,
and vitamins
Synthesis of plasma proteins, lipoproteins, fatty acids, cholesterol,
phospholipids, and glucose
Bile synthesis and secretion
Degradation and detoxification of exogenous and endogenous compounds
Stellate cells 5 Storage of vitamin A
Synthesis of extracellular matrix
Support of homeostasis of hepatocytes and endothelial cells
Cholangiocytes 3 Fluid and electrolyte secretion/resorption
Protein translocation
Kupffer cells 15 Phagocytosis and clearance of microorganisms, endotoxins, tumor cells,
particulate matter
Immune defense
Tumor cell surveillance
Endothelial cells 15 Endocytic uptake of glycoproteins
Scavenging of denatured circulating proteins
Immune cells 2 Cytotoxicity toward virus-infected and tumor cells

cell death. Hepatocytes can undergo apoptosis via an plasma concentration of HGF, produced primarily by
extrinsic, death receptor–mediated pathway or alterna- stellate cells, increases dramatically within 1 hour of a
tively the intracellular intrinsic pathway of apoptosis. PH, and it acts through its receptor, c-Met, which is
The molecular pathways leading to cell death are highly highly expressed on hepatocytes.26 Studies of growth sig-
regulated and overlapping. Key regulatory signals from nals in cultured hepatocytes have shown a fivefold to ten-
innate immunity cells (Kupffer cells, NKT cells, and NK fold increase in DNA synthesis of HGF, and receptors
cells) responding to injury interact with hepatocytes to for the ligands EGF and TGF.13 TNF-α, released pri-
initiate a molecular cascade resulting in hepatocyte apop- marily from Kupffer cells, although not directly mito-
tosis. Cytokine release (TNF, interferon-γ, IL-6) results genic itself, appears to play a critical role in the initiation
in activation of multiple transmembrane signaling path- of the transcriptional cascade contributing to hepatocyte
ways (FasL, TNF-related apoptosis-inducing ligand replication and experimentally is shown to enhance the
[TRAIL], c-jun N-terminal kinase [JNK]), which in turn effects of HGF, EGF, and TGF.13,27 Furthermore, pro-
activate transcription factors (NF-κВ, c-jun, c-fos), mito- liferation is strongly enhanced by combining HGF and
chondrial proteins (Bcl-2, Bid, Bim, Bax, and Mcl-1), and EGF.13,27,28
caspases. Ultimately these pathways converge on the The molecular mechanisms underlying hepatic
mitochondria, causing mitochondrial dysfunction, which regeneration have been elucidated primarily in the PH
is a prerequisite for hepatocyte apoptosis.22 rodent model, in which two thirds of the liver, including
Prognosis in ALF depends on the balance of liver cell the left lateral and medial lobes, is removed intact.26
death with liver repair and regeneration. Indeed, survival Under normal conditions, only a small fraction of hepa-
critically depends upon rapid and robust recovery of liver tocytes (∼1/20,000) are in mitosis. When hepatocytes
cell function before the life-threatening complications, are injured and die, they are usually replaced by mature
such as cerebral edema and sepsis, of ALF supervene. hepatocytes. This was demonstrated by a critical early
experiment in rodents using radiolabeled nucleotides
after 70% PH that showed that nearly all hepatocytes
Liver Regeneration and Repair
incorporate radioactive nucleotides during liver regen-
Although many of the main molecular pathways involved eration. This landmark observation established that
in liver regeneration after PH have been deciphered, resident hepatocytes actively divide to recover the origi-
recent studies highlight new insights into mechanisms nal cell number and liver mass, and that hepatocytes
involved in this process. undergo roughly one or two rounds of cell division after
The adequacy of liver repair and regeneration follow- 70% PH.14,23,29 After PH the onset of liver cell replica-
ing acute liver injury appears to be as important as the tion is rapid, with the peak of hepatocyte DNA synthesis
extent of the injury in determining outcome. Hepatic occurring within approximately 24 hours, and the peak
regeneration represents the culmination of a complex of nonparenchymal cell DNA synthesis occurring
interaction among liver cells, matrix, cytokines, and hor- approximately 24 hours later.24 Amazingly, normal liver
mones and is characterized by the activation of more mass is restored after only 7 to 10 days following 50%
than 100 genes encoding cytokines, growth factors, tran- PH in rats.23,30 More recent studies using a genetic trac-
scription factors, and cellular constituents.15,23-25 HGF, ing method to directly assess cell division has shown that
EGF, TGF-β, TNF-α, and IL-6 appear to have par- not all hepatocytes undergo cell division.14 Interest-
ticularly important roles in hepatic regeneration. The ingly, in the 70% PH model no cell division was observed
44 PART I General Considerations

FIGURE 3-1 n The main steps of liver regeneration after partial hepatectomy (PH). (1) “Priming” phase: This initial step involves cyto-
kines pathways interactions between hepatocytes and nonparenchymal cells. As a result of tumor necrosis factor-α (TNF-α) secretion,
NF-κB becomes activated in Kupffer cells, leading ultimately to signal transducer and activator of transcription 3 (STAT3) expression
in hepatocytes via the upregulation of interleukin-6 (IL-6). STAT3 pathway will then induce transcription of early genes in hepatocytes,
such as c-fos, c-jun, c-myc, promoting the G0/G1 transition. (2) Metabolic and growth factors phase: Metabolic changes in the liver
are notably illustrated by a transient lipid droplet accumulation inside hepatocytes. Simultaneously, growth factors coming from dif-
ferent tissues are expressed, including amphiregulin (AR), epidermal growth factor (EGF), heparin-binding (HB)-EGF, transforming
growth factor-α (TGF-α), and hepatic growth factor (HGF) binding to their cognate receptors on hepatocytes (epidermal growth factor
receptor [EGFR] and c-Met, respectively). Eventually this leads to the activation of multiple pathways such as mitogen-activated pro-
tein kinase (MAPK), STAT3, phophatidylinositol-3 kinase (PI3K)/Akt, and extracellular signal-regulated kinase (ERK1/2) involved in
liver regeneration to allow cell cycle progression. (3) Termination phase: Once liver regeneration is achieved, stop signals are
expected to suppress proliferation. Proteins from the TGF-β family display growth-inhibitory effects on hepatocytes. More recently,
the Mst1/2 has been proposed to be involved in the end of liver regeneration in inhibiting Yap activation. ACVR, (From Gilgenkrantz H,
Collin de l’Hortet A. New insights into liver regeneration. Clin Res Hepatol Gastroenterol. 2011;35[10]: 623-629.)

in more than 40% of hepatocytes, and in a 30% PH during the second phase and stimulate progression
model no cell division occurred even though liver cell through the cell cycle (G1 through S phases). EGFR
mass was recovered in a shorter time interval compared downregulation induces a delayed and reduced hepato-
to the 70% PH model.14,31 These observations indicate cyte proliferation because of a defect in G1/S progres-
that hepatocyte proliferation alone does not account for sion34 with a compensatory activation of other ErbB
liver regeneration after PH. Therefore recovery of liver receptors and c-Met.15,35 c-Met receptor regulates G2/M
mass encompasses both hypertrophy and hyperplasia. progression through an ERK1/2 activation.15,36 Both
Increased hepatocyte size occurs much earlier than entry EGFR and c-Met will then recruit scaffolding proteins
into the cell cycle, suggesting that cell size increase is and activate multiple intracellular intertwined networks,
the first response of hepatocytes to the loss of liver mass. among which MAPK, STAT3, PI3K/Akt, and ERK1/2
This very early stage of liver regeneration is known as are the most important for liver regeneration.16 The early
the priming phase, in which hepatocytes dramatically activation of NF-κB by a rapid posttranscriptional mecha-
change their gene expression pattern to prepare for nism activates expression of IL-6, which in turn activates
regeneration.14,32 STAT3 and other genes. When NF-κB activity is blocked
Biochemical studies and gene targeting technology after PH, the residual liver undergoes massive apopto-
have revealed influences of several signaling molecules in sis.24 Genetically modified mice that lack IL-6 or the
activation of cell cycle–associated genes and key tran- receptor for TNF-α have deficient liver regeneration
scription factors (e.g., cyclin D1, STAT3, and NF-κВ).13 and develop liver failure following PH that is ameliorated
Three main phases of liver regeneration after PH have by recombinant IL-6 administration, strongly suggesting
been used to illustrate the molecular pathways of hepato- that IL-6 is acting downstream of TNF-α in the regen-
cyte repopulation (Fig. 3-1). In the “streaming liver eration cascade. Much less is known about how liver
hypothesis,” during the initial priming phase of replica- regeneration is terminated once the appropriate liver
tion, normally quiescent hepatocytes enter the cell mass is restored. Although this final phase of regenera-
cycle—moving from the G0 to the G1 phase—and tion must occur, the factors involved remain elusive. The
become receptive to growth factors and replication com- TGF-β superfamily is known to be involved in this step.
petent. This phase, which lasts 4 to 6 hours, requires the However, in mice lacking TGF-β receptor, hepatic over-
secretion of cytokines such as TNF-α and IL-6. Increased growth is only transient. Studies in Drosophila wing mass
circulating levels of TNF-α and IL-6 lead to the activa- development have yielded conserved nuclear receptor
tion of the STAT3 pathway within the hepatocytes.15 kinases in mammalian species that also control hepato-
Activation of the STAT3 pathway induces transcription cyte proliferation.21 This suggests that other regulatory
of early genes in hepatocytes, including the proto-­ factors are involved and collaborate to stop liver growth.15
oncogenes c-fos, c-jun, and c-myc.15,23,30,33 Activation of However, in the setting of severe ALF, hepatic regen-
these genes ultimately leads to progression through the eration is impaired despite high serum levels of IL-6,
early to mid-G1 phase of the cell cycle.26 Epidermal TNF-α, and HGF, suggesting another pathway of regen-
growth factor receptor (EGFR) and c-Met are activated eration. Whether new hepatocytes in the regenerating
 3 Molecular and Cellular Basis of Liver Failure 45

FIGURE 3-2 n Signaling events during the hepatic oval cell response. A time line representing the stages of oval cell activation: activation,
proliferation, migration, and differentiation. The factors that are involved in each stage of the response are listed at the bottom. Cox-2,
Cyclooxygenase; CXCR4, chemokine receptor type 4; Dlk, delta interacting protein kinese; FGF-1, fiberblast growth factor1; HGF, hepatic
growth factor; IFN-γ, interferon-γ; IL, interleukin; LIF, leukemia inhibiting factor; LT-β, lympotoxin-B; OSM, oncostatin M; Pref-1, preadipocyte
factor 1; SCF, stem cell factor; SDF-1, stromal cell–derived factor-1; STAT3, signal transducer and activator of transcription 3; TGF, trans-
forming growth factor; TNF, tumor necrosis factor; tPA, tissue plasmenogen activator; TWEAK, TNF-like weak inducer of apoptosis; uPA,
uroplasminogen activator. (From Duncan AW, Dorrell C, Grompe M. Stem cells and liver regeneration. Gastroenterology. 2009;137[2]: 466-481.)

liver are derived from adult hepatocytes, intrahepatic stem in the liver. Hedgehog has also been implicated in pro-
cells, or circulating stem cells remains unclear. Current genitor activation induced by alcoholic steatohepatitis.21,37
studies favor the hypothesis of an expansion of a progeni- Hedgehog inhibitors can impair progenitor proliferation,
tor cell population during regeneration and normal liver and indirect evidence suggests that activation of hedgehog
homeostasis, or the so-called streaming liver hypothesis signaling might be downstream of TGF-β.37 The ability to
(Fig. 3-2). In this model, differential gene expression by generate, manipulate, and then potentially transplant these
hepatocytes arises during the hepatocyte maturation pro- hepatic progenitor cells could prove immensely valuable as
cess, which represents lineage progression. A population a therapeutic intervention to treat severe ALF.
of small portal zone cells in the Canal of Hering with a
high nuclear-to-cytoplasmic ratio known as oval cells pro- Necrosis, Apoptosis, and Hepatic
liferate extensively and, upon migration into the lobule,
differentiate into hepatocytes.21 The oval cell is best
Cell Death
described as a heterogeneous liver progenitor cell whose Like other cells, liver cells die from apoptosis and necrosis.
exact phenotypic markers are not clearly defined, although These two pathways of cell death are morphologically dis-
cellular markers in multiple species have been identified tinct but interrelated, and that probably should be viewed
(c-kit, flt-3, CD34, leukemia inhibiting factor, Thy-1, as two ends of a cell-death continuum. The cell-death path-
Sca-1/CD34/CD45, and OV6).21 Numerous studies have way taken, either apoptosis or necrosis, appears to be
shown that in massive liver injury, where the typical regen- related to the nature and severity of the inciting insult, the
erative pathways are overwhelmed, regeneration is strongly cell type, its metabolic status, and the integrity of the cell-
dependent on oval cell proliferation.19,21 The reliance on death machinery. Both types of cell death probably occur
hepatic oval cells/progenitor cells to repopulate the liver in simultaneously in most forms of ALF, and the same stimu-
massive hepatic injury, such as seen in ALF, makes them a lus can result in either pathway.38 Morphologically, necro-
key focus for targeted therapy. The molecular mechanisms sis results in cell swelling, loss of cell membrane integrity,
regulating the activation, proliferation, and differentiation and lysis, which invariably elicits a secondary immune
of these cells is being elucidated. Both in vitro and in vivo response. Adenosine triphosphate depletion due to loss of
studies demonstrate the importance of interferon-γ, TGF- mitochondrial oxidative phosphorylation is a biochemical
β, IL-6, and TNF in activation and proliferation of oval hallmark of necrosis. Mitochondrial dysfunction in necro-
cells.37 The most well-defined pathway used transgenic sis is characterized by the mitochondrial permeability tran-
mice expressing TNF-like weak inducer of apoptosis sition (MPT), pores that collapse the ion gradient across
(TWEAK) and showed hepatocytes from these mice dis- the inner mitochondrial membrane. MPT results in failure
play an oval cell response and progenitor-specific signaling of the ion gradient, which drives oxidative phosphorylation.
46 PART I General Considerations

TNF-
TRAIL
TRAIL-R2
ER stress TNFR1

Bax Bim
Calcium
TRAIL Bid
P
sensation JNK Calcineurin Bax
CHOP Bcl-2 Bad
Bcl-xL Lysosomal
TRAIL-R2 Bcl-2 permeabilization
Bcl-xL
Bax Cathepsin B
Bim

Mitochondria
Bax
Bax
Bax
oligomerization
Mitochondrial permeabilization

APOPTOSIS

FIGURE 3-3 n Extrinsic and intrinsic pathways of hepatocyte apoptosis. The extrinsic pathway is activated by death receptors. Fas or
tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL; depicted here) binds to its cognate receptor, leading to the
formation of the death-inducing signaling complex (DISC), with caspase-8 activation, Bid cleavage, and subsequent mitochondrial
permeabilization. Bim activation can also occur downstream of death receptor signaling, leading to Bax activation and mitochondrial
permeabilization. The TNF-α signaling pathway also leads to Bid cleavage with lysosomal permeabilization, leading to release of
lysosomal contents and mitochondrial permeabilization. The intrinsic pathway of cell death can be initiated by myriad intracellular
stressors that can activate the endoplasmic reticulum (ER) stress pathway, lysosomal permeabilization, or c-jun N-terminal kinase
(JNK) activation. These cascades lead to inhibition of the antiapoptotic proteins (Bcl-xL, Bcl-2) and activation of the proapoptotic
proteins (Bax, Bim, Bad, Bid). Mitochondrial permeabilization occurs eventually and is required for hepatocyte apoptosis. (From Malhi H,
Gores GJ. Cellular and molecular mechanisms of liver injury. Gastroenterology. 2008;134[6]:1641-1654.)

Cyclophilin D knockout mice have been shown to inhibit to organogenesis and immune cell homeostasis that was
MPT and limit ischemic tissue injury. Necrosis is a promi- first recognized pathologically in liver 3 decades ago as
nent feature of APAP-induced liver injury, and N-acetyl- acidophilic (Councilman) bodies. However, fundamental
p-benzoquinone imine detoxification is associated with insights into the molecular details of the apoptosis path-
oxidative stress. Studies show that mice deficient in way are more recent, initially gleaned from experiments
cyclophilin D are protected from APAP-induced liver in the worm Caenorhabditis elegans and only later in mam-
injury and DNA damage. Also, JNK kinase is activated by malian cells.
APAP and mediates liver injury, whereas inhibition of JNK Diverse factors trigger liver cell death, such as hypoxia
in APAP-injected mice protects from APAP toxicity.39 Oxi- (e.g., with ischemia-reperfusion), reactive oxygen species
dative injury to mitochondria secondary to TNF-α will also (e.g., generated during drug metabolism), viral infection,
result in opening of MPT pores. This leads to release of and autoimmune injury. Susceptible hepatocytes then
intramitochondrial cytochrome c and apoptosis-inducing undergo apoptosis via an extrinsic death receptor–medi-
factor and to initiation of the apoptosis cascade via cas- ated pathway, or an intracellular stress-mediated intrinsic
pase-9.40 In general, liver cell necrosis rather than apoptosis pathway. In either case, participation of mitochondria
tends to predominate, with extensive oxidative damage to appears to be essential for apoptosis in hepatocytes (Fig.
mitochondria because this depletes cellular adenosine tri- 3-3).22 The extrinsic pathway of apoptosis involves the
phosphate stores and also may inhibit caspase activity, both sequential activation of death receptors (Fas or TRAIL),
of which are necessary for the successful execution of the followed by activation of a series of cysteine proteases
apoptosis pathway. called caspases and subsequent mitochondrial permeabiliza-
In contrast, apoptosis, or programmed cell death, is tion. An alternative pathway via TNF-α signaling leads to
characterized by a more orderly process of nuclear and lysosomal activation and subsequent mitochondrial fail-
cytoplasmic shrinkage, condensation, and blebbing with- ure. The intrinsic pathway is triggered by a variety of insults
out loss of cell membrane integrity or release of intracel- signaling apoptosis via JNK activation, or cellular organelles,
lular contents; thus it allows cellular debris to be removed such as mitochondria, endoplasmic reticulum (ER), and
without intense secondary inflammation and marked per- lysosomes. These cascades converge with the activation of
turbation of neighboring cells. Hepatocyte apoptosis can apoptotic proteins (Bax, Bim, Bad, Bid) and inhibition of
be considered to be a pivotal step in most forms of liver antiapoptotic proteins (Bcl-2, Bcl-xL), which results in
injury. Apoptosis is a highly conserved process essential mitochondrial permeabilization.22,38
 3 Molecular and Cellular Basis of Liver Failure 47

Death Receptors. The expression of death receptors on hepatocytes, may be critical to the development of some
hepatocytes is relatively well established. Death receptors forms of ALF.45
belong to the TNF/nerve growth factor superfamily and MicroRNAs constitute a new class of regulators
are essential for death ligand–mediated cell death. Fas, orchestrating proliferation, and their role in liver regen-
TNF receptor 1 (TNFR1), and TRAIL receptors have eration is under active investigation. Recent studies in
recognized roles in liver injury. Receptor binding of its murine models suggest that inhibiting Fas expression in
cognate ligand leads to trimerization and formation of a the liver may prevent or ameliorate ALF (Fig. 3-4). For
death-inducing signaling complex (DISC). The intracel- example, liver Fas expression could be reduced by RNA
lular portion contains “death domains” that recruit adap- interference (RNAi), a method of experimentally knock-
tor proteins leading to the activation of caspase 8 and ing down gene expression in cultured cells and in mouse
cleavage of Bid, which then translocates to mitochondria models. Knocking down expression of Fas in this fashion
and leads to mitochondrial permeabilization. largely protected mice against an otherwise lethal chal-
lenge with either an apoptosis-inducing anti-Fas anti-
Fas. The best-studied extrinsic trigger of hepatocyte body, or concanavalin A, which causes immune-mediated
apoptosis is engagement of the cell surface receptor, Fas liver damage.46 This work not only directly implicates
(CD95/APO-1), which is highly expressed on activated Fas-mediated apoptosis in liver injury but also suggests
lymphocytes and also constitutively expressed on a variety that selectively inhibiting this process, in this case by
of nonlymphoid cells, including hepatocytes. The ligand RNAi, may be therapeutic. A similar study using RNAi to
for Fas, Fas ligand (FasL/CD95L), is a cell surface pro- decrease expression of caspase-8, a key enzyme in death
tein that is expressed by NK cells and activated T cells in receptor–mediated apoptosis, also demonstrates a signifi-
which it mediates lymphocyte homeostasis and, together cant therapeutic effect even if the RNAi was initiated
with the perforin/granzyme system, T-cell cytotoxicity. after liver injury, in this case by a viral (adenovirus) infec-
In addition to lymphocytes, hepatocytes also appear to be tion.47 More recent studies have highlighted the impor-
capable of expressing FasL in certain situations. Binding tant role of microRNA in liver development, regeneration,
of FasL or agonist antibodies (e.g., Jo2) to Fas causes the liver disease (e.g., ALF, nonalcoholic steatohepatitis
latter to trimerize, resulting in the recruitment of a series [NASH], fibrosis, alcoholic liver disease), and hepatic
of intracellular molecules in a signaling cascade that acti- stem cell differentiation. Global analysis of microRNA
vates caspases responsible for degrading cellular compo- expression during the first 36 hours after PH identified
nents and ultimately results in the morphological features intense upregulation of specific microRNAs that regulate
of apoptosis. Furthermore, injection of Fas-agonistic the G1 to S transition phase, thus facilitating efficient cell
antibodies induces FHF in mice. cycle progression. Other studies focus on elucidation of
A physiological role for Fas in liver homeostasis is signal transduction pathways, which appear to be medi-
suggested by the observation that mice genetically defi- ated through TNF apoptotic signaling via Bcl-2.48,49
cient in Fas develop, among other abnormalities, signifi-
cant liver hyperplasia.41 Based on immunohistological Tumor Necrosis Factor-α. TNF-α–induced hepato-
studies, Fas is expressed at low levels in a normal human cyte apoptosis is implicated in a wide range of liver dis-
liver, but expression appears to be upregulated in the eases including viral hepatitis, alcoholic hepatitis,
setting of both acute and chronic liver disease.42 In par- ischemia-reperfusion liver injury, and FHF.50 TNF-α is
ticular, Fas-mediated apoptosis plays a major role in a cytokine mainly produced by macrophages, mono-
development of liver failure from Wilson’s disease and cytes, and T cells in response to infection and inflam-
viral hepatitis B.43 Hepatocytes constitutively express a matory conditions and by other cell types, including
lower level of certain antiapoptotic proteins (e.g., Bcl-2 hepatocytes. Similar to FasL, TNF-α facilitates apop-
and Bcl-xL) than most other cells, which may partly tosis via activation of caspases and belongs to the TNF
explain their special sensitivity to Fas-mediated apopto- receptor superfamily. TNF-α has two cognate recep-
sis. Also, mice deficient in the proapoptotic protein Bid tors, TNF-R1 and TNF-R2, both expressed on hepato-
(Bid-/-) treated with agonistic Fas antibody are resistant cytes. However, only TNF-R1 contains a death domain
to apoptosis and fulminant liver failure.38 FasL expres- and is involved in apoptotic signal transduction. TNF-α
sion on hepatocytes has also given rise to the idea that facilitates apoptosis via activation of caspases. The
under certain circumstances hepatocytes may actively apoptotic signal transduction cascade is initiated by
induce apoptosis in neighboring cells, a process termed TNF-R1 receptor binding, which leads to release of an
fratricide. inhibitory protein and binding of the intracellular
Fas expression has been demonstrated on murine TNF-R1 domain by the adaptor protein TNF recep-
endothelial cells, stellate cells, and cholangiocytes.44 tor–associated death domain (TRADD). In turn,
When it was reported more than a decade ago that intra- TRADD recruits Fas-associated death domain (FADD),
venous administration of an activating anti-Fas antibody then the initiator proteolytic caspase-8 to the TNF-R1
to mice results in ALF secondary to massive hepatocyte complex, where it becomes activated, leading to the
apoptosis and death, it was initially assumed that direct activation of executioner caspases and apoptosis.22,38,50
engagement and activation of hepatocyte Fas was respon- This signal transduction cascade is made even more
sible. However, injury to sinusoidal endothelial cells complex in that TNF-α also has prosurvival signals
appears to play a predominant role in the development of transmitted through NF-κВ and activation of prosur-
FasL-induced ALF in this model, highlighting that vival genes, and signaling via a caspase-independent
injury and death of nonparenchymal cells, as opposed to mechanism with formation of reactive oxygen species.23
48 PART I General Considerations

Hydrodynamic
transfection Inject
Jo2 antibody

Survival (10 days after Jo2 injection)

siRNA vs. control

Fas receptor siRNA

33/40 mice 0/40 mice

P
2 P
siRNA 3
Dicer

P
P
RISC
1
TTTTT
5' 3'
4
Nucleus
Fas mRNA
P

Hepatocyte

FIGURE 3-4 n Knocking down Fas expression improves outcome of mice with acute liver failure (ALF). RNA interference (RNAi) is an
evolutionarily conserved, posttranscriptional, homology-dependent gene-silencing mechanism used by eukaryotic cells to target
destruction of messenger RNA (mRNA). RNAi has been exploited as a powerful and popular experimental method to knock down
gene expression with great precision both in cultured cells and in mice.17 Within cells, RNAi is initiated by small interfering RNA
(siRNA), a double-stranded form of RNA that is 21 to 23 bases in length, usually generated by cleavage of larger double-stranded
transcripts by an endonuclease complex (Dicer). Experimentally, RNAi can also be accomplished by expressing siRNA precursors
(small, hairpin RNAs) from DNA templates (1) or by introducing synthetic siRNA directly into cells (2) by transfection. siRNAs intro-
duced into cells by either route assemble with a multiprotein complex, termed RNA-induced silencing complex (RISC), (3) that uses
the siRNA as a guide to identify and degrade homologous mRNA target sequence, thus acting as a sequence-specific nuclease (4). In
the study by Song and colleagues,18 investigators used a technique called hydrodynamic transfection to deliver and express anti-Fas
siRNAs in a mouse liver to specifically decrease Fas expression. Mice treated in this fashion were largely resistant to the subsequent
administration of an activating anti-Fas antibody (Jo2), which otherwise results in uniformly lethal ALF by inducing massive hepato-
cyte apoptosis.

Despite the complexity, several studies have confirmed Patients with steatosis or hepatitis C virus infection also
the importance of TNF signaling in liver disease. In display enhanced sensitivity to TRAIL-mediated apopto-
patients with FHF, serum levels of TNF-α, TNF-R1, sis with increased expression of TRAIL receptors and
and TNF-R2 are markedly increased, and these changes upregulation of proapoptotic Bcl-2 proteins.38,51 In mice,
directly correlated with disease activity.22 TRAIL expression is induced after alcohol consumption
and is associated with hepatic steatosis. TRAIL-induced
TRAIL. TRAIL is a transmembrane protein expressed apoptosis through death receptor DR5 also plays a role in
primarily in immune cells, especially NK cells, NKT cholestatic liver injury and cholangiocytes of human pri-
cells, and macrophages. TRAIL receptors (TRAILR1 mary sclerosing cholangitis and primary biliary cirrhosis
and TRAILR2, also known as death receptor 4 and 5, patients.51
respectively) are ubiquitously expressed in hepatocytes.
Similar to Fas, TRAIL receptors induce apoptosis via cas- Organelle Dysfunction. The intrinsic pathway of liver
pase activation. TRAIL receptor binding promotes for- cell death is mediated through intracellular stress on
mation of the DISC complex, which recruits FADD and organelles. In fact, apoptosis can be initiated through any
activation of caspases.38 TRAIL signaling is of great cellular organelle. Numerous stressors, such as hypoxia
interest in liver pathobiology. TRAIL-mediated apopto- (e.g., with ischemia-reperfusion), reactive oxygen species
sis is involved in the pathogenesis of viral hepatitis. (e.g., generated during drug metabolism), viral infection,
 3 Molecular and Cellular Basis of Liver Failure 49

and autoimmune injury can initiate the cascade of events factors and can enhance expression of the TRAIL recep-
leading to apoptosis of the hepatocyte. Despite the incit- tor DR5 and the proapoptotic Bcl-2 family protein Bim.
ing event, all the intracellular signaling pathways con- Overexpression of these transcription factors in cell lines
verge on the mitochondria, resulting in mitochondrial sensitizes ER stress–induced apoptosis with reduced cel-
outer membrane permeabilization (MOMP) and cell lular glutathione and decreased expression of the anti-
death. apoptotic protein Bcl-2.51

Mitochondria. The role of mitochondria in apoptosis is JNK. JNK signaling is associated with cell death, sur-
well established. Indeed, mitochondrial dysfunction is the vival, differentiation, proliferation, and tumorigenesis in
commitment step in apoptotic cell death. Mitochondrial hepatocytes. JNKs are known to regulate signaling mol-
permeabilization is governed by the Bcl-2 apoptotic pro- ecules, such as Mcl-1 and Bid by phosphorylation.
tein family. Bcl-2 proteins share conserved regions of Although the signal transduction pathways can produce a
homology termed Bcl-2 homology (BH) 1-4 domains. They variety of physiological outcomes, membrane/organelle-
are further subclassified based on homology and function initiated cytotoxic signaling pathways often converge on
into the antiapoptotic proteins Bcl-2, Bcl-xL, Bcl-w, JNK. Two of the three known JNK proteins are expressed
Mcl-1, and A1; the proapoptotic multidomain proteins in the liver. Both of these can be activated by ER stress
Bax, Bak, and Bok; and finally, the proapoptotic proteins pathways of apoptosis and may also be the pathway of
Bid, Bim, Bad, Bik, Bmf, Hrk, Noxa, and Puma, which all caspase-independent reactive oxygen species–mediated
possess only the BH3 domain (the so called BH3-only cell death.22 Sustained JNK activation leads to cell death
proteins). Intracellular stress activates BH3-only pro- and occurs via modulation of Bcl-2 family proteins, with
teins, which activate the key regulators of MOMP, subsequent mitochondrial permeabilization. Recruitment
namely Bax and/or Bak. These proteins (Bax and Bak), of activated JNK to the outer membrane of mitochondria
either in isolation or together, insert into the outer mito- is an important step in induction of JNK-mediated hepa-
chondrial membrane, forming pores. Mitochondrial tocyte death, and mitochondrial Bcl-xL and Mcl-1 are
outer membrane permeabilization releases mediators of substrates for JNK. Furthermore, ischemia-reperfusion
apoptosis (e.g., SMAC, DIABLO) into the cytosol, which liver injury has been shown to cause JNK1 activation.
then recruit and activate downstream effector caspases In experimental models, specific inhibitors of JNK pre-
resulting in apoptosis (see Fig. 3-3). Interestingly, in mice vented Bak induction, Bid degradation, caspase-3 activa-
with conditional deletion of either Bcl-xL or Mcl-1 in the tion, and mitochondrial cytochrome c release, eventually
liver produces a phenotype characterized by chronic liver attenuating hepatocyte necrosis and apoptosis after isch-
damage and liver fibrosis. These mice show widespread emia-reperfusion or liver transplantation.52
activation of caspases, hepatocyte apoptosis, and elevated
serum aminotransferase levels.38 Summary of the Pathogenesis of
Acute Liver Failure
Lysosomes and Endoplasmic Reticulum. The lysosomal/
endosomal compartment comprises single membrane- The preceding discussion is by necessity incomplete and
bound, cytosolic organelles responsible for degradation largely ignores several important areas of research rele-
and recycling of cellular components. Under physiologi- vant to the pathogenesis of ALF. For example, both pro-
cal stress, lysosomes undergo selective permeabilization inflammatory and antiinflammatory cytokines play
and release of the contents. The lysosomal enzymes critical roles in the pathogenesis of ALF. Interferon-γ, a
known as cathepsins play a major role in the execution of proinflammatory cytokine involved in macrophage and
the apoptotic cell death These proteases can activate T-lymphocyte activation, mediates liver cell injury in a
apoptosis either by cooperating with caspases or via cas- mouse model of hepatitis B. Similarly, by acting through
pase-independent mechanisms. The apoptotic pathway interferon-γ, IL-12 appears to play a role in liver injury in
for lysosomes acts upstream of the mitochondria, and some murine models of ALF.43
several lines of evidence show the involvement of Bax, A variety of cytokines, including IL-10, IL-11, IL-13,
Bim, Mcl-1, and Bid in lysosomal permeabilization in dif- and IL-4, protect against liver injury when administered
ferent models of liver injury.51 In general, release of lyso- to mice, presumably by downregulating proinflammatory
somal proteases activate Bcl-2 family members, resulting cytokines, nitric oxide, and reactive oxygen species. Pre-
in MOMP and apoptosis. Bid is cleaved and activated by liminary immunocytochemical analysis of livers from
a number of cathepsins; cysteine cathepsins also cleave patients with ALF suggests that an imbalance of proin-
the antiapoptotic Bcl-2, Bcl-xL, and Mcl-1, and Bax is a flammatory (interferon-γ) and antiinflammatory (IL-12
substrate for cathepsin D.38,51 and IL-10) cytokines may in fact contribute to the patho-
The ER is the major site of protein folding, matura- genesis of liver failure.19 Nitric oxide—a gas that is gen-
tion, and trafficking. When unfolded or misfolded pro- erated during enzymatic conversion of l-arginine to
teins accumulate in the ER, the ER becomes stressed. l-citrulline by hepatocytes, Kupffer cells, and endothelial
This stress is emerging as a potential cause of damage in cells—is both constitutively expressed and induced by
hypoxia and ischemia-reperfusion injury. Although less is proinflammatory cytokines (e.g., TNF-α) in the liver and
known about the mechanisms of ER stress–associated may contribute to oxidative stress in certain situations
apoptosis, current data suggest that apoptotic pathways (e.g., APAP toxicity).43 However, nitric oxide may also
are activated by protein degradation. Protein degradation have protective effects, and its role in liver injury is still
induces a series of genes that regulate transcription incompletely defined.
50 PART I General Considerations

The relative rarity of ALF speaks to the resiliency of causes of cirrhosis are hepatitis C, NASH, and alcoholic
the liver, which is normally capable of withstanding tre- liver disease. NASH was recently recognized as a major
mendous insults caused by an impressive array of protec- cause of cirrhosis in industrialized nations, in which up
tive, repair, and regenerative mechanisms. It is only in the to 5% of the population has NASH. The proportion of
rare situations, when these mechanisms are critically those with NASH that progresses to cirrhosis is not
impaired or have been overwhelmed, that clinically overt known, but emerging data indicate that NASH may be
liver failure becomes manifest. Despite its relative rarity, the principal cause of cryptogenic cirrhosis among those
ALF represents an important medical problem because it undergoing evaluation for liver transplantation. Alco-
typically affects otherwise healthy individuals and is asso- holism is reported to contribute to 40% to 90% of cases
ciated with high mortality. A more complete understand- of cirrhosis in North America and Europe. Alcohol-
ing of the fundamental molecular mechanisms underlying associated cirrhosis is a leading indication for this sur-
development of ALF, particularly those responsible for gery. Hepatitis C is the primary indication for liver
liver cell death and regeneration, is clearly needed before transplantation. One hundred million persons around
rational therapeutics can be developed. Until that time the world are chronically infected with hepatitis C, with
liver transplantation must continue to be considered for approximately 4 million cases in the United States. Of
any patient developing ALF. those with hepatitis C, 15% to 20% of livers are believed
to progress to cirrhosis. Currently approximately 60% of
those receiving liver transplants are chronically infected
CIRRHOSIS with hepatitis C. Table 3-2 lists other less common
causes of cirrhosis.53
Clinical Manifestations
Cirrhosis is defined as the histological development of
Pathogenesis
regenerative nodules surrounded by fibrous bands in Historically, substantial effort has been made to eluci-
response to chronic liver injury, which leads to portal date the molecular and cellular mechanisms underlying
hypertension and end-stage liver disease. The majority of the development of cirrhosis. Because space constraints
individuals have compensated cirrhosis, in which liver permit us to provide only an overview, the reader is
biopsy results demonstrate cirrhosis, but patients exhibit directed to a number of excellent reviews for a deeper
no symptoms or signs of liver disease, and their test results examination of the pathogenesis of cirrhosis. In the dis-
show that liver synthetic function is intact. Diagnosis of cussion to follow, primary references are provided for
asymptomatic cirrhosis is usually made when incidental data that are not already found in these comprehensive
screening tests such as determination of liver transaminase review articles.53-63
levels or radiological findings suggest liver disease. Com- Fibrosis is a reversible scarring response that occurs in
pensated cirrhosis, however, can progress, eventually com- almost all patients with chronic liver injury. It is a dynamic
promising hepatocyte function and hepatic circulation. If process associated with the continuous deposition and
cirrhosis becomes sufficiently severe, liver failure and por- resorption of ECM. Ultimately, hepatic fibrosis leads to
tal hypertension can occur. The first signs of advanced cir- cirrhosis, associated with nodule formation and organ
rhosis are commonly laboratory test result abnormalities, contraction. Cirrhosis is defined as the histological devel-
which can include thrombocytopenia, prolonged pro- opment of regenerative nodules surrounded by fibrous
thrombin time, hyperbilirubinemia, or hypoalbuminemia. bands in response to chronic liver injury. Increased depo-
When cirrhosis causes hepatic decompensation, any or all sition and altered composition of ECM components in
of a number of clinical manifestations can occur (see Table the portal tracts, around the central veins, or in the peri-
3-1). Advances have been made in prevention and treat- sinusoidal spaces of the liver distorts the hepatic vascula-
ment of the common complications of cirrhosis such as ture, resulting in compromised hepatocyte function. The
variceal bleeding, ascites, spontaneous bacterial peritoni- resultant vascular distortion leads to shunting of the por-
tis, and encephalopathy. Although some of these compli- tal and arterial blood supply, compromising exchange
cations (e.g., variceal bleeding, spontaneous bacterial between hepatic sinusoids and the adjacent hepatocytes.
peritonitis, hepatorenal syndrome) are in themselves life The space of Disse, which contains HSCs, also fills with
threatening, the prognosis for any patient with decompen- fibrotic tissue. If sufficiently severe, fibrosis can result in
sated cirrhosis is poor and warrants consideration for liver compromised hepatocyte function and is responsible for
transplantation. nearly all the complications of end-stage liver disease,
including portal hypertension, ascites, encephalopathy,
synthetic dysfunction, and impaired metabolic capacity.
Etiology Despite the source of injury, the alterations in hepatic
Nearly all causes of chronic liver injury can produce structure and function associated with cirrhosis are simi-
fibrosis and lead to the development of cirrhosis (see lar, which indicates that the general mechanisms underly-
Table 3-2). Alcoholic liver disease and hepatitis C are ing fibrosis of the liver are shared. The primary source of
the most common causes in developed countries, whereas ECM in fibrosis is the myofibroblast. Hepatic myofibro-
hepatitis B is the prevailing cause worldwide. Cirrhosis blasts are not present in the normal liver but transdiffer-
will develop in 25% to 33% of the estimated 400 million entiate from heterogeneous cell populations in response
individuals chronically infected with hepatitis B through- to a variety of fibrogenic stimuli. Currently the origin of
out the world. In the United States the most common hepatic myofibroblasts remains under debate; however,
 3 Molecular and Cellular Basis of Liver Failure 51

two populations of fibrogenic cell types, HSCs and portal marrow stem cells. Portal fibroblasts appear to be espe-
fibroblasts, are believed to mediate hepatic fibrosis. The cially important in cholestatic liver diseases and ischemia.
activation of resident HSCs into proliferative, contractile, Portal fibroblasts are spindle-shaped cells that are present
and fibrogenic cells in liver injury remains the predomi- in the portal area. Under normal conditions they partici-
nant focus of research in hepatic fibrosis. pate in normal ECM turnover and do not express smooth
muscle α-actin. Myofibroblasts derived from portal cells
Myofibroblasts Mediate the Liver’s Response have a distinct phenotypic expression pattern, and the
to Injury markers have been used experimentally to differentiate
this population of cells. Immunohistochemical studies
The origin of fibrogenic hepatic myofibroblasts remains using these specific markers demonstrate that portal
under intense debate, and multiple sources of myofi- fibroblasts contribute to myofibroblasts in cholestatic
broblasts have been identified, including HSCs, portal liver injury.64 Epithelial-to-mesenchymal transition is an
fibroblasts, epithelial-to-mesenchymal transition, and important biological concept that describes the reversible
bone marrow–derived mesenchymal stem cells (MSCs). transition of differentiated epithelial cells into mesenchy-
These different cellular pools reflect differing contribu- mal cells with increased motility and changes in gene
tions to fibrosis, disease progression, and likely differ- expression. The concept was initially demonstrated in
ent causes. other model systems of fibrosis (e.g., kidney, lung). Stud-
Hepatic stellate cells occupy the space of Disse (i.e., ies in vitro have shown that both hepatocytes and cholan-
perisinusoidal space) and make up 5% to 8% of the cells giocytes in response to TGF undergo phenotypic changes
in the liver. In a normal liver these cells have a starlike with gene expression patterns characteristic of mesenchy-
appearance, radially extending numerous cytoplasmic mal cells. Bone marrow–derived MSCs also differentiate
protrusions that contact the basal face of the hepatocytes into hepatic myofibroblasts. MSCs are multipotent pro-
and run along and encircle the endothelial cells that line genitor cells with the capacity to differentiate into a vari-
the sinusoids (Fig. 3-5). Stellate cells synthesize small ety of cell types. They differ from hematopoietic stem
amounts of ECM proteins, including laminin and type IV cells in that they do not express hematopoietic markers.
collagen, which make up the basement membrane. A key MSCs are the most infrequently isolated population in
attribute of this cell type is that it displays prominent experimental models of liver fibrosis.
cytosolic vesicles in which retinoids, primarily vitamin A, Myofibroblasts are considered as the main producers
are stored. In addition, stellate cells release soluble of the ECM in the liver. Hepatic myofibroblasts are not
growth factors, cytokines, and peptides that contribute to present in the normal liver but transdifferentiate from
liver cell development, differentiation, and survival. heterogeneous cell populations in response to a variety
Thus, under normal conditions, stellate cells store vita- of fibrogenic stimuli. Thus the myofibroblast is a piv-
min A, support the homeostasis of hepatocytes and the otal player in development of liver cirrhosis. Upon liver
endothelium, and may contribute to regulation of the injury the quiescent stellate cells transdifferentiate into
microcirculation. myofibroblasts, a process highlighted by the loss of
Other cells postulated as a source of myofibroblasts vitamin A stores, upregulation of interstitial-type col-
include portal fibroblasts, epithelial cells, and bone lagens, smooth muscle α-actin, matrix metalloprotein-
ases (MMPs), proteoglycans, and the induction of cell
survival pathways. The stellate cell responses facilitate
parenchymal restitution after an acute hepatic insult. If
liver injury resolves, stellate cell chemotaxis and prolif-
eration end, excess stellate cells undergo apoptosis, and
surplus ECM is broken down (fibrolysis) by extracellular
MMPs. In this way the wound-repair response is termi-
nated once injury has resolved and tissue healing has
been accomplished.
However, if liver injury persists, hepatic myofibro-
blasts are also recruited to affected sites. Chronic hepatic
injury stimulates HSCs to differentiate into hepatic myo-
fibroblast cells, to proliferate, lay down ECM, and medi-
ate contraction-dependent remodeling of ECM. Clearly,
synthesis of ECM components (e.g., collagens and fibro-
nectins) is essential for the development of fibrosis, but
other properties of these fibrogenic cells are also neces-
sary. For example, chemotaxis and proliferation augment
the number of stellate cells and hepatic myofibroblasts
located within areas of liver injury, which intensifies the
FIGURE 3-5 n The three-dimensional microanatomy of the liver. synthesis and remodeling of ECM. Remodeling of ECM
The stellate cell occupies the perisinusoidal space between the also requires regulation of extracellular MMP activity and
hepatocytes and sinusoidal endothelial cells. Note the defining
starlike shape with protrusions extending around the sinusoid.
the contractile tension generated by the fibrogenic cells.
(From Friedman SL, Arthur MJP. Targeting hepatic fibrosis. Sci Med. Accumulation of excess ECM in the form of contracted
2002;8:194-205.) fibrotic bands is the result of chronic liver injury. Thus
52 PART I General Considerations

fibrosis occurs when injury-induced stimuli persist and cells, immune cells, and ECM mechanics. The com-
keep the homeostatic balance tipped toward migration, bined result is a series of diverse extracellular stimuli
proliferation, fibrogenesis, and contraction and away on many interconnected signaling pathways that dif-
from apoptosis, fibrolysis, and relaxation. ferentially modulate critical dynamic and well-coordi-
From a molecular perspective, activation of HSCs is nated behaviors of the fibrogenic cells of the liver
a result of a complex interplay between the parenchymal (Fig. 3-6).

Chronic alcoholism
Autoimmune hepatitis 1-antitrypsin deficiency

Nonalcoholic steatohepatitis Drugs and toxins

Wilson’s disease Hemochromatosis

Stimulation of Kupffer cells, neutrophils and T cells leading to the secretion of various
cytokines like TNF-, TGF- which in turn activates LECs, resulting in the production
of profibrotic mediators and expression of their receptors

Profibrotic mediators like TGF-, PDGF, ET-1

Quiescent HSCs Activated HSCs

Autocrine
stimulation

TGF-, CTGF, ET-1, angiotensin II

ET-1 MMP-1, MMP-2, MMP-3

Abnormal
Contractility GF MC
, PD P-1 degradation of ECM
P-1 PD
TGF-

MC G
F

HSC F WBC
G
PD

Chemoattraction Chemoattraction

Proliferation Fibrogenesis Loss of retinoids

Abnormal degradation and synthesis of collagen leading to structural

and functional impairments in liver

Hepatic Fibrosis

FIGURE 3-6 n In this proposed model for the liver’s injury response, fibrosis is the combined result of the effects of a series of diverse
extracellular mediators of injury on many interconnected signaling pathways that differentially modulate dynamic and well-coordinated
behaviors of the fibrogenic cells of the liver. Whether normal healing or fibrosis occurs depends on the location, duration, and intensity
of the injury response. CTGF, Connective tissue growth factor 1; ECM, extracellular matrix; ET-1, endothelin-1; HSC, hepatic stellate cell;
LEC, liver epithelial cell; MCP-1, momocyle chemoattractant protein-1; MMP, matrix metalloproteinase; PDGF, platelet-derived growth
factor; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; WBC, white blood cell. (From Ahmad A, Ahmad R. Under-
standing the mechanism of hepatic fibrosis and potential therapeutic approaches. Saudi J Gastroenterol. 2012;18[3]:155-167.)
 3 Molecular and Cellular Basis of Liver Failure 53
Hepatic Stellate Cell Activation
• Vascular endothelial growth factor
The HSC is the primary effector cell, orchestrating the • Endothelin-1
deposition of ECM. HSC activation can be divided into • Leptin
two phases, initiation and perpetuation, followed by a ter- • IL-8
mination phase called resolution. During the initiation • Monocyte chemotactic protein
phase, early changes in gene expression and phenotype • Cytokine-induced neutrophil chemoattractant
allow the cells to become responsive to cytokines and • Fibronectin
other stimuli. Initiation is primarily the result of para- • Laminin
crine stimulation, due to changes in the surrounding • Collagens I, III, IV, VI, XIV, and XVIII
milieu. The initial paracrine stimulation, including expo- In addition, significant amounts of certain factors, includ-
sure to lipid peroxides and products of damaged hepato- ing PDGF, HGF, vascular endothelial growth factor, and
cytes and signals from Kupffer and endothelial cells, drive TNF-α, can bind to the ECM and be released, particu-
early activation, as well as changes in surrounding ECM. larly during fibrolysis.
Once the cell is primed for activation, perpetuation The effects of these injury-associated extracellular
ensues as a continuous and dynamic process. During this mediators are primarily transduced by plasma membrane
phase autocrine and paracrine stimulation enhance receptors (i.e., receptor tyrosine kinases, G-protein–
growth factor expression and amplify the activated phe- coupled receptors, and integrins) or intracellular recep-
notype and generate fibrosis. Several phenotypic changes tors (i.e., nuclear receptors). These receptors in turn act
occur during this phase, including proliferation, contrac- through intracellular signaling pathways that control
tility, fibrogenesis, matrix degradation, retinoid loss, che- protein expression or directly regulate the physical
motaxis, and inflammatory cell infiltration. The net effect behavior of stellate cells and hepatic myofibroblasts. It
of these changes is an increased accumulation of ECM. has become clear that no single mediator or signaling
Resolution activates pathways to terminate the deposi- pathway is sufficient to trigger hepatic fibrosis. More-
tion of ECM driving the stellate cell to apoptosis, or to a over, the functional consequence of any given mediator
more quiescent phenotype. In this dynamic model, or signaling pathway is not stereotypical, but depends on
hepatic damage leads to injury-induced signaling that the timing and subcellular localization of the signal, as
regulates a wound-healing response that requires accu- well as crosstalk from other pathways. The emerging
mulation of the liver’s fibrogenic cells and ECM at the model for wound healing in the liver is one in which
site of injury. During chronic liver disease, injury-induced diverse stimuli orchestrate the activation and inhibition
signaling persists, causing a continuing wound-healing of multiple interconnected signal transduction pathways
response that results in the pathological accumulation of that regulate distinct cellular responses (e.g., chemotaxis-
fibrogenic cells and ECM at sites of injury. With time, chemostasis, proliferation-apoptosis, fibrogenesis-fibrolysis,
this sustained wound-healing response results in the contraction-relaxation).
development of fibrosis and subsequently cirrhosis. In
other words, fibrosis occurs when the net balance of Effects of Platelet-Derived Growth Factor. PDGF,
injury-induced signaling is tipped toward the wound- especially PDGF-β, is the strongest chemotactic and
healing response for too long. mitogenic agent for the fibrogenic cells of the liver.
PDGF signaling is among the best-characterized path-
ways of HSC activation. During liver injury, expression
Fibrosis Results From a Complex Cascade in
of this growth factor and its cognate receptor are highest
Interconnected Signaling Events
in areas of greatest damage. PDGF is secreted in response
Current knowledge is insufficient to provide a complete to injury by platelets, Kupffer cells, stellate cells, and
picture of the pathogenesis of fibrosis. However, a pleth- hepatic myofibroblasts.
ora of studies over the past 2 decades provides a glimpse Moreover, it is sequestered by the ECM and can be
into the intricate signaling pathways that govern the released during fibrolysis. An early response to injury is
wound-healing response. Much of this research has the upregulation of PDGF receptors, which enhances the
depended on well-characterized stellate cell and hepatic sensitivity of stellate cells to this growth factor. Rapid
myofibroblast culture models. The relevance of this work induction of PDGF-β receptor, development of a con-
is not entirely certain, but key elements have been vali- tractile and fibrogenic phenotype, as well as modulation
dated by animal and human studies of liver injury. During of growth factor signaling are the cardinal features of the
injury the behavior of stellate cells is regulated by para- initiation phase of HSC activation.
crine interactions with damaged hepatocytes and endo- PDGF receptors are members of the receptor tyrosine
thelial cells; activated platelets, Kupffer cells, and kinase superfamily that acts via protein phosphorylation
infiltrating leukocytes; and other stellate cells and hepatic cascades. PDGF induces migration through signaling
myofibroblasts. These interactions are mediated by pathways that involve PI3K and p38 MAPK. PDGF binds
growth factors, regulatory peptides and lipids, cytokines, its receptors; the receptor subunits dimerize with subse-
ECM components, and toxic metabolites (Table 3-4). quent phosphorylation of the tyrosine residues in the
Stellate cells and hepatic myofibroblasts themselves can intracellular domain. This leads to Ras-MAPK pathway
secrete soluble and insoluble factors that can act in para- activation, signaling through the PI3K-Akt/protein kinase
crine or autocrine fashion, including the following: B (PKB) pathway and mobilization of intracellular calcium
• TGF-β ions to activate protein kinase C (PKC) family mem-
• Platelet-derived growth factor (PDGF) bers.54,65 Activation of the PDGF signal transduction
54 PART I General Considerations

TABLE 3-4 Effects of Selected Mediators of Hepatic Fibrosis

Molecule Source Effects on Fibrogenic Cell Functions

Receptor Tyrosine Kinase Ligands

Transforming GF-β K, F, E, P (+) fibrogenesis, migration; (−) proliferation,
fibrolysis
Platelet-derived GF B, K, F, P (+) proliferation; (±) migration; (−)
contraction
Insulin-like GF I H, E, P (+) proliferation
Epidermal GF P (+) proliferation, migration
Vascular endothelial GF H, F, E, P (+) proliferation; (−) contraction
G-protein–Coupled Receptor Ligands
Endothelin-1 E, F (+) migration, contraction; (±) proliferation
Lysophosphatidic acid P (+) migration, contraction
Angiotensin II F (+) proliferation, fibrogenesis, contraction
Thrombin F (+) proliferation, contraction
Leptin F (+) fibrogenesis; (−) fibrolysis
Tumor necrosis factor-α (TNF-α) K (+) apoptosis
Interleukin-1 K, E (+) fibrogenesis
Interleukin-4 K (+) fibrogenesis
Interleukin-6 K (+) fibrogenesis
Interleukin-10 K (−) fibrogenesis
Interleukin-13 K (+) fibrogenesis
Interferon-γ K (−) fibrogenesis, migration
Monocyte chemotactic protein-1 F (+) migration
Integrin Receptor Ligands
Collagen I F (+) proliferation, migration, fibrolysis
Collagen III F (+) proliferation
Collagen IV F (+) proliferation, fibrolysis; (−) fibrogenesis
Fibronectin E, F (+) fibrogenesis
Miscellaneous Factors
Reactive oxygen intermediates H, K, E (+) fibrogenesis
Lipid peroxides H, K (+) fibrogenesis
Nitric oxide E, H, K (−) proliferation, contraction

B, Biliary epithelium; E, sinusoidal endothelium; F, stellate cells and myofibroblasts; GF, growth factor; H, hepatocytes; K, Kupffer and other
inflammatory cells; P, platelets; (+), stimulate; (−), inhibit.

cascade induces HSCs to express the contractile, fibro- within injured areas of the liver through distinct effects on
genic phenotype and correlates with the degree of fibrosis chemotaxis and proliferation that are mediated by discrete
and inflammation. The PI3K signaling pathway, leads to signal transduction pathways.
Akt and p70s6 kinase activation, resulting in increased
HSC proliferation and chemotaxis. All these events ulti- Effects of Transforming Growth Factor-β. The most
mately lead to cellular proliferation. Inhibition of the well-characterized component of hepatic scar is collagen
PDGFR-β chain has shown promise as an antifibrotic type I. It is the prototype constituent of the matrix in
agent. In fact, sorafenib, a receptor tyrosine kinase inhibi- fibrotic liver, which is regulated both transcriptionally
tor targeting the PDGF receptor and the Raf/ERK signal- and posttranscriptionally in HSCs by a growing number
ing pathway, is effective in patients with advanced of stimuli and pathways. The most potent stimulus for
hepatocellular carcinoma and displays antifibrotic activity production of collagen I and other matrix constituents
in animal models of fibrosis.54,66 PDGF is also a potent by stellate cells is TGF-β. This cytokine, which is pro-
stimulus for the proliferation of fibrogenic cells in the duced by Kupffer cells, platelets, and sinusoidal endothe-
liver. However, PDGF-induced proliferation is mediated lial cells in response to injury, is derived from both
primarily by pathways that signal through Ras/MEK/ paracrine and autocrine sources. TGF-β induces sinusoi-
ERK, rather than p38 MAPK.67 To make matters even dal endothelial cells to express a fibronectin splice vari-
more complex, PDGF increases the synthesis of prosta- ant that stimulates stellate cell fibrogenesis. In fibrogenic
glandin E2, which inhibits proliferation through a cyclic cells, TGF-β stimulates its own expression, which per-
3′,5′-adenosine monophosphate (cAMP)-dependent mits the development of a powerful autocrine-positive
mechanism. This implies the possibility of a PDGF-trig- feedback loop. TGF-β is stored as an inactivated protein
gered negative feedback loop that would self-limit the bound to a latency-associated peptide. TGF-β signaling
growth of these cells. Taken together, these data suggest is modulated by the conversion from its latent to its
that PDGF facilitates accumulation of fibrogenic cells active form by sinusoidal endothelial cells and by
 3 Molecular and Cellular Basis of Liver Failure 55

augmenting the expression and ligand affinity of TGF-β light-chain phosphorylation through G-protein–coupled
receptors in the fibrogenic cells of the liver. Once acti- activation of Ca2+-dependent myosin light-chain kinase
vated, TGF-β signals via its cognate receptors to Sma and rho-dependent inhibition of myosin phosphatase.68
and Mad (SMAD) proteins, which lead to induction of Phosphorylation of the myosin light chain activates myo-
collagen production. Quiescent HSCs are induced by sin, which interacts with bundles of polymerized actin,
TGF-β to transdifferentiate into myofibroblasts that resulting in the generation of tension. The tension gener-
secrete ECM. ated by these fibrogenic cells permits orientation and
In the cirrhotic livers of humans the expression of remodeling of the ECM. Evidence also suggests that
TGF-β is greatest in areas where ECM is most abundant alterations in the tension generated by stellate cells,
and is the principal stimulus for ECM accumulation. which encircle the sinusoids, modulates hepatic blood
TGF-β induces the accumulation of ECM by enhancing flow.54,69
ECM synthesis and reducing ECM degradation. In addition to its role in the regulation of contractile
Although the molecular mechanisms linking TGF-β to tension, ET-1 modulates the migration and proliferation
its observed effects on fibrogenic cells are incompletely of fibrogenic cells in the liver. The effect of ET-1 on
understood, evidence suggests that they involve the reg- migration is predicted by the essential role that retrograde
ulation of transcription by pathways that signal through contraction plays in cellular locomotion. As expected,
SMAD-related proteins. Signals downstream of TGF-β ET-1 stimulates migration through a rho-associated,
converge on SMADs, upon which many extracellular kinase-dependent pathway. The role that this peptide
and intracellular signals converge to fine-tune and plays in the regulation of proliferation is more complex.
enhance the effects of TGF-β during fibrogenesis. Also, ETA stimulates proliferation through Ras/MEK/ERK-
TGF-β enhances the transcription of collagen I, proba- signaling pathways, whereas ETB inhibits proliferation
bly by reducing the expression of negative regulators of through a prostaglandin/cAMP-signaling pathway.
transcription and through putative TGF-β responsive Because the relative ratio of ETB:ETA increases with time
elements in the gene encoding for collagen I, while in after injury, the effects of ET-1 on cell growth change
turn collagen I upregulates synthesis of other ECM with the duration of injury.
components, including fibronectin and proteoglycan. As discussed, PDGF, TGF-β, and ET-1 each act via
TGF-β inhibits ECM degradation by reducing synthesis multiple signal transduction pathways to regulate pat-
of important MMPs (e.g., MMP-1, MMP-2, MMP-3) terns of cellular behavior that are essential for the devel-
and by upregulating plasminogen activator inhibitor opment of cirrhosis:
(PAI) and tissue inhibitors of metalloproteinases • PDGF is a powerful regulator of chemotaxis and
(TIMPs), which are proteins that inhibit the breakdown proliferation.
of ECM. MMP-1 is the main protease that can degrade • TGF-β strongly induces the accumulation of ECM
type I collagen. Stellate cells express MMP-1 messenger but also facilitates migration and inhibits
RNA (mRNA), and also produce functional TIMP-1 and apoptosis.
TIMP-2. Stellate cells express uroplasminogen activator • ET-1 is a strong agonist for contraction but also
receptor and its inhibitor (PAI-1), as well as other com- affects chemotaxis and proliferation.
ponents of the plasmin system. These findings suggest Yet, PDGF, TGF-β, and ET-1 represent only three of
that stellate cells contain most, if not all, of the molecules the numerous soluble and insoluble molecules that are
necessary to either activate or inhibit metalloprotein- produced in response to hepatic injury (see Table 3-4).
ases.60 TGF-β also stimulates collagen in stellate cells All of these other injury mediators also have pleiotropic
through an MEK and ERK, hydrogen peroxide, and effects that are mediated by signal transduction pathways
CCAAT enhancer binding protein β [C/EBP-β]– that work in a coordinated manner. Thus the molecular
dependent mechanism. In addition to regulating the and cellular mechanisms underlying the development of
accumulation of ECM, TGF-β also modulates other pro- cirrhosis are incredibly complex. Despite this complexity,
cesses important for the development of fibrosis. TGF-β there have been advances to develop preventive and ther-
stimulates the migration of stellate cells and inhibits apeutic strategies for the management of cirrhosis.
apoptosis. Surprisingly, in different studies TGF-β stimu- Indeed, pharmacological antagonists of each of the three
lated, inhibited, or had no effect on proliferation. It is injury mediators discussed here prevent or reduce fibrosis
uncertain whether this phenomenon has physiological in animal models of chronic liver injury.62,63,70
importance or is simply a technical artifact. It is signifi-
cant, however, that TGF-β upregulates the expression of
Summary of the Pathogenesis of Cirrhosis
PDGF receptors, which play a fundamental role in fibrosis,
as described previously. It is increasingly clear that fibrosis of the liver is medi-
ated by the same molecular signals and cellular processes
Effects of Endothelin-1. Endothelin-1 (ET-1) is a vaso- that govern the normal wound-healing response. It is
active peptide that strongly stimulates generation of con- the location, duration, and intensity of liver injury that
tractile tension by the fibrogenic cells of the liver. dictate clinical outcome. For example, in most forms of
Sinusoidal endothelial cells and fibrogenic cells secrete chronic liver injury, including hepatitis C and autoim-
this peptide in response to hepatic injury. ET-1 binds to mune hepatitis, fibrosis is initially most prominent in the
ETA and ETB receptors, which are G-protein–coupled portal region, the location most affected by these dis-
seven-transmembrane receptors. Binding of ET-1 to its eases. In contrast, alcoholic and nonalcoholic steatohep-
cognate receptors causes an augmentation of myosin atitis, both of which are characterized by early lobular
56 PART I General Considerations

injury, initially display lobular fibrosis, especially around also involved in cell death, therapeutic targets will need to
the sinusoids. If hepatic injury is transient, such as occurs be chosen with great care.
with hepatitis A, complete healing occurs without any In the case of cirrhosis, efforts will be directed toward
evidence of excess accumulation of ECM. Conversely, the prevention or reversal of fibrosis. This will not be a
liver fibrosis occurs only months to decades after onset simple task for two major reasons. First, fibrosis results
of chronic hepatic injury. The clinical observation that from the liver’s response to injury, albeit a sustained and
only a portion of patients suffering from chronic liver exuberant response. Thus safe and effective therapies for
diseases—such as hepatitis B and C, alcoholic and nonal- cirrhosis must blunt the injury response that causes fibro-
coholic steatohepatitis, and hereditary hemochromato- sis without compromising the normal wound-healing
sis—develop cirrhosis suggests that there may be an response. Second, the large majority of patients with
intensity threshold for a given individual that must be chronic liver disease do not develop cirrhosis, and even
crossed in order for fibrosis to ensue. Finally, it has those who do often live many years before developing
become generally recognized that if the source of chronic clinical disease. Therefore improved strategies for deter-
liver injury is removed, fibrosis can be reversed.56,57 This mining which patients have the greatest disposition to
has been demonstrated in a number of liver diseases, progressing to decompensated cirrhosis are critical. Oth-
including biliary obstruction, hepatitis C, and autoim- erwise, any successful therapy for prevention must be
mune hepatitis. Whether cirrhosis itself can be signifi- very safe, because a large number of patients need to be
cantly reversed remains controversial. The pathogenesis treated for one to benefit. It is likely that a greatly
of cirrhosis is complex and is mediated by the dynamic increased understanding of the molecular and cellular
and multifaceted response of the fibrogenic cells of the mechanisms underlying fibrosis will be required to over-
liver to chronic injury. come the hurdles necessary to create effective and safe
therapies for cirrhosis.
PERSPECTIVES AND FUTURE
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 CHAPTER 4

Influence of Transplantation
on Liver Surgery
Jonathan R. Hiatt • Ali Zarrinpar • Ronald W. Busuttil

CHAPTER OUTLINE

PHYSIOLOGY AND ANATOMY OF THE LIVER AND Liver Trauma

BILIARY SYSTEM Liver Resection
Liver Growth and Regeneration Biliary Reconstruction
Hepatic Vascular and Biliary Anatomy SURGICAL EDUCATION
OPERATIVE TECHNIQUES SUMMARY
Exposure and Mobilization of the Liver

Liver transplantation is the gold standard treatment for Gene expression profiles of regenerating hepato-
patients with end-stage liver disease. The great success of cytes continue to be analyzed and are helping to refine
liver transplantation has produced a ripple effect on many our understanding of the role of hepatocyte growth
other medical and scientific disciplines and, in particular, factors accumulating in the serum after partial resec-
on general and hepatobiliary surgery. The anatomical tions.1 Growth factors may be synthesized in the liver
principles, technical refinements, and basic scientific or other tissues and include insulin, glucagon, norepi-
underpinnings of liver transplantation have immediate nephrine, vasopressin, and complement components,
relevance to the work of surgeons with interests in non- among others. The discovery that early activation of
transplant hepatobiliary surgery, trauma surgery, surgical the cytokines interleukin-6 and tumor necrosis factor-α
critical care, and surgical education. The addition of trans- serves to trigger the regenerative response has been
plantation as a therapeutic option for patients who were further explored. The generation of genetically modi-
previously considered at high risk for standard surgical fied mice with alterations in the expression levels of
therapy, such as patients with potentially resectable hepatic growth factors, cytokines, and their receptors and the
malignancies in the setting of cirrhosis, has changed man- use of these mice in liver regeneration studies have
agement algorithms and enabled more aggressive resec- provided some exciting results, including characteriza-
tions. This chapter examines the effects of the liver tion of synergistic functions of transforming growth
transplantation experience on modern liver surgery. factor-β and activin, the role of insulin-like growth fac-
tors and the insulin system in liver regeneration, and
the contribution of hepatocyte growth factor. Finally,
PHYSIOLOGY AND ANATOMY OF THE growing evidence suggests that the same cytokine-
dependent activation processes that drive hepatic
LIVER AND BILIARY SYSTEM regeneration are also responsible for the physiological
Liver Growth and Regeneration and histological changes typically seen in posttrans-
plant ischemia-reperfusion injury.6,7 This research is
The liver occupies a central role in the complex meta- potentially applicable to treatment of patients with loss
bolic interactions among organ systems during stress and of liver substance from a variety of causes, including
illness. This delicate homeostasis is further balanced by cirrhosis, inflammation, infection, trauma, and surgical
the remarkable capacity of the liver to expand hepatocyte resection. It may offer a better understanding of the
mass rapidly in response to changing metabolic demands phenomenon of small-for-size syndrome, character-
or significant hepatic injury. Simultaneous advances in ized by prolonged cholestasis and graft dysfunction
critical care, perioperative management, pharmacology, after partial and living donor liver grafts.8 Liver trans-
and oncology have paralleled the advances in liver trans- plantation has also spurred investigations into the gen-
plantation over the last 5 decades, stimulating a rapid eration of liver p­ rogenitor cells and stem cells9 and
growth of research in hepatic regeneration, ischemia- liver assist devices10 as an alternative to the use of
reperfusion injury, and acute liver failure.1-5 whole organ transplantation.

58
 4 Influence of Transplantation on Liver Surgery 59

Type 1
n = 757 Type 2 Type 3
n = 97 n = 106

Left
gastric a.

Common Splenic a.
hepatic a.
SMA

Type 4 Type 5
n = 23 n = 15

FIGURE 4-1 n Hepatic arterial anatomy variants. Dotted lines indicate that the variant artery may be accessory (if branch shown by
dotted line is present) or replaced (if absent). Type 1—normal; Type 2—replaced (accessory) left hepatic artery from left gastric; Type
3—replaced (accessory) right hepatic artery from superior mesenteric artery (SMA); Type 4—double replaced system; Type 5—common
hepatic artery (CHA) from SMA. In two patients (not shown), the CHA arose directly from the aorta. (From Hiatt JR, Gabbay J, Busuttil
RW. Surgical anatomy of the hepatic arteries in 1000 cases. Ann Surg. 1994; 220:50-52.)

Hepatic Vascular and Biliary Anatomy TABLE 4-1 Hepatic Arterial Anatomy
The donor and recipient hepatectomy procedures offer a
Pattern Description Frequency (%)
broad experience in upper abdominal surgery and pro-
vide supreme lessons in surgical anatomy, including Type 1 Normal, with the common 76
exposure, surgical approach, mobilization techniques, hepatic artery arising from
the celiac axis to form the
and hepatic vascular isolation, as well as an appreciation gastroduodenal and proper
for the variations of hepatic vascular and biliary anatomy. hepatic arteries, and the
Arterial variants have long been recognized,11 and portal proper hepatic dividing
venous and biliary anomalies are also recognized with distally into right and left
branches
growing frequency.12-16 The UCLA series of donor hepa-
Type 2 Replaced or accessory left 10
tectomies shows that specific variations in hepatic arterial hepatic artery arising from
anatomy are particularly common (Fig. 4-1).17 In this the left gastric artery
series (Table 4-1), subsequently corroborated by oth- Type 3 Replaced or accessory right 11
ers,18-20 24% of donor livers had anomalous hepatic arte- hepatic artery originating
rial supply, most often a replaced or accessory right from the superior mesenteric
hepatic artery arising from the superior mesenteric artery artery
(11%), followed by a replaced or accessory left hepatic Type 4 Both right and left hepatic 2.3
arteries arising from the
artery arising from the left gastric artery (10%). Aberrant superior mesenteric and left
portal venous anatomy is present in 20% to 35% of livers. gastric arteries, respectively
Portal vein trifurcation or an aberrant branch from the Type 5 Entire common hepatic artery 1.5
left portal vein supplying the right anterior lobe was the arising as a branch of the
most frequent anomaly (Table 4-2). superior mesenteric artery
The high incidence of biliary complications after split Type 6 Common hepatic artery 0.2
originating directly from the
and living donor liver transplantation has led to a greater aorta
interest in the common variants of biliary anatomy (Table
4-3). These include trifurcation of the common hepatic
duct into left, right anterior, and right posterior ducts,
with no significant length of right hepatic duct (12%), and
aberrant drainage of the right segmental duct into the left
60 PART I General Considerations

TABLE 4-2 Portal Venous Anatomy

Pattern Description Frequency (%)
Type 1 Normal: main PV divides into the 65-80
left PV and right PV; the right PV
then divides into right anterior
PV and right posterior PV
Type 2 Trifurcation: main PV divides 9-27
into the left PV, right anterior
PV, and right posterior PV all
at the same point
Type 3 Main PV divides into the right 10-35
posterior PV and a common
trunk; the common trunk then
divides into the left PV and
right anterior PV

PV, Portal vein.

TABLE 4-3 Biliary Anatomy

Pattern Description Frequency (%)
Type A Normal: short vertical right 57
hepatic duct joins a longer FIGURE 4-2 n Dissection of the right retrohepatic space during
horizontal left hepatic duct recipient hepatectomy demonstrates complete access to the ret-
near the hilar plate to form rohepatic vena cava. The right triangular ligament has been
the CHD divided, the liver is elevated upward and to the left, and the
Type B Trifurcation of CHD into right 12 suprahepatic and infrahepatic venae cavae are surrounded with
anterior, right posterior, and tapes.
left hepatic ducts
Type C Aberrant drainage of a right 20
segmental duct into the CHD
(right posterior more
OPERATIVE TECHNIQUES
commonly than right
anterior) Exposure and Mobilization of the Liver
Type D Aberrant drainage of a right 6
segmental duct into the left Both the donor and recipient operations depend on pre-
hepatic duct (right posterior cise mobilization of the liver by division of the major liga-
more commonly than right mentous attachments. The approach in which total
anterior) exposure of the upper abdomen is gained via a transverse
Type E Absence of confluence; a 3 upper abdominal incision, with selective use of a sternal
convergence of two or more
ducts from either lobe to
extension, has largely eliminated the highly morbid right
form CHD thoracotomy as a component of elective liver surgery.24
Type F Absence of right hepatic duct; 2 The principles of liver mobilization and hepatic vascular
right posterior duct drains isolation are particularly applicable to liver trauma and
into cystic duct liver resection.
CHD, Common hepatic duct.
From Chamberlain RS, Blumgart LH. Essential hepatic and biliary Liver Trauma
anatomy for the surgeon. In: Chamberlain RS, Blumgart LH, eds.
Hepatobiliary Surgery. Georgetown, TX: Landes Bioscience, The liver and spleen are the solid viscera most commonly
2003:1-19. injured in major abdominal trauma. Although infrequent,
retrohepatic vena caval and hepatic venous injuries are
hepatic duct (6%). The increasing experience with split particularly devastating, in part because of difficulty in
and living donor liver transplantation and the wider appli- gaining access to the privileged portion of the right sub-
cation of surgical treatment for hepatic malignancies obli- phrenic space containing the segment of the inferior vena
gate familiarity with these anatomical variations, which cava (IVC) between the renal veins and the right atrium
will provide challenges in complex reconstructions. (Fig. 4-2). In hypovolemic trauma patients, elimination
Recognition of the anatomy of the dual hepatic blood of venous return via the suprahepatic IVC produces car-
supply and dependence of hepatocellular carcinoma on the diac arrest. In contrast, experience from dedicated liver
arterial supply has enabled transcatheter techniques to transplant centers demonstrates that in resuscitated
direct chemotherapy, radioactivity, and embolization mate- euvolemic patients, temporary total occlusion of the por-
rial via the hepatic artery to treat these tumors.21,22 The dual tal structures and the suprahepatic and infrahepatic vena
hepatic blood supply has also led to increased use of portal cavae (Fig. 4-3) is well tolerated25-28 and can be combined
vein embolization before major liver resection to augment with a portosystemic shunt procedure with or without
the size of the liver that will remain postoperatively.23 venovenous bypass to permit treatment of other injuries
 4 Influence of Transplantation on Liver Surgery 61

IVC IVC

Hepatic a.

Hepatic a.

Portal v. CBD

Common bile duct

IVC
FIGURE 4-3 n Technique of hepatic vascular isolation with occlu-
sion of porta hepatis and vena cavae above and below the liver.
These methods are used for hepatic resection in euvolemic Portacaval shunt
patients. In the hypovolemic trauma patient, aortic occlusion is
FIGURE 4-4 n Total hepatectomy with temporary end-to-side por-
added to facilitate repair of injured hepatic veins or retrohepatic
tacaval shunt allows maintenance of portal venous return dur-
vena cava (see Fig. 4-2). IVC, Inferior vena cava.
ing an extended anhepatic phase. CBD, Common bile duct; IVC,
inferior vena cava.
or delay of definitive repair until resuscitation is com-
pleted. With the addition of aortic occlusion for the transplantation as a continuum within an obligatory
hypovolemic patient, vascular isolation continues to play armamentarium.34
a critical role in management of injuries to the retrohe- New resection techniques have improved the surgical
patic IVC.29,30 Several reports31 document the efficacy of approach to challenging liver and retroperitoneal
total hepatic vascular isolation with selective addition of a tumors39-41 where the use of portal clamping, with or
portal decompressive procedure for major hepatic without caval occlusion, diminishes blood loss and allows
trauma.32 In addition, recent evidence suggests that in for safe management of the hepatic veins involved or
situ cold perfusion may significantly extend the duration abutted by the tumor mass.42,43 More recent experience
of total vascular isolation tolerated in these patients. For with intermittent portal vascular occlusion (ischemic pre-
major liver injuries with massive parenchymal destruc- conditioning) for major resection procedures shows that
tion, liver avulsion, or unreconstructable damage to the hepatic parenchymal ischemia is well tolerated and sig-
porta hepatis, total hepatectomy with orthotopic trans- nificantly extends the safe period of ischemia while simul-
plantation is a potential treatment that has been used taneously reducing the subsequent reperfusion injury.44-46
occasionally (Fig. 4-4).33 Taken together, these methods Experience with in situ hypothermic perfusion for hepatic
derived from liver transplantation have given surgeons resection47 has stimulated the development of the more
greater ability to treat patients with severe traumatic liver radical ex situ, or extracorporeal, bench procedures for
injuries and have improved the outlook for patients who resection of tumors otherwise deemed untreatable by
previously had few treatment options. conventional means.48,49 The ensuing increase in liver
resections (and transections for living donor operations)
has also stimulated research regarding improvements in
Liver Resection liver transection techniques, though none have proven to
Over the past 30 years, developments in liver resection be superior to the clamp-crush technique.50
and liver transplantation have been intertwined.34 Trans-
plant surgeons’ intimate familiarity with subsegmental Biliary Reconstruction
liver anatomy, further strengthened by experience using
reduced-size grafts for transplantation, has immediate Construction of the biliary anastomosis is a crucial com-
application to techniques of liver resection for benign and ponent of the transplant operation. Although early expe-
malignant processes. As an example, the surgical treat- rience relied almost exclusively on drainage through a
ment of isolated caudate lobe lesions, once considered Roux-en-Y choledochojejunostomy,51 later studies showed
extremely hazardous, is now easily accomplished using that preservation of the delicate blood supply to the bile
methods of caval preservation (the piggyback technique) duct would allow reconstruction using a duct-to-duct
and generous exposure gained by dividing the gastrohe- anastomosis.
patic ligament.35-37 The same is true for mesohepatec- To investigate healing of the biliary anastomosis,
tomy.38 An emerging concept is one of liver resection and Northover and Terblanche52 performed polyester resin
62 PART I General Considerations

cast studies of the vascular supply to the supraduodenal evolved from infrequent, exceedingly risky operations
common bile duct. These data are of interest to all bili- fraught with high mortality to complex procedures regu-
ary surgeons. The blood supply was found to arise from larly performed in most tertiary centers. Liver transplan-
the right hepatic and cystic arteries above and the retro- tation encompasses crucial anatomical and technical
duodenal branch of the gastroduodenal artery below. lessons for the general surgeon, represents an important
A previously undescribed retroportal artery also was component of surgical training in the era of minimally
identified. invasive surgery, and has provided a profound stimulus to
Currently the preferred reconstruction is by choled- technical and scientific innovation in the surgery of liver
ochocholedochostomy when the recipient common bile disease. This fertile interaction among related surgical
duct is available, reserving the more difficult and time- disciplines should not be overlooked when the benefits of
consuming Roux-en-Y choledochojejunostomy for a the procedure are tallied.
donor-recipient size mismatch or an inadequate recipient
bile duct. Considerable experience in bile duct recon-
struction has grown from the living donor liver trans- Pearls and Pitfalls
plantation, in which multiple small-caliber ducts are
frequently encountered.53,54 Important advances include • Similar cytokine-dependent activation processes drive
the use of magnification to facilitate the precise place- the physiological and histological changes in hepatic
ment of fine sutures, the use of stents in small choledo- regeneration and ischemia-reperfusion injury.
chojejunal anastomoses, and an algorithmic approach to • A quarter of all livers have an anomalous hepatic arte-
the evaluation and treatment of biliary complications. rial supply, most often a replaced or accessory right
Biliary complications include leaks, strictures, and hepatic artery.
• Aberrant portal venous anatomy (trifurcation or
problems with the Roux-en-Y limb.55,56 Various radio-
branching of the right anterior vein from the left) is
logical procedures are important for diagnosis and present in up to a third of all livers.
management. These include nuclide cholescintigraphy • The most common variant of biliary anatomy is the
and magnetic resonance cholangiography to demon- trifurcation of the common hepatic duct, present in
strate routes of bile flow and invasive procedures such 12% of livers.
as percutaneous transhepatic cholangiography, endo- • Total hepatic vascular isolation, with or without portal
scopic retrograde cholangiography, stricture dilation, decompression or in situ cold perfusion, permits the
and stent placement for definitive therapy of specific treatment of severe traumatic liver injuries.
complications.35,55,57 • Intermittent portal vascular occlusion significantly
prolongs the safe period of ischemia during challeng-
ing liver and retroperitoneal resections.
• The organ procurement operation and graft prepara-
SURGICAL EDUCATION tion, in addition to the transplant operation itself, ex-
pose trainees to the privileged and delicate anatomy
As a consequence of advances in the application of lapa- of the biliary and upper gastrointestinal systems, thus
roendoscopic techniques to general surgical procedures,    enhancing teaching and exploration.
most common biliary and upper gastrointestinal opera-
tions are now performed laparoscopically. This places
training of open biliary and upper gastrointestinal sur-
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11. Michels NA. The hepatic, cystic and retroduodenal arteries and 36. Midorikawa Y, Takayama T. Caudate lobectomy (segmentectomy
their relations to the biliary ducts with samples of the entire celiacal 1) (with video). J Hepatobiliary Pancreat Sci. 2012;19:48-53.
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13. Nakamura T, Tanaka K, Kiuchi T, et al. Anatomical variations and 38. Mehrabi A, Mood ZA, Roshanaei N, et al. Mesohepatectomy as an
surgical strategies in right lobe living donor liver transplantation: option for the treatment of central liver tumors. J Am Coll Surg.
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14. Abdel-Misih SR, Bloomston M. Liver anatomy. Surg Clin North 39. Ryan Jr JA, Faulkner 2nd DJ. Liver resection without blood trans-
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15. Sahani D, D’Souza R, Kadavigere R, et al. Evaluation of living liver 40. Emre S, Schwartz ME, Katz E, Miller CM. Liver resection under
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20. Ugurel MS, Battal B, Bozlar U, et al. Anatomical variations of 45. Petrowsky H, McCormack L, Trujillo M, et al. A prospective, ran-
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with multidetector CT angiography. Br J Radiol. 2010;83:661-667. clamping versus ischemic preconditioning with continuous clamp-
21. Wong R, Frenette C, Gish R. Hepatocellular carcinoma: locore- ing for major liver resection. Ann Surg. 2006;244:921-928, discus-
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intraarterial therapies: rationale and overview. Radiology. 2011;259: tent Pringle manoeuvre. Br J Surg. 2011;98:1236-1243.
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for major hepatic and caval trauma. J Trauma. 1995;39:671-673. reconstruction in adult living donor liver transplantation. Hepatobi-
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liver transplantation. Surgery. 1991;109:792-795. complications in adult living donor liver transplantation by magnetic
32. Biffl WL, Moore EE, Franciose RJ. Venovenous bypass and resonance cholangiography. Transplantation. 2008;85:1569-1572.
hepatic vascular isolation as adjuncts in the repair of destructive 56. Takatsuki M, Eguchi S, Kawashita Y, Kanematsu T. Biliary
wounds to the retrohepatic inferior vena cava. J Trauma. complications in recipients of living-donor liver transplantation.
1998;45:400-403. J Hepatobiliary Pancreat Surg. 2006;13:497-501.
33. Angstadt J, Jarrell B, Moritz M, et al. Surgical management of 57. Shen XD, Ke B, Zhai Y, et al. Absence of toll-like receptor 4
severe liver trauma: a role for liver transplantation. J Trauma. (TLR4) signaling in the donor organ reduces ischemia and reper-
1989;29:606-608. fusion injury in a murine liver transplantation model. Liver Transpl.
34. Iwatsuki S, Starzl TE. Personal experience with 411 hepatic resec- 2007;13:1435-1443.
tions. Ann Surg. 1988;208:421-434.
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1993;176:401-402.
 CHAPTER 5

Organ Allocation: The U.S. Model

Khalid Khwaja • Elizabeth A. Pomfret

CHAPTER OUTLINE

HISTORICAL PERSPECTIVE AND LEGISLATION IMPACT OF MELD-BASED ALLOCATION

ETHICAL PRINCIPLES IN LIVER ALLOCATION FUTURE U.S. POLICY
THE CURRENT ALLOCATION SYSTEM (MELD)
Hepatocellular Carcinoma
Other MELD Exceptions

HISTORICAL PERSPECTIVE AND offered mainly using recipient waiting time, with little
LEGISLATION importance given to recipient need or illness.
One of the earliest OPOs, the South East Organ
The process of liver allocation in the United States has Procurement Foundation (SEOPF), was established in
evolved significantly over the past 4 decades. At the time Richmond, Virginia, in 1968.8 It was instrumental in
of the first transplants there was no formal allocation sys- the development of an early organ allocation system and
tem.1,2 There were no established criteria defining brain registry of potential recipients. In 1977 SEOPF formed
death, and donor surgery proceeded only after cardiac the first national, computer-based matching system,
death. Transplants were limited to a few centers and a called the United Network for Organ Sharing (UNOS).
few select recipients. Donors were usually identified from In 1984 Congress passed the National Organ Trans-
within a transplant center, and the organs obtained were plant Act (NOTA), which remains the single most
transplanted into a patient from that center. Occasionally important transplant legislation in the United States.9
media sources were used successfully to help obtain an Among many things, the act outlawed the exchange of
organ for an individual recipient.3 As a result of rapid organs for “valuable consideration,” effectively making
growth in kidney transplantation, the Uniform Anatomi- the sale of organs for transplantation illegal in the
cal Gift Act was passed in 1968.4 This provided a legal United States. It also directed the Secretary of the
basis for the use of organs and tissue for transplantation Department of Health and Human Services to issue a
and research. At the same time the Ad Hoc Committee of final rule for regulation of organ allocation and trans-
the Harvard Medical School published their criteria for plant policy and led to the establishment of the Organ
defining brain death.5 Organs procured after brain death Procurement and Transplantation Network (OPTN),
but while cardiac function remained sufficient to main- the agency charged with increasing both the supply of
tain organ perfusion were less subject to warm ischemia organs for transplantation and the efficiency and equity
damage and could be stored for longer times. This opened with which they are distributed.
the way for wider organ sharing. Brain death was legally In 1986 UNOS, now separate from the SEOPF, was
recognized with the passage of the Uniform Brain Death awarded the federal contract to administer the OPTN
Act in 19786 and the Uniform Determination of Death and the national Scientific Registry of Transplant Recip-
Act in 1980.7 ients (SRTR). The mission of the SRTR is to improve
The rapid growth of transplantation in the 1970s transplant patient outcomes by analyzing current results
highlighted the need for a more regulated and organized and providing individual centers with risk-adjusted,
system of organ distribution. The development of organ impartial information that highlights their strengths and
procurement organizations (OPOs), entities distinct from indicates specific areas in need of improvement. A
a specific transplant center, allowed organ retrieval to be NOTA amendment in 1988 required that all OPOs and
conducted in a more systematic manner. OPOs were transplant centers become members of the OPTN and
being established throughout the country and were work- abide by its policies as a condition for receiving Medicare
ing within their geographical region with one or more and Medicaid reimbursement.10 OPOs were also required
designated transplant centers. There was little in the way to designate the geographical areas they would cover;
of “out-of-region” cooperation or sharing. Organs were these areas are called donor service areas (DSAs). There

64
 5 Organ Allocation: The U.S. Model 65

are currently 58 DSAs spread over 11 UNOS “regions” function, and did not measure severity of liver illness on
(Figs. 5-1 and 5-2). These regions are based on Medicare’s a linear scale. Within the different status categories,
administrative regions for end-stage renal disease waiting time was still the most important determinant of
(ESRD). In fact, much of the preceding policy was ranking. There was concern that the system could be
developed in the context of kidney transplantation, with “gamed,” and there continued to be a vast regional dis-
the rules later applied to liver transplantation. parity in waiting times and severity of illness at the time
Before 1997, livers were allocated based on a point of transplant. Following a report issued by the Institute
system composed of waiting time and patient location of Medicine,13 the Final Rule was amended in 1999 and
(intensive care, hospitalized, ambulatory).11 This system set forth several performance goals. These included
had limitations; candidates could be listed earlier than “more accessible, equitable and efficient allocation of
necessary or simply be hospitalized to obtain more points. organs,” setting “minimal suitability criteria for transplant
In an attempt to more objectively stratify potential liver candidates,” and “distribution of organs over as broad a
recipients, UNOS modified listing criteria in 1997.12 geographical range as possible.”14 This ultimately led to
The new criteria were based on the Child-Turcotte-Pugh the adoption of the Model for End-Stage Liver Disease
(CTP) score (Table 5-1), and candidates were grouped as (MELD) score for liver allocation in February 2002
status 1 (fulminant liver failure) or status 2A, 2B, or 3 (described later).15 Medicare Conditions of Participation
(Table 5-2) in descending order of priority. Although an for organ transplant programs became effective in 2007.16
improvement, this system too had several shortcomings. This delineated the specific requirements for personnel
The CTP score included parameters that were subjective and performance standards needed to maintain eligibility
(ascites and encephalopathy), did not account for renal for Medicare reimbursement.

ORGAN PROCUREMENT ORGANIZATION SERVICE AREAS

WA
MT NH
59 ND VT ME
MN MI
23
OR 34 NY 1
39 MA
WY 4
ID SD 33 7
5 9 6 2
58 NV WI 40 RI
NE IA
53 48 38 36 9 12 3 CT
56 13 52 51 31 IN OH PA 11 NJ
MO IL 3235 37 10 DE
CA WVVA14 MD
UT 50 28
CO KS 49 KY
AZ NM 22
55 TX TN 29 17 NC
44 26 SC 30
57 54 43 OK 41
47 AR 18 15
45 27
25 HI 42 MS AL GA
16 FL
59 LA 19
PR&USVI 46
20
8 AK 21
24

1. New England Organ Bank 21. Lifelink of Southwest Florida 41. Arkansas Regional Organ Recovery Agency
2. Northeast OPO and Tissue Bank 22. Carolina Donor Services 42. Louisiana Organ Procurement Agency
3. NJ Organ and Tissue Sharing Network 23. Pacific Northwest Transplant Bank 43. New Mexico Donor Services
4. Center for Donation and Transplant 24. University of Miami OPO 44. Oklahoma Organ Sharing Network
5. Upstate New York Transplant Services 25. Organ Donor Center of Hawaii 45. Southwest Transplant Alliance
6. New York Organ Donor Network 26. Mid-South Transplant Foundation 46. Texas Organ Sharing Alliance
7. Finger Lakes Donor Recovery Network 27. Lifelink of Georgia 47. Life Gift Organ Donation Center
8. Lifelink of Puerto Rico 28. Kentucky Organ Donor Affiliates 48. Iowa Donor Network
9. Center for Organ Recovery and Education 29. Tennessee Donor Services 49. Mid-America Transplant Services
10. Washington Regional Transplant Consortium 30. SC Organ Procurement Agency 50. Midwest Transplant Network
11. Transplant Resource Center of Maryland 31. Regional Organ Bank of Illinois 51. Nebraska Organ Retrieval System
12. Gift of Life Donor Program 32. Indiana OPO 52. Donor Alliance
13. Nevada Donor Network 33. Transplantation Society of Michigan 53. Intermountain Organ Recovery Systems
14. LifeNet 34. Lifesource Upper Midwest OPO 54. Donor Network of Arizona
15. Alabama Organ Center 35. Ohio Valley Life Center 55. Southern CA Organ Procurement Center
16. The OPO at the University of Florida 36. Lifebanc 56. Golden State Transplant Services
17. Life Share of the Carolinas 37. Lifeline of Ohio Organ Procurement 57. Organ and Tissue Acquisition Center of Southern CA
18. Mississippi Organ Recovery Agency 38. Life Connection of Ohio 58. California Transplant Donor Network
19. Translife/Florida Hospital 39. University of Wisconsin Hospital and Clinic 59. LifeCenter Northwest
20. Lifelink of Florida 40. Wisconsin Donor Network
FIGURE 5-1 n Organ procurement organization service areas as of July 2001 as certified by the Centers for Medicare and Medicaid
Services.
66 PART I General Considerations

ETHICAL PRINCIPLES IN LIVER and donors have the right to direct an organ to a specific
ALLOCATION individual. Finally, the principles of benevolence (doing
good) and nonmalfeasance (doing no harm) are as appli-
Livers remain a scarce resource, and the growth in the cable to organ allocation as they are to other human
transplant waiting list far exceeds the supply of organs.17 endeavors, such as research involving human subjects.18
Available organs must be distributed in a fair and equitable A good allocation system must carefully balance these
manner. Any allocation scheme must take several ethical ethical principles. Using only the principle of justice, one
principles into careful consideration. First is the principle could argue that everyone should be transplanted,
of justice, which addresses individual need or fairness. For regardless of how sick they were or how poor the pre-
example, directing the next available liver to the sickest dicted outcome. A totally utilitarian approach, such as
candidate is just, as is giving equal access to organs to peo- only transplanting candidates with the best outcomes,
ple of different ages or racial backgrounds, even though would also not be considered fair. Should we not offer
outcomes may vary. Second is the principle of utility, livers to retransplant candidates because they do worse
which addresses the greater benefit of an intervention or than primary transplants? Individual autonomy must be
the needs of society as a whole. For example, a utilitarian respected, but we do not allow people to actively harm
approach would favor allocating organs to those with the themselves, nor would we allow people to choose what
best chance of survival. Third is the principle of autonomy, race or gender should receive their organs.
which respects the individual’s right of self-determination. These ethical principles are at the core of the current
For example, patients have the right to refuse an organ, liver allocation system in the United States.

6 1

7
9
10
2
5 8

11

3
4

FIGURE 5-2 n United Network for Organ Sharing regions.

TABLE 5-1 Child-Turcotte-Pugh Score TABLE 5-2 U

 NOS Status Categories Used for
Ranking Before MELD System
Points
Status 2A CTP score ≥10, ICU care, <7 days to live
1 2 3 Status 2B CTP score ≥10 or ≥7 with refractory
Albumin (g/dL) >3.5 2.8-3.5 <2.8 complications of portal hypertension or
hepatocellular carcinoma meeting
Total bilirubin (mg/dL) <2 2-3 >3 following criteria: one lesion <5 cm in
International <1.7 1.71-2.3 >2.3 diameter OR up to three lesions all <3 cm
normalized ratio in diameter
Ascites None Controlled Poorly Status 3 CTP score ≥7 (minimal listing criteria)
controlled
Encephalopathy None Controlled Poorly CTP, Child-Turcotte-Pugh; ICU, intensive care unit; MELD, Model
controlled for End-Stage Liver Disease; UNOS, United Network for Organ
Sharing.
 5 Organ Allocation: The U.S. Model 67

THE CURRENT ALLOCATION SYSTEM older than 1 year) and the presence or absence of growth
(MELD) failure (see Table 5-3). The PELD score also has been
validated as an accurate predictor of waiting list mortal-
The MELD score was initially developed to estimate the ity.25 Livers from donors 18 years or younger are also first
3-month mortality risk in patients with cirrhosis undergo- allocated to pediatric candidates. When MELD and
ing transjugular portosystemic shunt placement.19 Several PELD scores are equal, the organ will be allocated to the
subsequent studies have validated its ability to predict child, even though greater mortality risk is associated
3-month mortality and survival after various proce- with the MELD score. This reflects a purposeful advan-
dures.20-23 The accuracy of MELD in predicting 3-month taging of the pediatric population to compensate for
transplant waiting list mortality has been validated. The C infrequency of suitably sized and age-appropriate organs.
statistic is 0.83, indicating that the model is robust.24 The The United States is divided into distribution units for
score is based on three objective measures: total bilirubin the purpose of liver allocation. This is a three-tiered sys-
level, serum creatinine level, and INR international nor- tem: local, regional, and national. Local units are geo-
malized ratio (INR) (Table 5-3). UNOS has modified the graphical areas covered by a single OPO and are also
scoring system to cap the lower and upper limits at 6 and referred to as DSAs. A single OPO may serve several
40, respectively. An increasing score indicates increasing transplant centers. The final allocation takes into account
mortality; for example, patients with a MELD of 10 have a both the recipient severity of illness (MELD/PELD
3-month mortality rate of close to 0%, compared to around score) and the distribution units (Table 5-5). In general,
90% for those with a score of 40 (Fig. 5-3). Within DSAs, adult donor livers are offered first to status 1 candidates
livers are allocated to candidates with the highest scores; in within the region in descending point order, then to local
the event that two or more candidates have the same score, candidates with MELD scores ≥35. If there are no local
the liver is allocated to the candidate with the most waiting candidates with a score of 35 or higher, the liver must
time. MELD allocation does not apply to status 1A or 1B first be offered regionally. If livers are not used in the
candidates (Table 5-4), who still take priority. region, they are offered nationally to status 1 candidates
For children 12 years of age and under, the Pediatric first, followed by candidates with a MELD score of 15 or
End-Stage Liver Disease (PELD) score replaces MELD. higher and then to all remaining patients in descending
The calculation is based on serum bilirubin level, INR, point order. There are separate allocation algorithms for
and albumin level and also factors in age (younger than or pediatric donor livers ages 0 to 10 and 11 to 17 years.

TABLE 5-3 MELD and PELD Equations*

Hepatocellular Carcinoma
In their landmark paper, Mazzaferro et al26 demonstrated
MELD score 0.957 × loge(creatinine† × mg/dL) + 0.378 × the efficacy of liver transplantation for hepatocellular car-
loge(bilirubin mg/dL) + 1.120 × loge (INR) +
0.643 × 10 cinoma (HCC) in recipients with defined criteria (a single
PELD score 0.436 (Age‡) − 0.687 × Loge (albumin g/dL) +
0.480 × Loge (total bilirubin mg/dL) +
1.857 × loge (INR) + 0.667 [Growth
failure§(<−2 SD present)] × 10 TABLE 5-4 Definition of UNOS Status 1
*Alllaboratory values less than 1.0 are set at 1.0. Scores are Status 1A Definition
capped at 40.
Fulminant Onset of hepatic encephalopathy within
†Creatinine is capped at 4. If candidate is on dialysis, a creatinine of
hepatic failure 8 weeks of the first symptoms of liver
4 is assigned.
‡Age younger than 1 year is assigned a value of 1, and age older
disease in the absence of preexisting
liver disease and the presence of at
than 1 year is assigned a value of 0. least one of the following: (1) ventilator
§Growth failure is assigned a value of 1, and no growth failure is
dependence, (2) requiring dialysis,
assigned 0. continuous venovenous hemofiltra-
MELD, Model for End-Stage Liver Disease; INR, international tion/hemodialysis, or (3) INR >2.0
normalized ratio; PELD, Pediatric End-Stage Liver Disease; PNF of Within 7 days of implantation with one
SD, standard deviation. transplanted of the following: (1) AST ≥3000 units/L
liver and INR >2.5 OR acidosis (arterial pH
≤7.30 or venous pH of 7.25 or lactate
PELD: 649 Pediatric patients ≥4 mmol/L) or (2) anhepatic
100 Hepatic artery Within 7 days of implantation with
Survival (%)

80 thrombosis evidence of severe liver injury as

60 defined for PNF
40 Wilson’s Acute decompensation
disease
20 MELD: 1230 Adult patients
Status 1B Chronically ill pediatric candidates
0
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 Modified from OPTN policies and bylaws. http://optn.transplant.hrsa
.gov/PoliciesandBylaws2/policies/pdfs/policy_8.pdf. Accessed
Severity score August 30, 2012.
FIGURE 5-3 n Model for End-Stage Liver Disease (MELD) and AST, Aspartate aminotransferase; INR, international normalized
Pediatric End-Stage Liver Disease (PELD) scores plotted as a ratio; PNF, primary nonfunction; UNOS, United Network for
function of mortality risk. Organ Sharing.
68 PART I General Considerations

TABLE 5-5 Donor Liver Allocation Sequence

Sequence Distribution Status/Score
1. Combined local and regional Status 1A candidates in descending point order
2. Combined local and regional Status 1B candidates in descending order
3. Local and regional Candidates with MELD/PELD scores ≥35 in descending order of mortality
risk (MELD) scores, with local candidates ranked above regional
candidates at each level of MELD score
4. Local Candidates with MELD/PELD scores 29-34 in descending order of
mortality risk scores (probability of candidate death)
5. National Liver-intestine candidates in descending order of mortality risk scores
(probability of candidate death)
6. Local Candidates with MELD/PELD scores 15-28 in descending order of
mortality risk scores (probability of candidate death)
7. Regional Candidates with MELD/PELD scores 15-34 in descending order of
mortality risk scores (probability of candidate death)
8. National Status 1A candidates in descending point order
9. National Status 1B candidates in descending point order
10. National Candidates with MELD/PELD scores ≥15 in descending order of mortality
risk scores (probability of candidate death)
11. Local Candidates with MELD/PELD scores <15 in descending order of mortality
risk scores (probability of candidate death)
12. Regional Candidates with MELD/PELD scores <15 in descending order of mortality
risk scores (probability of candidate death)
13. National Candidates with MELD/PELD scores <15 in descending order of mortality
risk scores (probability of candidate death)

Modified from OPTN policies and bylaws. http://optn.transplant.hrsa.gov/PoliciesandBylaws2/policies/pdfs/policy_8.pdf. Accessed.

August 30, 2012.
MELD, Model for End-Stage Liver Disease; PELD, Pediatric End-Stage Liver Disease.

lesion ≤5 cm or up to three lesions, each ≤3 cm). Most allows exception points for the following conditions
HCC patients have normal liver synthetic function, and (MELD 22/PELD 28 with allowance for an increase in
MELD scores do not estimate mortality risk associated points equivalent to a 10% mortality risk every 3 months):
with metastatic HCC. Recognizing this, UNOS incorpo- Hepatopulmonary syndrome: Candidates must have no
rated these “Milan Criteria” in prioritizing transplant can- underlying pulmonary disease, a room air Pao2 of
didates with HCC. Originally patients with stage I disease less than 60 mm Hg and evidence of a shunt (such as
(single tumor <2 cm) received 24 points (15% 3-month a positive “bubble study” on echocardiography).
mortality risk), and those with stage II disease (single Portopulmonary syndrome: This is defined as a mean
tumor ≤5 cm or two to three tumors, all ≤3 cm) received pulmonary artery pressure of greater than 25 mm Hg
29 points (30% 3-month mortality risk). Additional points in the setting of portal hypertension and absence
were given every 3 months, provided candidates remained of other pulmonary pathologic condition. Candi-
within the Milan criteria, equivalent to a 10% mortality dates must have mean pressures controlled to less
risk (3 MELD points). This led to a substantial increase in than 35 mm Hg to remain eligible for exception
the proportion of recipients receiving transplantation for points.
HCC at the expense of candidates with other diagnoses. Cystic fibrosis: Candidates must have impaired pulmonary
A reduction in exception points awarded for HCC was function, defined as a forced expiratory volume in the
instituted in April 2003 (20 MELD points for stage I and first second of expiration (FEV1) less than 40% of
24 points for stage II). It also became apparent that stage I predicted.
candidates did not have a significant 3-month mortality. Familial amyloid polyneuropathy: These candidates must
Consequently stage I candidates receive no exception, and have identification of the TTR gene mutation,
stage II candidates receive 22 MELD points, equivalent to biopsy-proven evidence of amyloidosis, and adequate
a 15% 3-month mortality risk. performance and cardiac status.
Candidates with tumor burden that falls outside the Primary hyperoxaluria: These candidates must be listed
Milan criteria do not receive an exception score. How- for a combined liver and kidney transplant and have
ever, some regions allow exception points for patients liver biopsy–proven alanine-glyoxylate aminotrans-
who have been successfully downstaged using local abla- ferase deficiency. An initial MELD score of 28 and
tive therapies.27 PELD of 40 may be assigned.
Hilar cholangiocarcinoma: These candidates should have
appropriate confirmation of the diagnosis by imag-
Other MELD Exceptions ing, biopsy, or tumor markers and no evidence of
There are several other conditions in which the MELD extra hepatic or intrahepatic metastases. The hilar
score does not reflect the true severity of illness. UNOS mass should be 3 cm or less in diameter and be
 5 Organ Allocation: The U.S. Model 69

unresectable. In addition, centers should submit a

TABLE 5-6 C
 riteria for Simultaneous Liver and
written protocol for multimodality management to
Kidney Transplantation
UNOS before requesting an exception.
Exception scores for other conditions, such as polycys- 1. End-stage renal disease patients with cirrhosis and
tic liver disease, may be granted on a case-by-case basis symptomatic portal hypertension or hepatic vein
after review and approval by a regional review board. wedge pressure with gradient >10 mm Hg
2. Patients with ESLD and CKD with GFR ≤30 mL/min
3. Patients with acute kidney injury, including
IMPACT OF MELD-BASED ALLOCATION hepatorenal syndrome with creatinine ≥2.0 mg/dL
and dialysis ≥8 wk
4. Patients with ESLD and evidence of CKD and kidney
Liver transplant outcomes closely correlate with MELD biopsy demonstrating >30% glomerulosclerosis
score at the time of transplant. In general, recipients with or 30% fibrosis
higher MELD scores have a worse posttransplant sur-
vival but a proportionally greater benefit when compared Modified from Eason JD, Gonwa TA, Davis CL, et al. Proceedings
of Consensus Conference on Simultaneous Liver Kidney
to recipients with lower scores. In fact, in an important Transplantation (SLK). Am J Transplant. 2008;8:2243-2251.
study by Merion et al28 it was shown that there is a CKD, Chronic kidney disease; ESLD, end-stage liver disease; GFR,
“watershed” MELD score, below which transplant car- glomerular filtration rate.
ries a higher mortality risk than remaining wait-listed.
This led to the adoption by UNOS of a “regional share
15” policy in 2005. Accordingly, a liver has to be offered
regionally for candidates with a MELD of 15 or higher centers.29,36 Stricter criteria for combined liver and kid-
before being used locally for candidates with a MELD ney listing have been developed and were recently incor-
score less than 15. porated into UNOS policy (Table 5-6).
In a system that directs organs to the sickest candidates
and essentially eliminates waiting time as a variable, one
would expect both a reduction in waiting list mortality FUTURE U.S. POLICY
and in time to transplant. Since the implementation of
MELD, SRTR data have shown a steady decline in wait- Clearly, implementation of the MELD system has had a
ing list mortality.29 Similarly, median time to transplant positive impact on liver allocation in the United States.
is less in the MELD era, decreasing from 3119 days in Several other countries have also adopted liver allocation
2000 to 382 days in 2009.29 systems based on MELD.37,38 Future U.S. policy will
There was a concern that MELD-based allocation focus on further refining this allocation system. A vast
would lead to worse posttransplant outcomes, given that amount of data has been collected by the SRTR in the
candidates would be sicker at the time of transplant. This past 10 years. The clinical impact of changes in allocation
has clearly not been the case, with patient and graft sur- can be predicted using statistical modeling techniques
vivals unchanged from the pre-MELD era.30 Under cur- such as Liver Simulated Allocation Model (LSAM), and
rent allocation policy, primary and retransplant candidates they will be used to refine proposed changes.39
are treated identically; when adjusted for MELD score at One of the foremost concerns regarding the existing
transplant, posttransplant outcomes are similar for the allocation policy is that there remains a considerable dis-
two groups.31 Racial disparities in liver transplantation parity, both between and within regions, in MELD
after introduction of MELD appear to have disappeared. score at transplant and in waiting list mortality. Achiev-
In the pre-MELD era, African American race was associ- ing more equitable allocation, as recommended by the
ated with a higher likelihood of waiting list death or Final Rule, would require changes in liver distribution
becoming too sick for transplantation compared to white or broader sharing of available organs. To address this,
candidates; there were no significant differences in the several workgroups have been convened by UNOS over
MELD era.32 Women still have a higher waiting list the past few years.
mortality and lower probability of transplant.32 Current liver distribution boundaries in the United
The introduction of MELD has seen a significant States are somewhat arbitrary and largely based on those
increase in the proportion of transplants for HCC. established for kidney transplantation. One proposal is to
Between 1997 and 2002, 4.6% of transplants were for expand distribution units into zones or concentric distance
HCC, increasing to 26% between 2002 and 2007.33 This circles, such as the five zones of distribution used in lung
has led to a revision of the allocation policy as it relates to allocation (0 to 500, 500 to 1000, 1000 to 1500, 1500 to
HCC on two occasions since 2002 and may require further 2500, >2500).40 Modeling data using LSAM show that
modification in the future. Interestingly, survival after liver such a system would lead to greater than two thirds of livers
transplant for HCC has remained unchanged in the being used outside the local area, with a decrease in waiting
MELD era.34 list mortality. Zonal distribution could also be based on
Renal function is an integral component of the population density instead of distance. Several historical
MELD score, and it is therefore not surprising that the and political boundaries will need to be overcome before
risk for posttransplant ESRD is higher in the MELD era implementation of this type of liver distribution.
(14.5% versus 12.8%).35 The rate of combined liver- Another strategy to decrease waiting list mortality would
kidney transplantation has also steadily increased since be the use of broader organ sharing for higher MELD score
2002 but varies considerably among individual candidates. This is already employed for status 1 candidates
70 PART I General Considerations

at a regional level. Expansion of the “regional share 15”

• Since the implementation of MELD there has been a re-
policy to a “national share 15” is under active consider- duction in waiting list mortality and time to transplant in
ation.41 A “regional share 35” policy was recently approved: the United States.
livers would first be allocated locally then regionally to can- • Patient and graft survivals remain the same in the pre- and
didates with MELD scores of 35 or higher, before being post-MELD eras.
offered to local candidates with scores less than 35.42 Mod- • Future liver allocation policy will focus on broader geo-
eling data show that this results in 80 fewer waiting list graphical organ sharing, redefining distribution units, and
deaths with an insignificant increase in the median distance improving the predictive accuracy of MELD.
between donor hospital and transplant center.43
Improving the predictive accuracy of the MELD score
should theoretically result in fewer waiting list deaths.
Several investigators have shown that the addition of
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Liver and Transplantation Committee. Results of the first year of policy_8.pdf
the new liver allocation plan. Liver Transpl. 2004;10(1):7. 43. Washburn K, Pomfret E, Roberts J. Liver allocation and distribu-
31. Kim HJ, Larson JJ, Lim YS, et al. Impact of MELD on waitlist tion: Possible next steps. Liver Transpl. 2011;17(9):1005-1012.
outcome of retransplant candidates. Am J Transplant. 2010 44. Kim WR, Biggins SW, Kremers WK, et al. Hyponatremia and
Dec;10(12):2652-2657. mortality among patients on the liver-transplant waiting list.
32. Moylan CA, Brady CW, Johnson JL, et al. Disparities in liver trans- N Engl J Med. 2008;359(10):1018.
plantation before and after introduction of the MELD score. 45. Ruf AE, Kremers WK, Chavez LL, et al. Addition of serum sodium
JAMA. 2008 Nov 26;300(20):2371-2378. into the MELD score predicts waiting list mortality better than
33. Ioannou GN, Perkins JD, Carithers Jr RL. Liver transplantation MELD alone. Liver Transpl. 2005;11(3):336.
for hepatocellular carcinoma: impact of the MELD allocation sys- 46. Leise MD, Kim WR, Kremers WK, et al. A revised model for end-
tem and predictors of survival. Gastroenterology. 2008 May;134(5): stage liver disease optimizes prediction of mortality among patients
1342-1351. awaiting liver transplantation. Gastroenterology. 2011;140(7):1952.
 CHAPTER 6

Organ Allocation: The

European Models
Lars Bäckman • John L.R. Forsythe • Till Gerling • Guido G. Persijn • Rafael Matesanz •
Gloria de la Rosa • Paolo Muiesan • Andrew Burroughs •
Gabriela A. Berlakovich • William Bennet

CHAPTER OUTLINE

LIVER TRANSPLANTATION IN EUROPE Fast Track

Living Donation
ORGAN ALLOCATION
SCANDIATRANSPLANT
SPAIN
THE EUROTRANSPLANT LIVER ALLOCATION
UNITED KINGDOM TRANSPLANT
SYSTEM
Donation After Cardiac Death
Split DISCUSSION
Super-Urgent

LIVER TRANSPLANTATION IN EUROPE countries and geographical areas, including the

following:
The number of liver transplants performed in Europe • Organizacion Nacional de Transplantes (ONT) in
has increased, reaching a plateau of close to 6000 liver Spain
transplants performed annually (Fig. 6-1).1 The num- • NHS Blood & Transplant (NHSBT) for the United
ber of listed patients waiting for a liver transplant con- Kingdom and Ireland
tinues to increase, and the gap is widening between • Eurotransplant (Germany, the Netherlands, Bel-
them and the number of available liver grafts. Table 6-1 gium, Luxembourg, Austria, Hungary, Slovenia,
lists the liver transplant activity and organ donation and Croatia)
rates in different European countries and regions.2 It is •  Scandiatransplant (Sweden, Norway, Finland,
obvious from Table 6-1 that the liver transplantation Denmark, and Iceland)
activity and organ donation rates vary in the different • North Italian Transplant (NIT)
countries and regions in Europe. Table 6-2 lists the • Etablissement français des Greffes (EfG) in France
main indications for end-stage liver disease and liver The majority of livers are allocated and transplanted
transplantation. As in the United States, liver cirrhosis within each procurement and exchange organization, but
resulting from chronic hepatitis C and alcoholic cirrho- there is collaboration in case of surplus organs among
sis are the main and increasing indications for liver these organizations.
transplantation. Most organizations have similar rules with an urgent
This chapter gives an overview and description of priority group that includes acute hepatic failure and
some different European organ allocation systems and early retransplantation following vascular thrombosis, as
organizations. The differences presented reflect differ- well as primary nonfunction. There are, however, impor-
ences in legislation, organ donation rates, indications for tant differences as well.
liver transplantation, and traditions in the practice of Although no universally accepted liver allocation rules
medicine in different countries and regions of Europe. exist, two methods are primarily followed. Organ alloca-
tion can be patient directed, as is the case in the United
States and some European countries, or center directed,
ORGAN ALLOCATION which is the case in other European countries (Spain,
Scandiatransplant, and UKT). An organ allocation sys-
There are no uniform rules or systems for organ alloca- tem is a matter of consensus among transplant teams,
tion in Europe or within the European Union. There organizational structures, health authorities, and cus-
are different organ exchange organizations for different tomer and patient organizations. Regardless of the model

72
 6 Organ Allocation: The European Models 73

Evolution of 108,124 Liver Transplantations in Europe

Azerbaijan
Yugoslavia Belarus
Hungary
Slovenia
Estonia 6229
6278 6117
Romania 5879 5964
5957 5924
Turkey 5717
Portugal 5353
Bulgaria 5342
5146
Czech Rep.
4939
Denmark
4664
Poland
4360

4058
3763
3633
3336
Sweden
Spain 2997
Norway 2756
Italy Ireland
Great Britain Germany The Netherlands Finland 2512
Swiss
Austria France 2118
Belgium
1695

1256

813
532
285
70 75 158
7 10 7 5 3 6 4 10 22 22 15 21 22 44

68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 2000 2002 2004 2006 2008 2010

European Liver Transplant Registry
FIGURE 6-1 n Development of liver transplantation in Europe between 1968 and 2010. Evolution of 108,124 liver transplantations in
Europe.

TABLE 6-1 L
 iver Transplantation Activity and Number of Patients on Waiting Lists in Different
Countries and Regions in Europe in 2010
Overall Mortality From
Liver Transplants/ Chronic Liver Disease
Liver Transplantation Waiting List (Absolute (Expressed per 100,000
Population (Millions) per Million Inhabitants Number) Inhabitants in 1996)
France 60 13.4 803/457 16.5
Eurotransplant* 125 15.4 1931/2695 20.2
Scandiatransplant† 24 8.7 209/45 8.9
United Kingdom 63 11.1 700/180 7.5
Transplant ‡
Organizacion Nacional 43 23.3 972/522 17.3
de Transplantes§

*Germany, Austria, Belgium, the Netherlands, Luxembourg, Slovenia, and Croatia.

†Sweden, Norway, Finland, Denmark, and Iceland.
‡Great Britain and Ireland.
§Spain.

chosen, all systems work with two factor categories. The nonmedical criteria, which include geographical distance
first category includes medical criteria such as blood and resources consumed. Waiting time or cold ischemia
group, human leukocyte antigen (HLA) compatibility time may appear in either category.
(kidney transplantation), primary disease, donor and The Committee of Ministers of the Council of Europe,
recipient matching, donor virological status, severity of considering that organ transplantation is severely
recipient status, and others. The second category is restricted by availability of organs for transplantation,
74 PART I General Considerations

donation rate in the world, thanks to the outstanding

TABLE 6-2 Indications for Adult Liver
donor detection and organ procurement organization,
Transplantation in Europe From
which is often referred to as the Spanish model for organ
October 1991 to December 2002*
donation. Deceased donor organ donation rates have
Diagnosis LD (%) DD (%) P Value exceeded 30 donors pmp every year since 1998, reaching
in 2011 the rate of 35.3 donors pmp. However, after ana-
Acute hepatic 4 7 NS
failure
lyzing the marked regional variability, with some autono-
Cirrhosis 55 53 NS
mous communities registering more than 40 donors pmp
Cancers 25 13 P < .0001
in recent years, we believe there is still room for improve-
Retransplantation 1 10 P < .0001
ment. Thus ONT has created a large-scale, comprehen-
Others 17 15 NS
sive strategy to achieve a substantial improvement in
donation and transplantation in Spain in recent years.8
*Data from the European Liver Transplant Registry. Liver allocation in Spain is center oriented, because all
DD, Deceased donor; LD, living donor; NS, not significant. available organs are referred to the national coordinating
office for the rest of Spain. The allocation rules are
recognizes the need to set up a public system with an offi- decided by consensus among professionals from every
cially recognized network of transplant centers and an transplant center and ratified by the representatives from
official register of patients on waiting lists.2 The commit- regional health authorities. These rules are updated
tee also recommends that such a system provide complete annually after analyzing in detail the liver transplant
information for health care professionals and the general activity and taking into account several aspects: donor
public. This information should include criteria for regis- and recipient characteristics, waiting list time, mortality
tration and allocation, figures and flows of registered on the waiting list, probability of being transplanted for
patients, and average waiting times for different groups of different groups of patients, and emergency and retrans-
patients. The system must ensure, as far as possible, that plantation rates per hospital.9
no group of patients waits longer than another group. Currently, national priority is given to liver emergen-
Currently, few livers are exchanged between the dif- cies, and it is clearly stated at a national level what is con-
ferent organizations. There is, however, an increasing sidered an emergency and the circumstances under which
collaboration with some former eastern European coun- a patient can be listed as an urgent patient. In the absence
tries with recognized allocation systems and organiza- of urgent patients, the organ is allocated successively to
tions. The goal is to use donor organs fully and, more the hospital, city, region, or area, trying to reduce isch-
importantly, to develop the field of organ transplantation emia time. Two autonomous communities (Catalonia
in these countries to the level of the rest of Europe. and Andalusia) have established a priority system at a
regional level, which implies managing a single waiting
list in the whole region. The final score for each patient
SPAIN takes into account the Model for End-Stage Liver Dis-
ease (MELD) score with several modifications according
Liver transplant activity started in Spain in 1984 and to different variables such as indication, combined trans-
reached 19,339 interventions on December 31, 2011, plants, pediatric recipients, possibility of split, and time
with a mean activity of more than 1000 transplants per- on waiting list.10
formed yearly.3 There are 25 transplant teams (1 per 1.88 Finally, once an organ is offered to the transplant cen-
million inhabitants), and 2 of them are pediatric.4 This ter, the final decision about the donor-recipient match-
liver transplant activity represents 6% of all the interven- ing is made internally by the transplant team. To
tions performed in the world, while the Spanish popula- facilitate this decision, consensus guidelines have been
tion represents only 0.7% of world population. It is also recently developed with the support of the Spanish Soci-
the largest relative activity, reaching 23 to 25 liver trans- ety of Liver Transplantation.11-13 If no adequate recipi-
plants per million population (pmp).5 This achievement ent is available in Spain, the liver is offered to the rest of
is a consequence of the strong effort made by all the pro- the European countries, although it is extremely unusual:
fessionals involved in donation and transplantation activi- we registered only one case in 2009 and no cases in 2010
ties working within a public health service that provides and 2011.
health care for 99% of the population. The analysis of the An emergency liver transplantation in Spain is consid-
long-term results of liver transplants is performed using ered in two situations: (1) a patient having acute liver fail-
data from the Spanish Liver Transplant Registry, jointly ure in the absence of any previous liver disease (a medical
managed by the ONT and the Spanish Society of Liver report must be sent to the national coordination office
Transplantation. As shown in other international regis- stating that the disease has developed in the last 8 weeks
tries, patient and graft survival have been improving in a previous healthy liver) or (2) retransplantation within
across time.6 the first 7 postoperative days (in pediatric recipients, a
Every hospital needs official authorization to perform period of 30 days is accepted). This emergency category
liver transplants, and this implies the obligation to offi- implies national priority with the possibility of donor
cially record all patients registered on the waiting list. selection for the transplant unit. In case of simultaneous
The ONT provides essential support for organ procure- urgent situations, livers are allocated first to pediatric
ment, allocation support, and management of the waiting recipients (under 16 years of age) and next to the rest of
list at a national level.7 Spain has the highest organ the patients according to the time they have been included
 6 Organ Allocation: The European Models 75

TABLE 6-3 Inclusions on the Waiting List and Liver Transplantation Activity in Spain, 2007-2011
2007 2008 2009 2010 2011 Total
Patients on the waiting list 2,165 2,149 2,151 2,092 2,172 10,729
Patients on the waiting list 109 85 85 88 99 466
(emergency code)
Liver transplants 1,112 1,108 1,099 971 1,137 5,427
Liver transplants (emergency 91 64 71 72 81 379
code)

on the waiting list. Every year, liver transplant profes-

sionals analyze emergency rates according to the category 100
and the center to design changes if necessary.3
A review of the outcomes of all patients admitted to

% Patients on the WL
80
the liver transplant waiting lists in Spain from 2007
through 2011 (Table 6-3) shows that a total of 10,729
patients were registered during that period. Of these, 466 60
(4.3%) were urgent patients. In the same period, Spanish
units performed 5427 liver transplants; 379 of them (7%)
were considered as national priority. Between 1.8 and 2.4 40
urgent liver patients pmp were registered every year. Log rank
Among them, an average of 60% (54% to 65%, depend- P > .05
20
ing on the year) were fulminant liver failures, whereas
primary graft failure within the first 7 days after surgery
accounted for only 2% to 3% of all the transplants per- 0
formed yearly in Spain. Analysis of the outcomes for
these urgent patients shows that 81% of them were trans- 0 5 10 15 20 25
planted (80% of transplants were performed in the first Time (months)
48 hours), with a mortality rate on the waiting list of
around 7%. Number of
As Figure 6-2 shows, patient clearance from the liver Patients on
transplant waiting list in Spain did not change signifi- Year Waiting List Mean (SD)* Median (ICR)*
cantly from 2007 to 2011, after excluding urgent cases 2007 1965 162 (165) 118 (43-223)
from the analysis (because of their specific priority), with
2008 1912 167.5 (161.5) 124 (44-255)
a median time on the waiting list that ranged from 103 to
124 days, with approximately 1800 analyzed each year. 2009 1826 155.5 (156.8) 103 (33-230.2)
If we analyze patient clearance from the waiting list in 2010 1757 165.5 (160.5) 118 (37-241)
Spain according to patient status, taking into account 2011 1783 161.8 (158.5) 114 (32-240)
data from 2011 (Fig. 6-3), 568 cases were still on waiting
lists at the end of the period (December 31), 113 had *Time in months.
died, and 1015 had received a liver transplant. The FIGURE 6-2 n Patient clearance from the liver waiting list (WL) in
median waiting time for the grafted patients was 121 Spain according to the year (2007 to 2011). ICR, Intercentile
range; SD, standard deviation.
days; the median waiting time for the deceased patients
was 84 days (intercentile range [ICR], 28.5 to 204), which
was less than the median time of 151.5 days (ICR, 52 to collaborative projects to increase the donor pool with
261.7) for those still waiting. These data indicate that the objective of giving greater opportunities to patients
patients are undergoing transplantation following medi- on the waiting list.14
cal criteria, with the sickest patients undergoing trans-
plantation first. No significant differences were observed
in clearance rates from the waiting lists in relation to age, UNITED KINGDOM TRANSPLANT
weight groups, primary liver disease, and other studied
variables. The first liver transplant in the United Kingdom (UK)
As regards to other modalities of liver transplants, the was in 1968 at Addenbrookes, Cambridge, by Sir Roy
living donor liver transplants and split-liver procedures Calne15; however, the first UK liver program started in
performed during the reviewed period accounted for 6% 1983. The number of deceased organ donors in the UK
of the activity: of the 5427 registered liver transplants, fell over a number of years. An effort to reverse this trend
130 were living donor livers (2.4%), 69 were split livers was made by setting up an Organ Donation Taskforce,
(1.3%), 55 were domino livers (1%), and 77 were from whose recommendations were implemented and followed
non–heart-beating donors (1.4%). Because we are con- by an increase in the number of donation after brain
vinced that some of these rates can be considered oppor- death (DBD) donors of 7% over the last 4 years. The
tunities for improvement, we have designed specific number of donation after cardiac death (DCD donors has
76 PART I General Considerations

rapidly increased by 118% since 2007, in an effort to

100 Still waiting bridge the gap between the number of donors and the
Death number of patients waiting for a transplant. Moreover,
Grafted the number of people on the Organ Donor Register rose
80 to 18.7 million, and deceased organ donation rose to
34.4%, reaching an unprecedented total of 1088 donors
in 2011. Of these, 652 were DBD and 436 were DCD.16
Approximately 700 liver transplants are performed
% Patients on WL

60 yearly in the UK (Fig. 6-4). Last year the number reached

791, registering an increase of 12% compared to the pre-
vious year. There are seven transplant units in the UK, six
40 in England and one in Scotland. Three of these also have
a pediatric liver transplant program. As of March 2012
there were 534 patients registered on the active waiting
list for liver transplantation, a 9% increase compared to
20 the previous year. Currently, on average, adult patients
Log rank wait 142 days for a liver transplant, whereas pediatric
patients wait an average of 78 days. A study looking into
0 postregistration outcomes of 891 new elective liver regis-
trations in the year 2008-2009 showed that at 1 year post
0 5 10 15 20 25 registration 13% of patients either had died or had been
Time (mo) removed from the list for deteriorating clinical condition
(Fig. 6-5).
The key players in regulating organ donation and
Number of
Patient Patients on transplantation in the UK are NHS Blood and Trans-
Status Waiting List Mean (SD)* Median (ICR)* plant (NHSBT) and the Human Tissue Authority (HTA).
NHSBT, a special health authority of the National
Grafted 1015 163.3 (154.6) 121 (36-245)
Health Service (NHS), was established on October 1,
Still waiting 568 186.6 (163.6) 151.5 (52-261.7) 2005, to take over the responsibilities of two separate
NHS agencies: UK Transplant (now renamed Organ
Death 113 146.2 (156.5) 84 (28.5-204)
Donation and Transplantation), founded in 1972, and
*Time in days the National Blood Service. Among its responsibilities is
FIGURE 6-3 n Patient clearance from the liver waiting list (WL) in to provide a reliable, efficient supply of organs for trans-
Spain according to the patient status at the end of the year plantation. The advisory groups, which include represen-
(2011). ICR, Intercentile range; SD, standard deviation. tation from all designated transplant units, propose and

Deceased Donor Liver Program in the UK, April 1, 2002, to March 31, 2012
Number of Donors, Transplants, and Patients on the Active Transplant List as of March 31
900
Donors
800 Transplants
Transplant list
705 706 712
688 668 686 679
700 676 657 675
637 649 636 647 632 633
611 600
600
553
Number

500 510

400 365
371
314 338
300
264 268
200 190
175
100

0
2002- 2003- 2004- 2005- 2006- 2007- 2008- 2009- 2010- 2011-
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
Year
FIGURE 6-4 n Deceased donor liver program in the United Kingdom (UK), April 1, 2002 to March 31, 2012. Number of donors, transplants,
and patients on the active transplant list as of March 31, 2012. (From Transplant activity in the UK, 2011-2012, NHS Blood and Transplant.)
 6 Organ Allocation: The European Models 77

Postregistration Outcome for 891 New Elective Liver Only

Registrations Made in the UK, April 1, 2008, to March 31, 2009

100
10 13 15
3
6
80 7
14 5
31
Died/removed 1
Percentage
60 Removed
Still waiting
Transplanted

40
73
67
55
20

0
6 months 1 year 2 years
Time since listing
1 Removals due to condition deteriorating

FIGURE 6-5 n Postregistration outcome for 891 new elective liver only registrations made in the United Kingdom (UK), April 1, 2008,
to March 31, 2009. (From Transplant activity in the UK, 2011-2012, NHS Blood and Transplant.)

monitor policies for organ donation, allocation, retrieval, called in to retrieve. The system is led by consultant sur-
and transplantation and recommend changes to the geons and is designed to improve efficiency and reduce
nationally agreed protocols for allocating organs. More travel time and costs.
specifically, the Liver Advisory Group and its subgroup Liver allocation in the UK is center oriented. All
Liver Selection and Allocation Working Party discuss potential liver donors in the UK or Republic of Ireland
matters regarding liver graft allocation, ensuring equity must be reported by telephone to the NHSBT Duty
of access to transplantation. Office. Donor zones are allocated to each center based on
The HTA is an independent watchdog that protects the number of new registrations on the waiting list of
public confidence by licensing and inspecting organiza- prospective candidates. This is to match the number of
tions that store and use tissue for transplantation and potential donors to the needs of the specific center,
other purposes. They also give approval for organ dona- reflected by the scale of their waiting list. Should the local
tions from living people through an independent assess- center decide not to use that liver, it is further offered to
ment process. The HTA provides advice and guidance the other centers in accordance with the liver center rota-
about two laws: the Human Tissue Act and the Quality tion on the basis of a full offer to the first center and a
and Safety Regulations. More recently the HTA was provisional offer to the second in line. If the organ is
named as the competent organization for the European declined, it will be fully offered to the second in line
Union (EU) Organ Donation Directive, a European through the liver allocation sequence. The rotation sys-
requirement that aims to bring all EU countries up to the tem is determined according to each center’s transplant
same high quality and safety standards, and took the lead activity, based on a rolling 4 week period. The center
in developing a regulatory framework and implementa- with the least number of transplants during this period
tion into legislation.17 These laws ensure human tissue is will appear at the top of the sequence, down to the center
used safely and ethically, with proper consent. with the most number of transplants.19
NHSBT provides essential support for organ pro- The allocation priority at each center is decided by
curement via the new National Organ Retrieval Service transplant surgeons and physicians on call. National
introduced in the UK on April 1, 2010.18 The service guidelines currently do not specify which patient to select
comprises seven abdominal organ retrieval teams and six when a liver suitable for more than one recipient is
cardiothoracic organ retrieval teams. These teams are offered. There is a significant number of factors influenc-
based in liver and cardiothoracic transplant centers, ing the decision of the transplant professional, including
respectively. Each team has a designated area for which quality and size of the donated liver, blood group, health
they are first on call, based on the premise that the travel condition of the potential recipient, and logistics of pres-
time to any hospital in their area should be less than sure on intensive care unit beds and on staff. The decision
3 hours. If a team is already retrieving when they are whether a liver should be transplanted into an individual
called to attend a donor, then a second team will be should take account of both recipient and donor factors.
78 PART I General Considerations

In fact where possible the donor should be matched to

the recipient who is expected to obtain the greatest trans-
Fast Track
plant benefit from the procedure. On certain occasions it is advantageous for a liver to be
offered quickly to all centers to allow transport to the
Donation After Cardiac Death accepting center as quickly as possible; this reduces cold
ischemic time to a minimum. For this reason a fast-track
A center that retrieves a liver from a DCD donor will liver offer scheme exists in the UK. This can be brought
have priority in using that liver and, if not accepted into operation when 4 hours of cold ischemic time has
locally, the liver will be offered through the fast-track already elapsed and a whole liver or lobe is on offer, or in
scheme to those centers that have registered their will- case the liver is from a domino donor or DCD donor.
ingness to consider offers of livers from non–heart- Common examples of when the fast-track system is used
beating donors. include the following:
• A right lobe donated following splitting of a whole
Split liver
• A liver that has become available when initial lapa-
Brain-dead donors who are less than 40 years of age, rotomy has revealed that the intended recipient is
weigh more than 50 kg, and have stayed in the intensive not fit for surgery
care unit for less than 5 days meet the basic liver-splitting Relevant information is entered on a form especially
criteria. Teams retrieving livers from such donors should designed for this situation, and the form is then sent
provide an acceptable reason if they decide not to split, simultaneously to all centers in the United Kingdom.
usually related to liver function, hemodynamic instabil- In all cases centers must respond by telephone within
ity, or quality of the graft. Recipient-related justifications, 30 minutes to advise whether they wish to accept or
for example, not splitting to use the graft as a whole for a decline the offer. If a center does not respond to a fast-
difficult retransplant candidate, are not considered track offer, the NHSBT Duty Office will assume that
acceptable. Left lateral segments are offered to UK pedi- the offer has been declined. The Duty Office will follow
atric liver centers in accordance with the liver allocation up those centers who fail to respond within the required
sequence. Left lateral segments from O blood group 30 minutes to ascertain reasons why the offer was
donors must be offered for O and B blood group pediatric declined. If a liver is accepted by more than one center,
patients nationally before consideration is given to other it is eventually allocated to the center placed highest on
blood group pediatric patients. the liver center rotation at the time of the offer.
Designated liver units may register with the NHSBT
Duty Office to receive offers of livers that are available
from other units in Europe. For all cases, acceptance is on
Living Donation
a first-come, first-served basis. Living donor liver transplantation (LDLT) was first suc-
cessfully performed in a child in 1990 and in 1994 in the
Super-Urgent UK.20 Adult-to-adult LDLT was first performed in the
UK in 1998.21 Over the years there have been significant
Patients are prioritized as super-urgent if they require a developments of the surgical techniques for the different
new liver as soon as possible because of rapid failure of kind of segmental grafts and of the donor assessment pro-
the native organ or of the liver graft. There are nine cat- tocols, which are now fairly standardized. Ethical consid-
egories of patients suitable for listing on the Super- erations continue to be discussed, mainly concerning the
Urgent National list: the first four concern acute liver donor morbidity and mortality associated with the proce-
failure (ALF) following acetaminophen overdose and are dure. The Human Tissue Act 2004 regulates the law
based mainly on the King’s College Hospital and lactate around living donor transplants. Initially adult-to-adult
criteria and on clinical deterioration. Categories 5 and 6 living donor procedures were performed in the UK only
include seronegative hepatitis, hepatitis A or hepatitis B, on foreign nationals, but they are currently available to
or an idiosyncratic drug reaction. Category 7 includes patients within the UK via the NHS. Although in other
Wilson’s disease or Budd-Chiari syndrome; category 8, countries in Europe LDLT procedures have been rela-
hepatic artery thrombosis up to day 14 after liver trans- tively frequent, the numbers have been stagnant despite
plantation; and category 9, graft dysfunction or nonfunc- the relatively high mortality of patients on the liver wait-
tion up to 7 days after liver transplantation. ing list. However, the trend is changing, as last year 38
In summary, for adult (age ≥ 16 years or weight ≥ 35 kg) LDLT procedures took place, an increase of 81%.
and pediatric (age < 16 years or weight < 35 kg) liver
donors, the sequence for allocating liver grafts is similar
and is the following: SCANDIATRANSPLANT
1. Super-urgent list
2. Combined liver–small bowel adult recipients Scandiatransplant was founded in 1969 and has its head-
3. Patients with hepatoblastoma quarters in Århus, Denmark. As with other organ
4. Designated zonal retrieval center exchange organizations, its initial purpose was to allocate
5. Other designated UK and Ireland liver transplant kidneys. Scandiatransplant is a collaboration of all organ
centers transplant centers in the Nordic countries—Sweden,
6. Designated zonal retrieval centers for adults Norway, Finland, and Denmark. Iceland is a part of
 6 Organ Allocation: The European Models 79

TABLE 6-4 M
 edian Time on the Scandiatransplant Liver Transplant Waiting List Between 2000
and 2011
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
Median 43 39 52 38 40 41 41 51 58 44 64 46
(days)

55

50
Median age (years)

45

40

Recipient age
Donor age

35
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
Year of first liver transplantation
FIGURE 6-6 n Median donor and recipient age at the time of first liver transplantation in Scandinavian countries. (From the Nordic Liver
Transplant Registry, 2011.)

Scandiatransplant but does not perform liver transplan- both the recipient age and donor age have continued to
tation. It currently has an agreement with Sweden for increase. In 2011 the median donor age for first-time liver
organ donation and transplantation. Scandiatransplant is a transplantation recipients was 53.0 years with a median
nonprofit organization that is owned and financed by all recipient age of 52.7 years.
the transplant centers in the Nordic region. There are There is no common waiting list in Scandinavia. Center-
currently five liver transplant centers within Scandiatrans- oriented allocation is used, and each transplant center has
plant (two in Sweden and one in each of the other Nordic its own waiting list and the right to transplant livers pro-
countries). By the end of 2011, 4550 liver transplantation cured from a defined geographical area. The MELD
procedures had been performed in the Nordic countries, score and/or the Child-Turcotte-Pugh scores are usually
with an overall 1-year graft and patient survival of 86% used in conjunction with clinical (e.g., medical urgency,
and 90%, respectively. The main indications for liver recipient size, recipient age) and nonclinical parameters
transplantation in patients with chronic liver disease in (e.g., waiting time) to select patients to be transplanted. If
the Nordic countries are primary sclerosing cholangitis a liver is not used at the local center, it will be offered to
(21%), hepatocellular carcinoma (16%), alcoholic cirrho- the other Scandiatransplant centers according to a rota-
sis (approximately 13%), acute fulminant liver failure tion system. The organs are, however, procured by the
(7%), and chronic hepatitis C (7%).22 In 2011 the median local transplant team and then sent to the transplanting
waiting time for a liver transplantation within the Nordic center. On rare occasions, if a liver cannot be transplanted
countries was 46 days (ranging from 14 days for blood within the Nordic countries, the liver is then offered to
group AB to 98 days for blood group 0; Table 6-4) and other European organ procurement organizations.
thus relatively short compared to both the United States Patients with acute hepatic failure have priority to
and other European countries. As illustrated in Figure 6-6, receive a liver from the next available deceased donor in
80 PART I General Considerations

the Scandiatransplant region (urgent call status). The was already refined in several of the ET countries. Organ
high urgent status is based solely on the diagnosis and allocation requires an algorithm based on medical and
clinical status and the evaluation made by the responsible logistical criteria.24 In December 2006 the new MELD-
hepatologist together with the transplant surgeon and based ELAS was implemented for elective recipients with
intensive care physicians. There are no rules for blood an end-stage chronic liver disease. Patient-oriented allo-
group compatibility or identity in high urgent cases, cation according to MELD is effective in five out of eight
which means that a blood group O liver can be used in countries within ET (Germany, Belgium, the Nether-
recipients in blood group A or B. The high urgent call lands, Luxembourg). This means that organ offers in
status of the patients who qualify remains in effect for a these countries are made for individual transplant candi-
maximum of 3 days. Thereafter, if the patient is still alive dates and not to transplant centers. In contrast, in Aus-
and transplantable, the center can declare a “kind request” tria, Hungary, Slovenia, and Croatia a center-oriented
status, which implies that other centers can assist with a allocation is effective, and all organ offers are handled as
liver but have no obligations do so. If there are two urgent center offers according to a center-specific allocation
calls simultaneously within Scandiatransplant, the patient algorithm. On the ET matching list all patients have to
first declared has priority. All livers received on urgent be registered with a laboratory MELD score, which has
call status or as a kind request have to be “paid back” to to be updated by the transplant centers at scheduled
the sending center within a 6-month period. intervals. An exceptional MELD can be requested for
High urgent status also applies for patients in need of patients whose disease severity is not adequately reflected
an acute retransplantation within 14 days of the trans- by the laboratory MELD. Some diseases have been iden-
plant because of primary nonfunction or hepatic artery or tified as standard exceptions (SEs) and are included in a
portal vein thrombosis. There are no rules for mandatory country-specific list. To be eligible for an SE, a recipient
organ exchange for patients with a chronic liver disorder must fulfill disease- and country-specific criteria.
or for patients in need of a late retransplantation. For example, for several malignancies fulfilling disease-
Pediatric liver transplantations constitute approxi- specific criteria, SEs can be requested with differences in
mately 5% of all liver transplantations performed in Scan- country-specific criteria. Patients suffering from hepato-
dinavia.22 In 2011 a common waiting list for pediatric cellular carcinoma in cirrhosis are eligible for an SE in all
patients in need of a left lateral segment liver graft was countries and have to be inside Milan criteria, either at
established to improve organ availability for pediatric time of request or after downstaging. Cholangiocarci-
patients and to make maximum use of livers suitable for noma less than 3 cm is only accepted in four countries
splitting. Liver transplantation with living donors is not (Austria, Germany, Slovenia, Croatia), and operating
widely practiced within the Nordic countries, mainly due according to a ratified protocol is recommended. Other
to the short median waiting times for transplantation (see tumor indications accepted in most countries are nonmet-
Table 6-4) and a waiting-list mortality of only 2.7%. astatic hepatoblastoma and hepatic hemangioendotheli-
Gothenburg, Sweden, is the center with the largest experi- oma. In liver transplantation for malignancies, centers
ence in adult LDLT in Scandinavia. DCD donation is not have to send a copy of the pathology report of the explanted
practiced among the Scandiatransplant countries with the liver to ET, where the reports are collected and analyzed.
exception of Norway, where a program for DCD dona- Besides allocation in elective recipients, some urgency
tion recently commenced. In Sweden a DCD donation categories within ET are given priority based on their
program is being discussed but has not been established. respective medical urgency (Table 6-5):
Scandiatransplant has few rules, which works well • High urgency (HU), which is the highest priority
because of the small size of the organization and the limited internationally
number of centers involved. The collaboration between the • Approved combined organ (ACO), which is a mul-
centers, both clinically and scientifically, is very good and tiorgan liver transplant, with the exception of
extensive. For liver transplantation in the Nordic countries, liver-kidney
Scandiatransplant has its own registry, the Nordic Liver Patients in these categories are ranked by the time they
Transplant Registry, from which participating centers have have spent in their current urgency.
access to data and from which a large number of multi- HU includes ALF (defined by King’s College or Cli-
center studies have been performed and published.23 chy criteria), acute graft failure (<15 days posttransplant),
rapidly progressive Wilson's disease or Budd-Chiari syn-
drome, life-threatening liver trauma, or anhepatic state
THE EUROTRANSPLANT LIVER secondary to ALF with toxic liver syndrome. HU patients
ALLOCATION SYSTEM are audited prospectively, and only after approval by ET
will urgency HU be granted. In doubtful cases, up to
Eurotransplant (ET) is an international nonprofit organ three members of the Eurotransplant Liver Advisory
exchange organization in which donor hospitals, tissue Committee are contacted to evaluate the HU request.25
typing centers, and transplant centers in Austria, Bel- An obligation is generated if a liver from a donor outside
gium, Germany, Luxembourg, the Netherlands, Hun- the transplant center's country or region is transplanted
gary, Slovenia, and Croatia collaborate. In ET, allocation into a patient in HU or ACO. The receiving country or
is governed by the different national laws on transplanta- region then has an obligation to the donor center to offer
tion, resulting in a standard allocation algorithm with the next available liver in the same blood group. The
occasional refinements for each country. As a result, the obligation is closed if the donor liver is accepted for
current Eurotransplant Liver Allocation System (ELAS) transplantation in this center.
 6 Organ Allocation: The European Models 81

pediatric and adult ACO, and split-liver transplantations.

TABLE 6-5 U
 rgency Codes in the Eurotransplant
ET-compatible is defined as a restricted compatibility
Liver Allocation System
(i.e., ABO-O to ABO-O and ABO-B recipients). This
Mandatory rule applies to adult HU and to pediatric and adult
Medical Urgency Priority Exchange patients with a MELD score of 30 or higher.
HU High urgency Internationally Yes
Figure 6-7 shows the development of liver transplant
first activity within ET.
ACO Approved Internationally Yes LDLT is mainly performed for pediatric recipients,
combined organ second and the outcomes are excellent. The numbers for adult-
T Laboratory MELD score Nationally No to-adult LDLT are rather low in the ET area, and adult
or exceptional MELD; LDLT is preferentially performed in nonresidents. The
country-specific rules overall proportion of LDLT is actually 7% of all liver
apply
transplantations; therefore the contribution of LDLT to
T Laboratory MELD score Internationally No
according to matching the donor pool is limited (see Fig. 6-7.)
list Split-liver transplantation is encouraged. Each liver
NT Temporarily not Not matched — donor who meets the conditions (weight ≥ 50 kg, no
transplantable upper limit and ≤ 50 years of age) is considered a poten-
tial split-liver donor. If a transplant center does not con-
sider a split procedure, a reason must be given. One split
must be transplanted to the patient initially selected by

3000

2500

2000

1500

1000

500

0
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Liver waiting list 229 253 203 212 263 327 374 492 593 803 1093 1366 1714 2035 2134 2319 2429 2442 2641 2695
Deceased donor transplants 710 765 878 892 944 1032 1097 1071 1132 1166 1111 1136 1264 1262 1364 1436 1625 1606 1691 1793
Living donor transplants* 5 15 14 24 25 22 41 38 64 116 124 127 133 106 121 116 101 82 98 138

FIGURE 6-7 n Development of liver transplantation activity and the number of patients on the waiting list in the Eurotransplant area
between 1991 and 2010. LDLT, Living donor liver transplantation.

Elective pediatric patients (<16 years of age) are allo- ELAS and for whom the splitting center accepted the
cated according MELD score and are provided with a whole liver. The splitting center is allowed to keep the
MELD equivalent depending on age (35% for <12 years, second split and allocate it to a suitable recipient from its
15% for ≥12<16 years). A pediatric donor (<46 kg) is own waiting list (with the exception of Germany, where
preferentially allocated to pediatric patients. the second split is always allocated by ET). If the second
ET countries can be divided into regions comprising split cannot be allocated or transplanted in the splitting
one or more transplant centers. ET countries with center, the second split is reported to the ET duty desk
regions are Austria (three regions) and Germany (seven for allocation through ELAS.
regions). ABO-incompatible liver transplants are not Livers from DCDs are allocated according to the same
allowed. Full ABO compatibility applies to pediatric HU, allocation algorithm as postmortem heart-beating
82 PART I General Considerations

donors. However, deviant national legislation exists con- 6. Spanish Liver Transplant Registry. Available at: http://www.ont.es
cerning procurement and transplantation of DCDs. /infesp/Paginas/RegistroHepatico.aspx. Last accessed: May 2012.
7. Matesanz R. Organ procurement in Spain. Lancet. 1992;340:733.
Despite these activities and initiatives for increasing the 8. Matesanz R, Marazuela R, Domínguez-Gil B, et al. The 40 donors
liver donor pool, the disparity between organ demand and per million population plan: an action plan for improvement of
available grafts has not been overcome so far (see Fig. 6-7.) organ donation and transplantation in Spain. Transplant Proc. 2009
Oct;41(8):3453-3456.
9. Spanish National Transplant Organization. Updated Allocation
Criteria. Available at: http://www.ont.es/infesp/Paginas/Criteriosde
DISCUSSION Distribucion.aspx. Last accessed: May 2012.
10. de la Mata M, Cuende N, Huet J, et al. Model for end-stage liver
The number of patients waiting and listed for liver trans- disease score-based allocation of donors for liver transplantation: a
plantation is increasing, and the gap between demand and Spanish multicenter experience. Transplantation. 2006 Dec
15;82(11):1429-1435.
supply will increase unless there are dramatic changes in 11. I Consensus Document of the Spanish Liver Transplant Society.
the donation rates in Europe. In addition, as in the United Gastroenterol Hepatol. 2008;31:82-91.
States, liver cirrhosis from chronic hepatitis C is an 12. II I Consensus Document of the Spanish Liver Transplant Society.
increasing indication for liver transplantation. In the Gastroenterol Hepatol. 2009 Dec; 32(10):702-716.
13. III Consensus Meeting of the Spanish Liver Transplant Society.
future, splitting of liver grafts may play an important role Cir Esp. 2011;89:487-504.
in increasing the number of transplants by optimizing the 14. Matesanz R, Domínguez-Gil B, Coll E, et al. Spanish experience as
use of donor livers. Splitting will definitely also increase a leading country: what kind of measures were taken? Transpl Int.
the exchange of organs between the different exchange 2011 Apr; 24(4):333-343.
and allocation organizations in Europe. An increase in 15. Calne RY, Williams R. Liver transplantation in man. I. Observa-
tions on technique and organization in five cases. Br Med J.
the number of living donors (adult to adult) would also 1968;4:535-540.
certainly result in reduced morbidity and mortality on the 16. NHS Blood and Transplant. Annual Activity Reports. Available at:
waiting lists. As pointed out, there are no uniform rules http://www.organdonation.nhs.uk/statistics/transplant_activity_re
or systems for liver allocation in Europe. Different sys- port/archive_activity_reports.
17. HTA Organ Donation Directive. Available at: http://www.hta.gov.
tems are used, ranging from center oriented to patient uk/organdonationdirective.cfm.
oriented. Some systems are constructed using rigorous 18. Commissioning of organ retrieval services: an update. Available at:
rules based on points and scores, whereas others are based http://www.nhsbt.nhs.uk/downloads/board_papers/may09/organ_
on the clinical judgment of the responsible transplant retreival_commissioning_update_09_33.pdf.
surgeon. The current diversity makes it impossible to 19. The Liver Organ Sharing Principles. Available at: http://www.org
andonation.nhs.uk/about_transplants/organ_allocation/liver/.
adopt a uniform organ allocation system in Europe in the 20. Baker A, Dhawan A, Devlin J, et al. Assessment of potential donors for
foreseeable future. living related liver transplantation. Br J Surg. 1999;86(2):200-205.
21. Williams RS, Alisa AA, Karani JB, et al. Adult-to-adult living
donor liver transplant: UK experience. Eur J Gastroenterol Hepatol.
2003;15(1):7-14.
Pearls and Pitfalls 22. Karlsen TH. The Nordic Liver Transplant Registry (NLTR)
Annual Report 2011. http://www.scandiatransplant.org/members/
nltr/ANNUAL_REPORT_2011.pdf.
• There is no uniform liver or organ allocation system
23. Scandiatransplant. http://www.scandiatransplant.org/members/nltr.
within Europe or the European Union. 24. De Meester J, Persijn GG, Wujciak T, et al. for the Eurotransplant
• There are different large organ allocation organizations International Foundation: The new Eurotransplant kidney alloca-
covering several countries. tion system. Report one year after implementation. Transplantation.
• There are varying donation and transplantation rates in 1998;66:1154-1159.
the allocation organizations. 25. Neuberger J, Ubel PA. Finding a place for public preferences in
• Liver allocation is center directed in Spain, in the Scan- liver allocation decisions. Transplantation. 2000;70:1411-1413.
diatransplant system, in the United Kingdom Transplant
system, and in some countries within Eurotransplant.
• Liver allocation is patient directed in some countries
within Eurotransplant.
• There is potential to increase the number of grafts by
developing split-liver and living related donor trans-
   plantation.

REFERENCES
1. European Liver Transplant Registry online: Available at http://
www.eltr.org/publi/index_rv.php3
2. International figures for organ donation and transplantation activi-
ties. Newsletter Transplant, Council of Europe. 2002;7(12).
3. Spanish National Transplant Organization. Annual Reports. Avail-
able at: http://www.ont.es/infesp/Paginas/DatosHistoricos.aspx.
Last accessed: May 2012.
4. Matesanz R, de la Rosa G. Liver transplantation; The Spanish
experience. Dig Liver Dis. 2009;(Sup 3):75-81.
5. Global Observatory on Donation and Transplantation. Available
at: http://www.transplant-observatory.org/Pages/Home.aspx. Last
accessed: May 2012.
 CHAPTER 7

Donation After Cardiac or Brain

Death: Regulatory and Ethical
Principles
Thomas Collins • Zoe Stewart • Alan Reed

CHAPTER OUTLINE

THE INTERESTING INTERSECTION OF Donation After Brain Death: Nonmaleficence

PROCUREMENT REGULATION AND ETHICS and Brain Death Criteria
Brain Death Versus Cardiac Death
BASES OF ETHICAL ARGUMENTS
Persistent Vegetative State Versus Brain
AND REGULATORY PROCESSES IN
Death
TRANSPLANTATION
Severe, Irreversible Brain Injury Versus Brain
REGULATION Death
History Donation After Cardiac Death:
Brain Death Nonmaleficence, Benefit, and Utilitarianism
Organ Procurement Organization Criteria for Determination of Death in
Organ Allocation Controlled Donation After Cardiac Death
Organ Recovery
The Impact of the Final Rule
Uncontrolled Donation After Cardiac Death
Donor-Recipient Matching Organ Recovery
Direct Donation
Increasing the Donor Pool REAL WORLD IMPLICATIONS: WHERE
REGULATIONS AND ETHICS COLLIDE
Donation After Cardiac Death Versus Donation
After Brain Death Conduct of a Donation After Cardiac Death
Case
Use of Marginal Grafts
Liver Allocation for Hepatocellular Carcinoma
ETHICS

information for recipients of deceased donors, and issues

THE INTERESTING INTERSECTION OF regarding organ allocation are just a few of them. Within
PROCUREMENT REGULATION AND this broad context, this chapter focuses on the regula-
ETHICS tory and ethical aspects of deceased organ donation for
the circumstances of both donation after brain death
Some of the most fascinating aspects in the practice of (DBD) and donation after cardiac death (DCD). Each of
medicine are the dilemmas that can arise at the intersec- these has unique and interesting ethical and regulatory
tions where laws, or for the purposes of this chapter, considerations.
transplant regulations and policy, can collide with one’s Following this brief introduction, this chapter deals
personal ethical values and responsibilities as a physician. with the regulations and policies developed to guide our
The conflicts and inconsistencies between what physi- field through brain death, deceased donor organ alloca-
cians are told to do and what they may believe to be the tion, and mechanisms to increase the deceased donor
proper thing to do in a particular situation can sometimes organ pool. It is difficult to dissociate these “rules” from
play out in uncomfortable ways. It is the stuff of both the ethical conversations that gave them life (for example,
great literary drama and sensational news headlines. the development of brain death laws and the conflicts
Nowhere in medicine are issues of ethical value and with the prevailing medical establishment at the time and
regulation put in closer proximity than in the field of also with religious beliefs). The third section explores
organ transplantation, one of the most highly regulated, similar issues from an ethical perspective. The final sec-
publicly transparent, and ethically complex areas of tion of the chapter examines two examples in the realm of
practice. There are many examples within transplanta- deceased organ donation in which policy and regulation
tion in which this paradigm can be examined: issues of dictate one course of action, but conscientious practice or
privacy for living donors, issues of disclosure of relevant ethical values might dictate another.

83
84 PART I General Considerations

BASES OF ETHICAL ARGUMENTS with irreversible coma and no hope of recovery but with-
out the cardiopulmonary collapse that traditionally
AND REGULATORY PROCESSES IN defined death. In 1968 a commissioned ad hoc committee
TRANSPLANTATION at Harvard Medical School published a landmark paper
describing the need for the determination of death by
The main sources of ethical value that must be balanced neurological criteria in addition to the already accepted
by any allocation system seeking to distribute highly irreversible cessation of a beating heart.3 This was the
desired but limited goods such as transplantable organs are first attempt to define the concept of brain death with
beneficence, autonomy, and justice. Justice is particularly neurological criteria. The committee proposed that the
interesting because “fair and impartial” really depends on criteria for brain death include irreversible coma with
which side of the fence you are standing on—the indi- absence of movement, breathing, and reflexes and an iso-
vidual or society as a whole. An individual’s rights, pro- electric electroencephalogram (EEG), all observed for at
fessional societal guidelines, religious beliefs, one’s own least 24 consecutive hours.
sense of conscientious medical practice, and personal With the recognition of brain death, a new source of
integrity must also be taken into account.1 In addition, donor organs emerged. The DBD donor provided a
financial implications are also particularly relevant to much more stable, controlled situation for organ pro-
transplantation. These values and other concepts have curement and soon became the source of the majority of
led to a series of rules, policies, and regulations devel- transplanted organs. The traditional non–heart-beating
oped over the past 30 years in an attempt to distribute donor, or DCD donor, remained a source of organs.
organs fairly. All of the current regulatory principles gov- However, because of additional ischemic injury during
erning deceased donation and their policy interpretations procurement, these organs proved less ideal. This remains
in some way have stemmed from the National Organ the case but has recently been balanced by a resurgence in
Transplant Act (NOTA) of 1984. Among other impor- interest spurred on by a growing disparity between trans-
tant provisions, it laid the groundwork for the Organ plantable organs and people with end-stage liver disease
Procurement and Transplantation Network (OPTN) (ESLD) on the transplant waiting list.
and set the stage for the governing body that would Over the past 4 decades the definition of brain death
become the United Network for Organ Sharing (UNOS), has evolved and been redefined. For example, the EEG is
a member organization designed to create the policies to no longer necessary for the diagnosis of brain death.4 The
equitably run the network and allocate organs. Disagree- Uniform Determination of Death Act (UDDA) was
ments over these policies, often on ethical grounds, are drafted in 1981 by the National Conference of Commis-
common and often lead to changes and improvements in sioners on Uniform State Laws with the purpose of pro-
the policies. A well-known example of this process, devel- viding a comprehensive and medically sound basis for the
oped more fully later in the chapter, was the use of the determination of death in all situations.2 Unfortunately,
Model for End-Stage Liver Disease (MELD) score as the the determination that coma is irreversible or that all
basis for allocation in liver transplantation; most would clinical criteria of brain death are present is not always
agree that using an objective, easy-to-measure score straightforward. Clinical advancements have made these
based on severity of illness represented an improvement determinations easier. Nuclear brain scans and cerebral
over the previous system. flow studies now enhance the physician’s ability to assess
brain death. These new technologies have affected the
field of organ transplantation and interpretation of com-
REGULATION pliance with the dead donor rule. A 2003 review of the
brain death criteria provides current diagnostic criteria
History used by most hospitals today.4 Paramount among those
Brain Death criteria are the need to ensure that no complicating con-
ditions such as metabolic intoxication, hypothermia, or
In 1968, soon after the first human heart transplant was shock are contributing to the coma, that there are no
performed, the Uniform Anatomical Gift Act (UAGA) brainstem reflexes, and that there is no spontaneous ven-
was written.2 It was universally enacted throughout the tilation on apnea challenge. In addition, these tests must
country and provided legal means for human organs to be be repeated after a variable amount of time that is depen-
gifted for the purpose of transplantation. Deliberations dent on the donor’s age and other test results. Finally, in
surrounding its passage also provided one of the corner- congruence with earlier versions, recommendations still
stone concepts of transplant ethics, the dead donor rule.2 emphasize the importance of the diagnosing physician
Although it seems a straightforward concept not to take having no conflict of interest in the transplant process.
organs for transplant from a donor unless the donor is
dead, what it means to be “dead” has been a source of
Organ Procurement Organization
controversy and ethical dilemma over the past half
century. The early period of organ transplantation was character-
One of the most significant medical advances affecting ized by a growing disparity between those needing trans-
the early growth of organ transplantation was the estab- plants and organs with which to transplant them. As more
lishment of “brain death.” The advent of effective life medical centers started performing transplants, it became
support technologies in the 1950s led to an ethical and clear that a centralized network was needed to oversee
diagnostic dilemma for physicians; patients now existed organ donation, procurement, and allocation. In 1984
 7 Donation After Cardiac or Brain Death: Regulatory and Ethical Principles 85

NOTA5 was signed into law. The law, among other to procure and transport it to any hospital in the country.
important things, provided for the establishment of the For these reasons, allocation policies include both medi-
OPTN to establish the rules for, and regulation of, the cal criteria and geographical criteria. Cost currently does
procurement and matching of donor organs with appro- not play into the equation but could be a significant con-
priately listed recipients. Two years later, in 1986, sideration in the future because the money required to
UNOS6 was contracted to administer the OPTN and has ship organs anywhere in the country on a moment’s
been the only organization to do so since.6 The federal notice can be extreme.
agency responsible for oversight of the OPTN and the Separate policies have been drafted by UNOS for the
contract holder for the government is the Health allocation of each organ. For some organs, such as kidney
Resources and Services Administration (HRSA), a divi- and pancreas, equitable distribution does not necessarily
sion of the Department of Health and Human Services mean the sickest patient gets priority. Rather, the intent
(DHHS). NOTA also required that data be kept on all of these allocation schemes was to optimize utility by aim-
donors and recipients through the Scientific Registry of ing to increase graft survival and improve the overall ben-
Transplant Recipients (SRTR).7 efit to the most patients. Allocation schemes are always
The only organization that can procure deceased under constant review and improvement. For example,
human organs for transplantation by federal law8 is an the original allocation scheme for liver transplantation
organ procurement organization (OPO). The OPO man- was based on subjective assessment of the status of disease
ages donors within a donor service area (DSA), from the and waiting time. Over time a major disparity was
identification and consenting process to the clinical care observed in waiting time to transplant between different
of the donor and facilitation of the operative recovery of geographical areas. The main complaints regarding the
organs. Each OPO is responsible for the care of donors system were that it lacked adequate objectivity and that
identified within its DSA and placing the donor organs patients could not control where they lived or when they
with transplant centers based on match runs generated by were listed, leading to the development of a new alloca-
UNOS through computerized algorithms.6 In addition tion scheme based on more objective criteria.9
to clinical services, OPOs participate in educating the
public about organ donation, facilitate donor family ser- The Impact of the Final Rule
vices, and work with hospitals to develop policies to
enhance organ donation. When new regulations are In 2000 the DHHS implemented the Final Rule,10 estab-
enacted (for example, that all hospitals must have a DCD lishing a new set of regulatory standards for OPTN oper-
policy to participate in Medicare), it is often the OPO ations. Among the many refinements included in the
that helps formulate this policy to keep its partner hospi- Final Rule, those pertinent to regulation of organ alloca-
tal compliant. It is important to point out that after con- tion sought to create a level playing field regarding organ
sent for donation is obtained, all costs incurred for the allocation and to reduce inequities resulting from socio-
care of the donor and the procurement procedure are economic status. The policies mandated in the Final Rule
billed directly to the OPO for distribution among its vari- are developed through the UNOS committees, are bind-
ous organ cost centers as prescribed by law and never to ing upon OPTN members, voted on by the UNOS board
the donor. of directors, and subject to approval by the secretary of
the DHHS. Hospitals that receive organs for transplant
and OPOs that manage organ procurement must be
Organ Allocation members of the OPTN and abide by these rules. This is
In the loosest of terms, allocation policy is regulation. the genesis of the MELD allocation system in 2002.
Because UNOS is a membership organization, the devel- The Final Rule called for greater objectivity to be
opment of policy is a complex process that by necessity achieved through the use of an easily measured, repro-
takes into account the needs of various stakeholder com- ducible, continuous medical severity score so that liver
mittees and professional and lay opinions, goes through a allocation could be more equitable. The MELD score
public comment cycle, and requires various levels of was developed from data collected on ESLD patients
approval and computer programming before the policy undergoing transjugular intrahepatic portosystemic shunt
can go into effect. It requires monitoring and constant (TIPS) placement.11 The score uses easily measured,
adjustment through the input of data from the SRTR and objective laboratory data that reliably predict in most
the UNOS committee structure. cases the survival of ESLD patients waiting for transplant.
From a regulatory standpoint, the allocation of The overall objectivity of the MELD score and the ease
deceased donor organs is essentially defined by the with which it can be tracked have made the job of moni-
UNOS policy that prioritizes patients on the waiting list. toring compliance with the regulations more straightfor-
Several major competing factors affect the distribution of ward for UNOS and the OPTN.
organs. Although there are some overarching guidelines,
these factors tend, in general, to be organ specific. First,
Donor-Recipient Matching
the ideal situation for immediate lifesaving organs such as
liver, heart, and lung is for the sickest patient that can Matching donor organs to recipients is a complex process
survive a transplant to receive the organ first, regardless regulated by UNOS policy and carried out by OPO per-
of location. Unfortunately, the amount of time the organ sonnel and other transplant professionals. When a patient
can remain viable while cold preserved is limited, and is listed by a transplant hospital, he or she is placed on a
thus with current technology it is not logistically possible centralized national list maintained by UNOS. When a
86 PART I General Considerations

donor becomes available, OPO personnel enter the donor interest. Because of concerns about autoresuscitation
data into the UNOS computer system and a match run is after withdrawal of support, the report recommended a
produced for each organ available for transplant. OPO waiting period after declaration of death before proceed-
personnel then call the transplant surgeon or the sur- ing with organ procurement. Finally, recommendations
geon’s designee (physician, coordinator) for the first were made to consider donor family options and to
recipient on the match run, and the surgeon (designee) increase funding to support implementation of the proto-
determines if the donor is appropriate for the recipient. If cols and education of the transplant community and pub-
the pair is declined, the next donor-recipient pair is lic. Our professional societies have made progress on
offered in sequence until the organ is placed. standardizing some of these recommendations; however,
as discussed later, wide variability remains in DCD pro-
Direct Donation curement protocols in the United States.

Recipients for organs must always appear on a UNOS

Use of Marginal Grafts
match run for safety reasons. There are two instances,
however, in which an organ can be allocated permissibly The identification of donor and recipient factors that
out of sequence. One is when a donor or donor family affect transplant outcomes has been facilitated in no small
requests that an organ be directly donated to a specific part by the extensive data collection required by NOTA
recipient, usually a friend or family member. The UAGA and refined by the Final Rule. As a result, transplant phy-
legalizes the practice of direct donation. Although not all sicians are faced with the following challenge: how can
states have enacted the updated anatomical gift laws, no physicians adequately explain to patients the risks and
states forbid the practice.12 OPTN policy provides for benefits of using a less-than-ideal graft, knowing that it is
direct donation as long as there is no evidence of financial more likely to result in a worse outcome than a perfect
influence on the donor family to do so and the recipient graft but that it may be better than waiting on the list,
is a listed, viable medical candidate for transplant. The given the limited supply of organs? Equally important,
other circumstance in which organs may be placed out of how are physicians to evaluate patients’ understanding of
sequence is when an OPO is having difficulty placing these risks and benefits? Excellent evidence-based work
organs from a marginal donor and time limitations man- has been done to determine the right decision medically,
date that they expeditiously place organs with known but helping patients understand is a different problem
aggressive centers. altogether. So far in this regard, regulation has been lim-
ited to the elements that should be contained within an
informed consent without specifying the content. There
Increasing the Donor Pool is some movement underway at UNOS to have policy
Donation After Cardiac Death Versus Donation accompanied by acceptable or suggested verbiage to help
After Brain Death standardize these consents and to help patients under-
stand these risk/benefit profiles.
Given the aforementioned disparity between organ sup-
ply and patient demand, the transplant community is
continually looking to maximize the deceased donor ETHICS
organ pool. In recent years this has led to focused efforts
to use more marginal donors, including DCD donors Donation After Brain Death:
that were used before brain death was recognized. Nonmaleficence and Brain Death Criteria
In 1997 the Institute of Medicine (IOM) was asked to
study the practice of procurement of organs from DCD Transplant physicians and surgeons have always been
donors. The 1997 study, referenced in the 2006 report,13 guided by the principle of nonmaleficence, that is, to do
found considerable variation among OPOs and trans- no harm, which is one of the four basic sources of ethical
plant hospitals regarding policy and procedure for DCD value. For transplant physicians to be compliant with the
procurements. Differences in the definition of death, principle of nonmaleficence, patients must be declared
antemortem donor patient medical interventions, and dead before the removal of any vital organs from donors
attention to donor family options were significant areas for transplantation.14 Before the development of mechan-
of concern. The IOM report stated that DCD donor pro- ical ventilation and modern critical care support, there
curement is an ethically acceptable and medically neces- was little ambiguity to the definition of death. Patients
sary way to increase the number of implantable organs. were considered dead when they no longer had evidence
However, the IOM made several strong recommenda- of ventilation, circulation, and neurological function.15
tions. First, to ensure uniformity the report recom- Unfortunately, organs from such cadaveric patients were
mended that all hospitals have written, locally approved not suitable for transplantation. However, with advances
DCD procurement protocols and that the protocols be in intensive care support, it became possible for patients
made available to the public. This recommendation was to have ventilation and circulation maintained in the
adopted as a condition of hospital participation in Medi- absence of full neurological function. With these techno-
care funding. Second, the IOM recommended that the logical developments the traditional concepts defining
decision to withdraw care be made independently of, and death became obsolete, and the criteria for brain death
before, the initiation of any discussion regarding organ were subsequently defined in the UDDA in 1981.2 These
donation to prevent even the perception of a conflict of criteria are now the standard for determining death and
 7 Donation After Cardiac or Brain Death: Regulatory and Ethical Principles 87

suitability for organ donation in the United States and purposeful or voluntary behavioral responses to visual,
throughout much of the world. auditory, tactile, or noxious stimuli and have no evidence
of language comprehension or expression.22 The apparent
permanent state of unconsciousness in patients in PVS
Brain Death Versus Cardiac Death
has led some individuals to compare them to patients that
As noted previously, the traditional definition of death meet brain death criteria. However, patients in PVS
was grounded in circulatory criteria. However, severe maintain independent respiratory and cardiac function
neurological injury can be the cause for cessation of car- and may survive years with basic nursing care and nutri-
diac and respiratory function for some patients, although tional support.23 Furthermore, physicians are unable to
the time between the brain injury and the cessation of predict which patients in PVS may regain consciousness
circulation will be limited without critical care support. after a prolonged period of time. These variables pre-
Advances in ventilatory and intensive care unit (ICU) clude consideration of patients in PVS for organ dona-
support of severely brain-injured patients ultimately led tion, because to do otherwise would violate the principle
to the need to determine which, if any, life-sustaining of nonmaleficence.
interventions physicians could remove without violating
the principle of nonmaleficence.16 The development of a Severe, Irreversible Brain Injury Versus Brain
definition of brain death using neurological criteria was Death
also a critical turning point in the field of transplantation,
because successful transplantation requires organ recov- Patients may also suffer a severe, irreversible brain injury
ery in circumstances that minimize ischemic damage. in which the majority of brainstem reflexes are absent but
Although the criteria defined in the UDDA remain there is some residual neurological function present that
the accepted standard for determination of death, debate precludes fulfilling brain death criteria.24 Unlike patients
persists over the concept of “irreversible cessation of all in PVS, those with a severe, irreversible brain injury are
functions of the entire brain” as stated in the UDDA. dependent on cardiopulmonary intensive care support for
The concept of “whole brain death” is often challenged their survival. These patients presumably have a perma-
on several fronts. For example, many brain-dead patients nent state of unconsciousness, and they fail to achieve
maintain hypothalamic endocrine function,17 whereas medical stability in a non-ICU setting; most die despite
other brain-dead patients may have evidence of cerebral maximal critical care support.24 In some cases, medical
electrical activity on EEG18 or the jaw jerk and snout futility leads the appropriate legal representative to per-
reflexes.19 These findings have led some to conclude that mit the withdrawal of life support.25 Thus patients with a
organ donation based on brain death criteria might vio- severe, irreversible brain injury may become potential
late the principle of nonmaleficence and that organs organ donors under controlled DCD protocols, as dis-
should be procured only from cadavers declared on the cussed in the next section. This carries with it a different
basis of circulatory criteria to ensure that organ donation set of ethical challenges and consequences both in the
is never the cause of death. However, supporters of the ICU and in the operating room.
UDDA whole brain death criteria counter by noting that
the residual functions described do not constitute mean-
ingful brain function. Furthermore, the clinical features Donation After Cardiac Death:
used to diagnose brain death evolved from the finding Nonmaleficence, Benefit, and
that patients with these clinical features inevitably have a
cardiac arrest within 1 to 2 weeks despite maximal life
Utilitarianism
support.20 In addition, there are no documented cases in In the early 1990s controlled DCD organ donor proto-
which a patient meeting the UDDA criteria for brain cols were developed in the United States, with the first
death ever regained consciousness.21 Taken together, it is protocol published by the University of Pittsburgh in
reasonable to conclude that using the UDDA neurologi- 1993.26 Under controlled DCD criteria, patients with
cal criteria for death determination does not violate the conditions such as an irreversible brain injury are removed
transplant physician’s obligation to honor the principle of from life support at the request of family members or
nonmaleficence. A full discussion of the ethical implica- individuals with medical power of attorney privileges.27
tions might also include examining other core values such After withdrawal of life support and declaration of cardiac
as autonomy, beneficence, and justice (and other noncore death by a nontransplant physician, attempts can be made
sources of ethical value), as well as the perspectives of to recover organs for the purposes of transplant. A critical
other stakeholders such as the donor and society, which is component of all DCD protocols is that the decision to
well beyond the scope of this chapter. withdraw life support is made by the patient’s family before
any decision to pursue organ donation.28 This component
Persistent Vegetative State Versus Brain of DCD protocols ensures that the decisions made for the
Death care of these patients are not based upon the utilitarian
reasoning that the organs from these patients can be used
Patients who are in a persistent vegetative state (PVS) for other patients’ benefit rather than prolonging the life
after a brain injury have complete unawareness of self and of their loved one. It is a critical concept that the physi-
their environment because of lack of cerebral function cians providing the care for these patients are not instigat-
but maintain hypothalamic and brainstem autonomic ing the decisions for withdrawal of care for the purpose of
functions.22 In addition, patients in PVS have no organ donation, because the lay public often has concerns
88 PART I General Considerations

about becoming an organ donor for fear that they may Unfortunately, there is no consensus as to what the
receive suboptimal care if they present to the hospital. duration of the observation time after pronouncement
However, there is a striking lack of uniformity in DCD of cardiac death must be to prevent autoresuscitation.
organ-recovery protocols in the United States. Current This controversy has fostered the current variability in
Centers for Medicare and Medicaid Services rules state the mandated waiting period in DCD protocols, which
that hospitals must have a DCD policy, but there is no typically ranges from 2 to 5 minutes.26 A recent study of
recommendation for best practices. For example, even several hundred DCD organ donors found that sponta-
within a single OPO, individual hospitals may have pro- neous return of cardiac activity was never observed
tocols that differ significantly from each other. DCD beyond 65 seconds of asystole.35 Furthermore, a system-
protocols often vary between recovery hospitals on the atic review of autoresuscitation found no instances of
following criteria: (1) where life support may be with- resumption of circulation in extubated patients who did
drawn (e.g., the operating room versus the ICU); (2) not receive CPR, even among the few patients who
whether family may be present at the time of life support demonstrated resumption of cardiac electrical activity.36
withdrawal; (3) who may withdraw life support and These findings have led to a consensus that mechanical
declare death (e.g., attending staff physician versus resi- asystole corresponds to cessation of circulation and that
dent house staff); (4) the dosage, timing, and ordering electrical asystole is not a requirement for cardiac death
source of donor organ-recovery drugs (e.g., heparin, anti- determination.27
biotics, phentolamine); (5) the length of time transplant These variations in policies clearly can place trans-
physicians must wait after pronouncement of death plant physicians at an ethical crossroads when they
before proceeding with organ recovery. Although this list attempt to optimize the organ quality for their potential
is certainly not an all-inclusive one, it highlights the ethi- recipients within the construct of current practices. For
cal challenges facing transplant physicians and OPOs example, some DCD protocols allow heparin administra-
when participating in DCD protocols. The potential tion before withdrawal of life support, whereas others
exists for DCD protocol violation because of confusion allow it to be administered only after withdrawal of life
over variation in institutional practices. Further, the support. The IOM has written that giving heparin, as
potential for ethical tension exists between the existent well as specified other medications to preserve organ
policies and the transplant physician’s legitimate desire to quality during the process, is reasonable and permissible
procure the best-quality organs for his or her patient, as under strict protocol.13 This certainly has important ram-
is examined in further detail in the next section. ifications for organ quality. Similarly, the variability in
the waiting period of 2 minutes versus 5 minutes will also
affect organ quality. From the perspective of the trans-
Criteria for Determination of Death in
plant physician, it is disconcerting that accepted practice
Controlled Donation After Cardiac Death
at one institution is not accepted at another and high-
Organ Recovery
lights the need for the development of a uniform national
Yet another challenge in controlled DCD organ recovery DCD policy.
is the ongoing debate over the criteria for determination
of death. Critics of DCD organ recovery argue that the Uncontrolled Donation After Cardiac Death
practice violates the principle of nonmaleficence because Organ Recovery
DCD donors fail to meet brain death criteria and may
have the potential for autoresuscitation or reversibility of The preceding section focused on the ethical issues
cardiac death if cardiopulmonary resuscitation (CPR) is involving controlled DCD organ recovery. A separate
initiated.26,29,30 Furthermore, DCD critics also argue that aspect of DCD organ recovery concerns the uncontrolled
some of the drugs (e.g., heparin) administered to DCD DCD organ donor. Uncontrolled DCD organ protocols
organ donors may hasten death and that other interven- involve patients who suffer an out-of-hospital cardiac
tions (e.g., placement of catheters for extracorporeal arrest in which resuscitation was initiated by an emer-
membrane oxygenation [ECMO]) are not being per- gency response team.37 If resuscitation is deemed unsuc-
formed for the benefit of the donors.29,31-33 These argu- cessful and the patient meets organ donation criteria and
ments assert the ethical impropriety that it is the process consent can be confirmed, organ recovery can be initiated
of DCD organ donation itself that causes or hastens the after a waiting period to ensure cardiac death. Spain has
donor’s death.26,28 the largest collective experience with uncontrolled DCD
If cessation of circulation were not irreversible when organ recovery,15,37 and there has been renewed interest
death is declared in DCD organ recovery, then transplant in uncontrolled DCD kidney recovery in the United
physicians would clearly be maleficent. However, care- States with the recent development of a protocol in New
fully designed DCD organ-recovery protocols ensure that York.38
the principle of nonmaleficence is upheld. Under DCD A critical aspect of any organ donation protocol, par-
organ recovery, a donor’s breathing, cardiac activity, and ticularly uncontrolled DCD recovery, is that of consent.
circulation must cease beyond the point when autoresus- In some countries, by law, there is “presumed consent”
citation can occur before initiation of organ recovery. for organ donation, and individuals must specifically des-
Because CPR will not be initiated (DCD patients have a ignate if they do not wish to be an organ donor. How-
do not resuscitate order in the chart), the DCD patient’s ever, the concept of presumed consent raises ethical
circulation has ceased permanently, and transplant physi- concerns that the rights of some individuals will be vio-
cians are not the proximate cause of the patient’s death.34 lated because their failure to “opt out” may be from a lack
 7 Donation After Cardiac or Brain Death: Regulatory and Ethical Principles 89

of understanding of the system. Presumed consent cre- donation. Done in this manner, both nonmaleficence and
ates an ethical dilemma between autonomy and benevo- the donor’s autonomy are protected.
lence because the decision must be made as to which
should take precedence: the individual’s right to self-
determination, which may be violated by unwanted organ REAL WORLD IMPLICATIONS: WHERE
donation under presumed consent, versus the greater REGULATIONS AND ETHICS COLLIDE
societal benefit to increased organ availability for trans-
plantation.39 In the United States consent can become an Conduct of a Donation After Cardiac Death
issue during organ donation when there is first-person Case
consent by the potential donor (for example, driver’s
license designation or state organ donor registry) but One area of transplantation in which regulatory policy
family members contest the organ donation. Although and ethics regularly intersect is during a DCD organ
first-person consent of a donor is legally binding, some recovery. As discussed in the previous section, a driving
hospitals or OPOs may elect not to proceed with organ force behind this is the lack of a uniform DCD policy in
donation without family consent, often out of desire to the United States. In this not-so-hypothetical example,
avoid stressful situations for their donor hospitals or bad the transplant surgeon may be involved in a DCD recov-
press. From an ethical perspective, not honoring the ery one week in which the donor medications (e.g., hepa-
individual’s first-person consent to be an organ donor is rin, antibiotics) are administered before withdrawal of life
a clear violation of his or her autonomy. support and the waiting time after pronouncement by the
Several features of the New York protocol have raised critical care team is 2 minutes, and the following week, at
concerns that the ethical rights of potential donors may another recovery in a different hospital even within the
be violated.40 In the protocol if emergency responders same DSA, the donor medications cannot be adminis-
decide to terminate resuscitative efforts because of pro- tered until the time of pronouncement and the waiting
nouncement of cardiac death and first-person consent for period after declaration of death is 5 minutes.43 The
organ donation is verified, a separate organ-recovery transplant surgeon has the ethical obligation to ensure
team will perform a neurological examination to ensure that his or her care of the donor does not violate the prin-
absence of brainstem reflexes, then administer heparin ciple of nonmaleficence and is not driven by beneficence
and resume cardiopulmonary support of the donor dur- for the potential organ recipients manifested through the
ing transportation to the hospital.38 Brainstem assess- surgeon’s desire to optimize the quality of the organs for
ment will be repeated at the hospital to be certain that those potential recipients. If not carefully weighed, these
donation procedures do not prevent “natural progression two goals can be incongruent and lead to decisions that
to irreversible brain death,” and after confirmation of strain regulatory policy.
absent brainstem function, normothermic ECMO will be There are also several other important regulatory con-
established with placement of a balloon in the abdominal siderations in any DCD organ recovery. It is critical that
aorta to prevent brain circulation.38 the transplant team members not be involved in the death
Opponents of this uncontrolled DCD protocol argue pronouncement of the patient, and they should not be in
that the possibility exists that the DCD donor could be the same room at the time the critical care team is assess-
declared “dead” even though that person’s brain may ing the patient after withdrawal of life support.43 In addi-
have the potential for continued functioning, because tion, transplant team members must not participate in the
only a clinical evaluation is performed without confirma- orders or decision to administer any non–procurement-
tory tests.37 Adding to this concern is the question of specific medications (such as narcotics or sedatives) that
whether the waiting periods specified in uncontrolled the critical care team may decide to administer during
DCD protocols are long enough to ensure total brain withdrawal of care. It is crucial to avoid any potential
failure.30 Advocates of uncontrolled DCD policies coun- association with these medication decisions, for to do oth-
ter by pointing out that loss of circulation quickly results erwise could be construed as the transplant team ordering
in irreversible loss of brain function if no attempt to these medications to hasten cardiac death, potentially
restore cardiac activity is initiated.41 It has also been motivated by their desire to obtain the highest quality
argued that this protocol, which restores donor circula- organ for their recipients. There may even be legal impli-
tion with chest compressions, mechanical ventilation, and cations if one fails to abide by these rules, as demonstrated
ECMO, may lead to the conclusion that death was pro- by a court action against a transplant surgeon charged
nounced inappropriately.42 For example, some physicians with, and later acquitted of, dependent adult abuse for
argue that ECMO prevents the inevitable progression of ordering excessive doses of narcotics after withdrawal of
brain ischemia necessary to lead to brain death because life support during a DCD organ recovery.44
oxygen and blood flow are restored to the brain.42 It is In conclusion, DCD organ recovery will continue to
likely that these concerns led to the requirement in this be controversial even if a uniform policy is adopted in the
protocol to include brainstem assessments and insertion future. Given the relative rarity of DCD organ donors
of a balloon in the aorta to prevent reperfusion of the versus DBD organ donors, many hospitals and their staff
brain.33 With the specifications of the current protocol members will still lack familiarity and comfort with DCD
under consideration in the United States, organ recovery organ procurement. It will remain the transplant team’s
would be initiated only under circumstances in which responsibility to mediate these situations and to ensure
cardiac death has already been declared and there has that the DCD protocol is understood and followed by all
been verification of prior first-person consent for organ participants. Taking time before the case to discuss the
90 PART I General Considerations

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18. Truog RD, Fackler JC. Rethinking brain death. Crit Care Med.
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dead brain stem. Br Med J. Jan 8 1983;286(6359):123-124.
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the best intentions, the desire to do good for patients based guideline update: determining brain death in adults: report
with the limited resources available can put ethical values of the Quality Standards Subcommittee of the American Academy
and the regulations that govern organ allocation into of Neurology. Neurology. Jun 8 2010;74(23):1911-1918.
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sistent vegetative state. N Engl J Med. 1994;330:1499-1508.
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Pearls and Pitfalls scious states. Rev Neurosci. 2009;20(3-4):203-220.
24. de Groot YJ, Jansen NE, Bakker J, et al. Imminent brain death:
• Though the goals are to have them in harmony, the point of departure for potential heart-beating organ donor recog-
regulations that govern deceased organ donation and nition. Intensive Care Med. Sep 2010;36(9):1488-1494.
the ethical principles by which they are practiced are 25. Wilkinson DJ, Savulescu J. Knowing when to stop: futility in the
ICU. Curr Opin Anaesthesiol. Apr 2011;24(2):160-165.
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• Transplant teams must adhere to the specific policies donation. Philos Ethics Humanit Med. 2007;2:17.
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when traveling away from the home transplant center. 2006;6(2):281-291.
• Many donor hospitals have individualized DCD pro- 28. Truog RD, Miller FG. Counterpoint: are donors after circulatory
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with the specifics at each hospital either at the time of 2010;138(1):16-18; discussion 18-19.
the organ offer, if that would make a difference in ac- 29. Verheijde JL, Rady MY, McGregor J. Recovery of transplantable
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33. Gravel MT, Arenas JD, Chenault 2nd R, et al. Kidney transplanta- 39. Beloucif S. Opt-in or opt-out for organ transplantation. Curr Opin
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 CHAPTER 8

Current Indications,
Contraindications, Delisting
Criteria, and Timing For
Transplantation
Vandana Khungar • Alyson N. Fox • Robert S. Brown, Jr.

CHAPTER OUTLINE

ORGAN ALLOCATION SYSTEM Cholangiocarcinoma

Hepatocellular Carcinoma
THE EVALUATION
Inherited/Metabolic Liver Disease
MANAGEMENT ON THE WAITING LIST Autoimmune Liver Disease
INDICATIONS FOR TRANSPLANTATION Vascular Disorders of the Liver
Alcohol-Related Liver Disease Fulminant Hepatic Failure
Hepatitis C CONTRAINDICATIONS FOR TRANSPLANT
Hepatitis B Absolute Contraindications
Cholestatic Liver Disease Relative Contraindications
Malignant Diseases of the Liver
CONCLUSION

Liver transplantation (LT) is now a widely accepted more sophisticated, and awareness of transplantation is
lifesaving therapy for the complications of cirrhosis and more widespread. Overall patient survival at 1, 3, and
acute liver failure. Before the availability of LT, medical 5 years is currently 87%, 78%, and 73% respectively.3
management provided a temporizing measure but not a With these improvements the number of transplant can-
definitive cure for the complications of end-stage liver didates and recipients has grown. Each year approximately
disease (ESLD). Chronic liver disease accounts for more 6,000 patients in the United States with ESLD receive a
than 2 million outpatient visits and more than 750,000 liver transplant. Unfortunately, because of current organ
hospitalizations per year in the United States.1 More than shortages, 5% to 10% of patients listed for liver transplant
40,000 patients progress to ESLD, liver failure, and death die each year without receiving an organ. As with any lim-
annually. Acute or fulminant liver failure accounts for ited resource, principles of distributive justice must be
2,000 patients every year in the United States.2 considered and paradigms created to allocate this scarce
Dr. Thomas Starzl is acknowledged as the first person resource. With that in mind, it is vital to have a clear
to successfully perform deceased donor LT in the 1960s. understanding of the indications, contraindications, del-
In the 1970s developments in surgical techniques helped isting criteria, and timing of LT to maximize appropriate
to advance the field, but rejection of the organ was a lim- use of a limited resource. It is also important to keep in
iting factor in survival. mind that the indications and contraindications for listing
A vital discovery in the advancement of the field was the are perpetually changing as new data emerge about the
development of cyclosporine in 1979 by Sir Roy Calne. most efficient and fair method of distributing organs.
Cyclosporine allowed for longer graft and patient survival.
In 1983 the National Institutes of Health deemed that LT
was no longer an experimental therapy. Shortly thereafter ORGAN ALLOCATION SYSTEM
the United Network for Organ Sharing (UNOS) was
developed to manage organ procurement, allocation, and The organ allocation system has caused more controversy
distribution and still exists today. Thirty years later, surgi- and discussion than any other in the field of LT. The
cal techniques have been refined, medical therapies are ­earliest system was based on the Child-Turcotte-Pugh

94
 8 Current Indications, Contraindications, Delisting Criteria 95

(CTP) score. The CTP score takes into account the pres- priority. Waiting time becomes a secondary factor because
ence of hepatic encephalopathy, ascites, serum bilirubin, waiting time accrued at prior lower MELD scores is not
albumin, and increase in prothrombin time above control included and thus only the waiting time at the highest
values.4 From 1 to 3 points for each of the five parameters MELD score is used for ties. Thus the prioritization is
are assigned, and then a score is calculated with 5 to 6 now based on severity, rather than waiting time. Imple-
points being class A, 7 to 9 points class B, and 10 to 15 mentation of the MELD system led to the first reduction
points class C. CTP class A patients have compensated dis- in liver transplant waiting list registrations in the history of
ease with better prognoses, and class C represents severely LT, and the median waiting time to LT decreased. It was
decompensated disease with poor prognosis. Before 2002 found that in patients with MELD scores of 14 or below,
the CTP score was used to prioritize for the liver transplant the mortality rate with LT was higher than that of patients
waiting list, with listing using a status code (1, 2a, 2b, 3) with the same MELD score who had not undergone trans-
based on a combination of CTP class (B versus C) and if plantation (Fig. 8-1).8,13 Currently a MELD score higher
the patient was at home, in the hospital, or in the intensive than 15 is considered a valid indication for LT in patients
care unit. Because of the broad groups, priority was given with ESLD. At each liver center a detailed multidisci-
within each group to patients who had been on the trans- plinary evaluation is conducted to ensure that LT is both
plant list for a longer period, and waiting time became the feasible and indicated.
major driver of transplant priority. It also allowed for a There are limitations to the MELD system, and not all
degree of subjectivity and claims of altering the data by patients with ESLD are well served by the current system.
overstating the degree of subjective variables (ascites, Some have diseases that do not carry an immediate mor-
encephalopathy) to advocate for particular patients. It tality risk or a risk that is not manifest by elevation in the
became clear that a different method of determining international normalized ratio or bilirubin or creatinine
transplant priority was needed. levels (e.g., portal hypertension). Those with hepatocel-
A more objective, laboratory-based measure of the risk lular carcinoma (HCC) have a relatively well-preserved
for death on the waiting list was derived from a tool to synthetic function and were initially not given priority in
assess the risk for death after transjugular intrahepatic organ allocation, consequently suffering high dropout
portosystemic shunt procedures,5 the Model for End- because of tumor progression and thus mortality on the
Stage Liver Disease (MELD) score. This score is calcu- waiting list. HCC became the most common of several
lated from a logarithmic transformation of the serum accepted “MELD exceptions” to the standard allocation
bilirubin, international normalized ratio of prothrombin algorithm, which have been identified to be underserved
time, and serum creatinine. Though the values of MELD by the MELD score allocation system and which receive
have no upper bound, for organ allocation purposes the “exception points” to rise higher on the list. These include
minimum value is 1 for each value (to prevent negative HCC (and in some regions cholangiocarcinoma [CCA]),
logarithm values), for creatinine the maximum is capped amyloidosis, hepatopulmonary syndrome, and recurrent
at 4 (with a 4 given for hemodialysis), and the scale is cholangitis, which receive automatic increases with proper
capped at 40. This yields a MELD range from 6 to 40 for documentation. Other conditions, including refractory
adults, with an open-ended scale for children called the hepatic encephalopathy, portopulmonary hypertension,
Pediatric End-Stage Liver Disease model. The MELD intractable pruritus, Budd-Chiari syndrome, cystic fibro-
score was validated to predict short-term mortality for sis, hereditary hemorrhagic telangiectasia, polycystic liver
patients with chronic liver disease and subsequently disease, primary hyperoxaluria, and small-for-size syn-
adopted by UNOS in 2002.5-9 Following the change to drome, can receive extra MELD points if approved by a
the MELD system, median waiting time was reduced, regional review board.
waiting list size decreased (6% reduction), new waiting list Some studies have tried to improve the predictive
registration decreased (12% reduction between February accuracy of the current MELD system to address the
2002 and February 2003) with increased rates of trans- populations that are underserved by the model. Values
plantation (6% increase) as patients who were more such as serum sodium (MELD-Na), age (integrated
gravely ill were prioritized.10-12 As a result, waiting list MELD), albumin, and ΔMELD, using a time-dependent
mortality was reduced without adversely affecting post- analysis, have all been examined, but the standard MELD
transplant survival. remains the model used at the present time. Other cri-
One group of patients that takes precedence over those tiques of the MELD system are that it has increased the
with the highest MELD scores is those with acute liver number of combined liver/kidney transplants and the
failure, including those with primary nonfunction of a transplants for HCC, increasing the waiting time and
transplanted liver. The need for rapid transplant in this waiting list mortality for patients without HCC. Finally,
group and its relative rarity (<10% of total transplants) though it addresses prioritization within each organ allo-
has allowed these most critically ill patients to be better cation unit, it has not significantly affected allocation
served in recent years with an allocation system that and has not substantially reduced geographical differ-
allows for acute liver failure patients to be listed above ences in organ availability. A study of the impact of the
chronically ill patients. MELD system in Switzerland showed that post MELD
Allocation of livers to patients with chronic liver disease there was a lower mortality on the waiting list (386 ver-
is conducted slightly differently. Since February 2002, sus 242 deaths per 1000 patient-years, P < .0001), increased
allocation of organs has been from the highest MELD to posttransplant morbidity mainly because of renal failure
the lowest MELD. Through the MELD system, patients (46% versus 13%, P < .0001), and a 55% increase in the
with the highest risk for short-term mortality are given cost of LT. The increase in cost is likely due to the
96 PART II Patient Evaluation: Adult

Hazard ratio
4

0
6-11 12-14 15-17 18-20 21-23 24-26 27-29 30-39 40
MELD
Hazard 3.64 2.35 1.21 0.62 0.38 0.22 0.18 0.07 0.04
ratio
P <.001 <.001 0.41 <.01 <.001 <.001 <.001 <.001 <.001
values
FIGURE 8-1 n The Model for End-Stage Liver Disease (MELD) has been shown to predict survival of patients while awaiting transplan-
tation. Patients with MELD scores higher than 15 derive a survival benefit with each subsequent point increase in their score.

transplantation of sicker patients who require more 3. Are there other comorbid conditions that severely
costly procedures and prolonged stays in the intensive limit patient survival, making transplantation
care unit.14 inappropriate?
Data from the Scientific Registry of Transplant Recip- 4. Can the patient comply with the complex medical
ients showed that liver transplants for candidates with regimen required after transplantation?
low MELD scores (<15) were associated with a higher 5. Is the recurrence rate of the disease in the trans-
risk for death with the transplant than that of similar can- planted liver acceptable?
didates who remained on the waiting list.13 This realiza- The process involves intense medical, surgical, psychi-
tion led to modifications of the allocation policy in 2005 atric, social, and financial screening to identify those who
under a rule called Share 15. The previous process of may have contraindications to solid organ transplantation
offering donor livers to all candidates within the donation (Table 8-1). Once the screening is completed, a commit-
service area of the local organ procurement organization tee, usually composed of hepatologists, transplant sur-
in descending order of MELD 6 to 40 was changed to geons, transplant coordinators, psychiatrists, and social
allow for regional candidates with MELD scores above workers, comes together to determine who is appropriate
15 outside the local area to receive offers before local can- for listing based on objective and subjective criteria. Once
didates with MELD scores below 15.15 a patient is deemed to be an appropriate candidate for
transplantation, he or she is placed on the national UNOS
waiting list.
THE EVALUATION
The evaluation process for LT seeks to define patients MANAGEMENT ON THE WAITING LIST
who will obtain the most benefit from transplantation,
have the best chance for postoperative recovery and sur- The transplant team must assist in the medical care of a
vival, and will value and take care of the precious resource patient who is listed for LT and awaiting an organ. This
(the organ graft) afforded to them.16 Referral is made includes standard screening and surveillance procedures
once liver failure develops, ideally in a timely fashion to for patients with decompensated cirrhosis, including
allow for a thorough assessment for candidacy. There are esophagogastroduodenoscopy screening for varices, pri-
several basic questions that must be answered, including mary or secondary prophylaxis against variceal bleeding,
the following17-19: HCC screening, and treatment of complications of ESLD,
1. Is there an alternative treatment for the liver including ascites, encephalopathy, gastrointestinal bleed-
disease? ing, and HCC. MELD scores are updated approximately
2. Can the patient survive the operation and postop- every 3 months on average, or when clinical deterioration
erative period? occurs.
 8 Current Indications, Contraindications, Delisting Criteria 97

TABLE 8-1 Components of Evaluation for Liver Transplantation*

Medical evaluation Review of medical records
History and physical examination by transplant hepatologist and transplant surgeon
Laboratory evaluation Electrolyte levels; liver function tests; complete blood count; coagulation studies; hepatitis
serological tests; markers for autoimmune, inherited, and metabolic liver diseases; blood
typing with antibody screen; RPR; EBV, CMV, and HIV testing; thyroid function studies
Radiological evaluation Abdominal sonogram with Doppler evaluation
Contrast-enhanced abdominal imaging
Bone density scan
CT scan of the chest (if HCC)
Cardiac evaluation Electrocardiogram
Echocardiogram (with agitated saline injection)
Nuclear stress test (if age >45 yr or cardiac risk factors are present)
Coronary catheterization (if stress test results are abnormal or high risk for cardiac disease)
Right heart catheterization (if increased pulmonary pressures on noninvasive studies)
Cardiology consultation
Pulmonary evaluation PPD testing
Chest radiograph
Pulmonary function testing
Room air arterial blood gas levels
Shunt fraction study if evidence of intrapulmonary shunt
Pulmonary consultation
Neurological evaluation Carotid Doppler if age >60 yr
Neuroimaging and neurology consultation if history of neurological disorder
Age-appropriate cancer Papanicolaou test
screening Mammogram
Colonoscopy
PSA
Psychosocial evaluation Psychiatry consultation
Social work consultation
Financial counselor consultation
Nutritionist consultation

*These are standard tests performed at many centers, though substantial variation may occur.
CMV, Cytomegalovirus; CT, computed tomography; EBV, Epstein-Barr virus; HCC, hepatocellular carcinoma; HIV, human immunodeficiency
virus; PPD, purified protein derivative; PSA, prostate-specific antigen; RPR, rapid plasma reagin.

As stated earlier, patients with MELD scores less INDICATIONS FOR TRANSPLANTATION
than 15 do not have a survival benefit in the first year,
and there is a larger survival benefit for each increase in LT is indicated in a variety of disease states (Table 8-2
the MELD score above 15.13 Other studies have shown and Fig. 8-2).13 Specifically, when a patient develops
the MELD score to be a relatively poor predictor of sequelae of chronic liver disease such as portal hyperten-
transplant outcomes in all except those with the highest sion or hepatocellular carcinoma, it is appropriate to refer
20% of MELD scores.20 There is no absolute MELD for transplantation. Referral for transplantation should
cutoff for transplant futility. For living donor recipi- also be considered for the rare disease states in which the
ents, an analysis of UNOS data determined the follow- liver is not failing but causing other systemic disease (e.g.,
ing to be predictors of allograft failure and need for amyloidosis or oxaluria). The benefit of transplantation
retransplantation: location in the intensive care unit must be weighed against the considerable potential mor-
before transplantation, retransplantation, female donor bidity and mortality of undergoing a major surgical proce-
to male recipient, age older than 44 years, and recipient dure. Therefore transplantation is generally reserved for
race.21 While considering patients on the waiting those who are felt to have a poor quality of life and high
list, remember to continue to reassess their medical mortality without transplant. Patients should be projected
conditions. to have a longer life with transplant than in its absence,
A decision is made to delist or temporarily deactivate referred to as transplant survival benefit.
patients from the transplant list if it is determined that
the patient would not derive a survival benefit from the Alcohol-Related Liver Disease
transplant, either from deterioration of their condition or
rarely, from improvement to the point that the risks of Alcohol-related liver disease represents the most com-
LT now outweigh the benefits. Factors that have an mon cause of cirrhosis in the United States. In addition to
adverse impact on the likelihood of posttransplant sur- alcohol being a primary cause of end-stage liver disease, it
vival include mechanical ventilation, requirement for is frequently a cofactor in the development of advanced
hemodialysis, fungal or resistant bacterial infections, and liver disease in patients with other diagnoses. Given the
a previous transplant. When several of these factors are stigma associated with alcoholism, the issue of transplan-
present, the posttransplant risk becomes prohibitive and tation for alcohol-related liver disease remains highly
transplant should be deferred. charged, particularly in the public eye.
98 PART II Patient Evaluation: Adult

Because active alcohol use is a contraindication to

TABLE 8-2 Indications for Liver Transplantation
transplant in most U.S. centers and because abstinence can
Viral result in reversal of illness, it is not the leading indication
Hepatitis C for transplant. In those with a history of excessive alcohol
Hepatitis B use, most centers require a period of documented absti-
Autoimmune liver disease nence before consideration of transplant. Typically, many
Alcohol-related liver disease centers will require this period to be at least 6 months in
Inherited/metabolic liver diseases duration.22 Although a time frame of 6 months is not based
Hereditary hemochromatosis on rigorous well-controlled data, it is known that longer
α1-Antitrypsin deficiency abstinence periods predict lower rates of alcohol recidi-
Wilson’s disease vism. In addition, 6 months may be adequate time to allow
Nonalcoholic fatty liver disease for hepatic recovery if the alcoholic injury is reversible
Tyrosinemia with abstinence. This delay in transplantation could pre-
Type IV glycogen storage disease vent an unnecessary transplant in a patient who will
Neonatal hemochromatosis recover without the need for transplant. This period also
Amyloidosis allows us to identify those at risk for return to drinking and
Hyperoxaluria allows for intensive therapy and counseling.
Urea cycle defects More recently centers around the world have explored
Amino acid defects the possibility of transplantation before 6 months of
Cholestatic liver disease abstinence for the indication of severe alcoholic hepatitis.
Primary biliary cirrhosis In the United States most centers require 6 months of
Primary sclerosing cholangitis abstinence. Those with severe alcoholic hepatitis who are
Biliary atresia not responding to medical therapy have a 6-month mor-
Alagille syndrome tality estimated at up to 70%. Recent retrospective stud-
Progressive familial intrahepatic cholestasis ies have shown that graft and patient survival have been
Cystic fibrosis similar in those transplanted for alcoholic hepatitis and
Bile duct loss others. Mathurin et al performed a prospective pilot
Malignancy study for severe alcoholic hepatitis that failed to respond
Hepatocellular carcinoma to prednisolone 40 mg/day for 7 days. In this highly
Cholangiocarcinoma selected group of patients with ideal psychosocial circum-
Fibrolamellar carcinoma stances, the primary end point of 6-month survival was
Epithelioid hemangioendothelioma 77.8% compared with 23.8% in historical controls.23
Hepatoblastoma This study demonstrated that in a population of highly
Metastatic neuroendocrine tumor selected patients, outcomes of transplantation for severe
Polycystic liver disease alcoholic hepatitis can be excellent. However, controversy
Vascular disorder surrounds this idea for several reasons, including the fact
Budd-Chiari syndrome patients with alcoholic hepatitis may improve on their
Fulminant hepatic failure own and there are no ideal prognostic scoring systems
Retransplantation (the Lille score is currently our best approximation). Fur-
thermore, there is still stigma associated with alcohol use,

Noncholestatic cirrhosis 72.6%

Cholestatic liver disease/

cirrhosis 9.6%

Acute hepatic necrosis 2.9%

Biliary atresia 1.2%

Metabolic disease 1.5%

Malignant neoplasm 3.0%

Other 9.3%

Unknown 0
FIGURE 8-2 n Distribution of diagnoses: U.S. waiting list characteristics, 2008. (Courtesy U.S. Department of Health and Human Services.
http://optn.transplant.hrsa.gov.)
 8 Current Indications, Contraindications, Delisting Criteria 99

and the idea that alcoholic liver disease is self-inflicted

persists. It may be difficult to achieve universal accep-
Hepatitis B
tance of transplant for alcoholic hepatitis in the near Before the use of hepatitis B immune globulin (HBIg) as
future because of these two reasons. Further studies will immunoprophylaxis after transplantation for chronic
hopefully clarify the issue and provide the transplant hepatitis B, recurrence of hepatitis B virus (HBV) in the
community with better prognostic scoring systems so liver allograft occurred in up to 80% and was usually
that patients with alcoholic hepatitis who would recover complicated by graft dysfunction and death. Recurrence
without transplant do not undergo LT. Also with more of hepatitis B surface antigen in serum was associated
investigation and attention given to the disease, the with the development of a fibrosing cholestatic hepatitis
stigma associated with it will likely decrease over time. and graft loss with 1-year mortality higher than 50%.
In those who can achieve the period of abstinence, a Because of these dismal outcomes, HBV was initially
transplant team may rely heavily on a social worker, coun- viewed as a contraindication to transplantation.
selor, or psychiatry consultant and a structured rehabilita- It is clear that pretransplant control of the virus is
tion program to maximize the likelihood of a successful important in preventing graft reinfection. With the avail-
intervention. Although recidivism after transplant is com- ability of antiviral medications with a high genetic barrier
mon (approximately 30%), problem drinking is rare, and to resistance, suppression of the virus before transplant is
recurrent alcohol use rarely causes significant graft dys- feasible. The combination of HBIg with oral antivirals
function and is not associated with decreased survival.24 has allowed HBV-infected patients to go from having the
poorest posttransplant outcomes to having survival rates
Hepatitis C among the best of all transplant recipients.28 With the use
of HBIg and oral nucleos(t)ide therapy, the 5-year graft
Cirrhosis resulting from chronic hepatitis C virus (HCV) survival for those transplanted for HBV is 85%, and
infection remains the leading indication for LT in the retransplantation for recurrent HBV cirrhosis is rare.
United States. Without curative treatment before trans-
plant nearly all grafts will become reinfected immediately
after transplant.25 In the posttransplant setting, HCV
Cholestatic Liver Disease
infection appears to be accelerated, leading to high rates Primary biliary cirrhosis (PBC) and primary sclerosing
of graft dysfunction and loss with decreased survival com- cholangitis (PSC) are the two adult-onset cholestatic
pared to those transplanted for other indications.26,27 To disorders that commonly lead to ESLD requiring trans-
mitigate this effect, transplant physicians should be pro- plantation. Patients with PBC may experience the com-
active in terms of developing antiviral strategies to reduce plications typical of cirrhosis but additionally may suffer
or eliminate the viral burden before transplantation and from disease-specific complications such as xanthelasma
thus decrease posttransplant recurrence. To prevent graft development, metabolic bone disease, and intractable
compromise, consideration should be given to treating pruritus. Occasionally the pruritus that accompanies PBC
those with well-compensated disease who are awaiting can be so detrimental to quality of life that additional
transplant with antiviral therapy. This strategy may be MELD exception points can be assigned when the native
helpful to prevent graft infection; however, treatment MELD score is low. The Mayo risk score is a model
with interferon-containing regimens in this setting is developed in the late 1980s that incorporates patient age,
poorly tolerated. Once transplant has occurred, consider- total bilirubin level, serum albumin level, prothrombin
ation should be given to antiviral therapy, although it is time, and severity of edema to predict survival in patients
associated with its own set of unique challenges in the with PBC.29 Although this risk score is not used as an
posttransplant setting. Data with protease inhibitors in allocation tool for transplantation, it can be helpful to
the pretransplant and posttransplant period are prelimi- predict which patients should be considered for trans-
nary but encouraging, though the difficulties with inter- plant evaluation. Patients with a Mayo risk score that
feron and ribavirin persist in these regimens. The denotes greater than 10% 1-year mortality risk should be
development of novel all-oral direct-acting antivirals that sent for transplant evaluation. Outcomes of transplanta-
do not require interferon will likely revolutionize peri- tion for PBC are good, with survival rates at 1, 5, and
transplant management but will bring hurdles of viral 10 years reported as 83%, 78%, and 67%, respectively.30
resistance and drug-drug interactions. PBC is a condition that can recur after transplant; how-
Graft failure resulting from recurrent hepatitis C rep- ever, it is unclear whether or not this affects survival.
resents a major source of morbidity and mortality. Often Patients with PSC may be at a disadvantage for trans-
retransplantation must be considered in this setting; how- plant with MELD-based allocation. This disadvantage is
ever, the criteria that establish the standards for retrans- based upon the fact that they often have relatively pre-
plantation for recurrent hepatitis C vary from center to served synthetic function, leading to a low calculated
center. Patients undergoing retransplantation for HCV MELD score, but can suffer recurrent bouts of cholangi-
disease have worse outcomes than recipients of primary tis. Cholangitis episodes can be used to petition for
transplants, and many centers will consider retransplant MELD exception points before life-threatening or
for HCV a contraindication, especially if the graft failure ­multidrug-resistant infection ensues. Up to 90% of those
has been rapid within the first year of transplant. How- with PSC may have concomitant inflammatory bowel
ever, it is not clear that outcomes for late retransplants (>1 disease. The risk for developing colorectal neoplasia in
year) from HCV are substantially worse than for other those with PSC is greater than with inflammatory bowel
causes of late graft failure. disease alone, so it is critical that these patients undergo
100 PART II Patient Evaluation: Adult

routine endoscopy pretransplantation and posttransplan- two to three lesions each ≤3 cm).35 Patients diagnosed
tation.31 As with PBC, the severity of illness from PSC with HCC who meet the Milan criteria are allocated
has been modeled with a Mayo risk score that incorpo- MELD exception scores that increase every 3 months
rates patient age; bilirubin, albumin, and aspartate ami- until the patient is offered a liver, suffers a complication,
notransferase levels; and history of variceal bleeding to or has progressive tumor. The rationale for assigning
determine survival.32 Recurrent PSC is uncommon but exception points lies with the fact that frequently these
can be difficult to manage with recurrent cholangitis and patients have very low calculated MELD scores and
secondary biliary cirrhosis in the graft. exception points afford them the chance to be competitive
for liver allocation before their malignancy worsens and
precludes transplant.
Malignant Diseases of the Liver While patients are on the list, most centers elect to
Primary malignant diseases of the hepatobiliary tract apply various modalities of locoregional therapy to reduce
such as HCC and CCA represent increasingly important tumor burden, thereby preventing recurrence and pro-
indications for transplant. When resection of a primary gression while on the waiting list. In those who present
tumor is not feasible, LT can be an excellent option for with disease beyond or progress beyond the Milan crite-
providing cure. Extrahepatic spread of primary liver ria, there are increasing options. It has been shown that
tumors renders transplantation futile, because it is associ- extending the size limits beyond the Milan criteria may
ated with a high risk for tumor recurrence. be possible without sacrificing survival outcome.36 Like-
wise tumors beyond the Milan criteria may be eligible for
downstaging with the ultimate goal of transplantation.37
Cholangiocarcinoma Patients successfully downstaged to within the Milan
CCA is a highly malignant neoplasm that arises from the criteria can petition for MELD exception points.
bile duct epithelia. Sixty percent of cases are Klatskin
tumors that occur in the perihilar region at the confluence
of the right and left hepatic ducts. PSC is the most com-
Inherited/Metabolic Liver Disease
mon risk factor for the development of CCA. Currently α1-Antitrypsin deficiency, hereditary hemochromatosis
no medical therapies are proven effective for CCA. (HH), Wilson’s disease, and nonalcoholic fatty liver dis-
Median survival is 9 to 12 months, with long-term survival ease (NAFLD) are all causes of cirrhosis and can lead to
being infrequent. Even with resection, local recurrence is ESLD. This cluster of diseases is marked by systemic
common. Patients with PSC and CCA are poor candi- involvement and requires recognition of extrahepatic
dates for resection because their disease is more frequently sequelae to pursue safe LT.
multifocal and they often have cirrhosis, making the risk α1-Antitrypsin deficiency is a cause of panlobular pul-
for perioperative decompensation prohibitive. monary emphysema and liver disease in those with the
Because of high rates of recurrence and low long-term PiZZ phenotype. Typically in adults liver disease does
survival rates when compared to other indications, CCA not present until the fifth decade. Because of the coexis-
has been a contraindication to transplantation.33 The out- tent lung disease seen in this condition, a thorough pul-
comes of those undergoing transplant for CCA are mainly monary evaluation should be mandated during transplant
from ill-defined patient populations who were in various evaluation. Both adult and pediatric patients undergoing
disease stages who did not receive any adjuvant or neoad- LT for α1-antitrypsin deficiency have excellent outcomes
juvant chemotherapy. In 1994 a new management proto- with 1-, 3-, and 5-year survival reported at 89%, 85%,
col involving preoperative chemoradiotherapy followed and 83%, respectively, for adults and 92%, 90%, and
by LT for patients with localized perihilar CCA and 90% in children.38
regional lymph node–negative disease was introduced.34 HH is a disorder of iron overload that results in hepatic
With this new protocol 88% of patients were alive 1 year damage and cirrhosis. Survival after transplant for HH is
after transplantation, and 82% were alive at 5 years. These low compared to other causes, with 1-, 3-, and 5-year sur-
data suggest that the use of neoadjuvant therapy selects a vival rates of 64%, 48%, and 34%, respectively.39 These
group of patients with CCA who will probably achieve a low survival rates may be attributed to increased rates of
clear survival benefit from transplantation. However, this infectious and cardiac complications seen in this popula-
indication remains controversial, and LT in such patients tion.40,41 It is therefore critical that HH patients undergo
should probably be performed in the context of clinical a rigorous cardiac assessment before transplant.
studies at experienced centers at the current time. Wilson’s disease is a rare disorder that results in path-
ological copper accumulation in the liver, brain, and eye.
Patients with this disorder can present with either chronic
Hepatocellular Carcinoma liver disease or an acute fulminant liver disease. Wilson’s
Unlike CCA, there are robust data to suggest that those disease in the fulminant setting universally requires trans-
with limited HCC can undergo transplantation with a low plant, because most patients will not recover hepatic
recurrence rate and good long-term outcomes. A land- function. Survival after transplant is excellent with one
mark study by Mazzaferro et al showed that the 4-year series showing 1-, 3-, and 5-year survival at 89.1%,
survival after transplant was 75% and the recurrence-free 82.9%, and 75.6%, respectively.42 With brain involve-
survival was 83% if the intrahepatic tumors were of a ment, neuropsychiatric symptoms are found in one third
certain size and quantity. These size characteristics are of patients with Wilson’s disease. Therefore it is impor-
commonly termed the Milan criteria (one lesion ≤ 5 cm, or tant to have comprehensive neurological and psychiatric
 8 Current Indications, Contraindications, Delisting Criteria 101

assessment before transplantation, because patients with jaundice in someone without known preexisting liver dis-
severe neuropsychiatric symptoms can have decreased ease, remains an important indication for LT. Transplan-
survival after transplant. With this said, medical therapies tation for FHF accounts for less than 10% of all
are able to greatly improve and reverse neuropsychiatric transplants done annually in the United States. Acet-
symptoms in some, particularly in children. In those aminophen toxicity accounts for approximately half of all
whose neuropsychiatric symptoms are not reversed with cases of FHF.50 Patients with FHF resulting from any
medical therapy, LT will not reverse the symptoms and cause can progress to a state of critical illness rapidly and
calcineurin inhibitors can further worsen them. should be referred to a transplant center for liver trans-
NAFLD is an increasing indication for LT in the plant evaluation emergently. Although some patents will
United States. In 2001 NAFLD accounted for 1.2% of recover hepatic function, some causes of FHF are uni-
liver transplants and has risen steadily such that in 2009 it formly fatal if transplant does not occur. There are several
accounted for 9.7% of all transplants.43 Survival after tools designed to help predict which patients will recover
transplant for NAFLD is comparable to survival for other and which will ultimately require transplant. These tools
indications. Because NAFLD is associated with the meta- include the Kings College criteria and the Clichy criteria,
bolic syndrome, it is crucial to carefully screen patients for and even the MELD score has been applied in this set-
conditions such as cardiovascular disease, renal disease, ting.51-53 Although these prognostic models can be help-
insulin resistance, and hyperlipidemia during the trans- ful, clinical judgment should take precedence. Patients
plant evaluation, because these conditions are associated with FHF are given priority for transplantation, recog-
with an independent risk for mortality. nizing that the mortality rate without urgent transplant is
nearly universal. This priority allows rapid transplant
before the onset of cerebral edema. Transplant outcomes
Autoimmune Liver Disease for FHF are excellent and exceed outcomes for those
Autoimmune hepatitis can develop into progressive liver transplanted for chronic liver diseases.54
disease that results in cirrhosis and decompensation. LT
outcomes for autoimmune liver disease are favorable;
however, age at transplant greater than 50 years has been CONTRAINDICATIONS FOR TRANSPLANT
associated with impaired survival.44 Postoperatively epi-
sodes of acute cellular rejection are more common in Contraindications for LT are conditions that either ren-
those with autoimmune liver disease.45 Because autoanti- der the surgical risk prohibitive or the likelihood of long-
bodies persist after transplant, recurrent disease is known term survival or quality of life after transplantation low.
to occur. This is usually treatable with an enhanced They tend to be dynamic and different between centers,
immunosuppression regimen but can lead to progressive depending on local expertise and level of comfort. There
graft dysfunction and affect survival.46,47 are both absolute and relative contraindications (Tables
8-3 and 8-4).
Vascular Disorders of the Liver
Vascular compromise to the liver can result in hepatic dys-
Absolute Contraindications
function that sometimes requires transplant. Portal vein It is important to select recipients who have an acceptable
thrombosis, for example, is common in fibrotic liver dis- chance of survival intraoperatively as well as after trans-
ease and rarely causes liver failure. A new portal vein plantation. ESLD alone is an operative risk factor, so it is
occlusion can present with a sudden worsening of portal important to select patients who do not have too much
hypertension. Portal vein thrombosis can also be seen with additional comorbidity that would increase mortality and
HCC, so careful screening for HCC should be undertaken operative risk. Severe cardiopulmonary disease, uncon-
in all new cases of portal vein thrombosis. Disorders such trolled HCC, and current or prior extrahepatic malig-
as Budd-Chiari syndrome or sinusoidal obstruction syn- nancies that do not meet oncological definition of “cure”
drome (formerly known as venoocclusive disease) can are all contraindications to transplantation. Once patients
result in liver failure when they occur rapidly. Although are placed on immunosuppression after transplantation,
shunt procedures can be temporizing, many patents have they are at higher risk for de novo malignancies and may
progressive liver disease and require transplantation. be at increased risk for recurrent malignancy.55 Active,
Because most patients with Budd-Chiari syndrome have uncontrolled infection, particularly sepsis or infection
underlying hematological disorders, they can be at risk for with resistant bacteria or fungi, at the time of transplant
recurrent thrombosis despite transplant and usually is associated with poor survival.
require lifelong anticoagulation. Transplant survival out- Psychosocial contraindications to transplant are crucial
comes vary, with some groups reporting 5-year survival of to understand because inadequate psychosocial support
65% and some reporting better rates at 88%.48,49 Aggres- systems portend poor prognosis post transplantation. Both
sive anticoagulation therapy post transplant may decrease the pretransplant decompensation from liver disease and
thrombotic complications and enhance survival. recovery post transplantation can be very physically and
mentally taxing, and patients must have a care partner out-
side the medical team. Because many patients with liver
Fulminant Hepatic Failure disease have a history of significant substance abuse, strict
Fulminant hepatic failure (FHF), defined as the rapid abstinence from addictive drugs and alcohol is important.
development of encephalopathy, coagulopathy, and Any substance abuse, including legal prescription drugs, is
102 PART II Patient Evaluation: Adult

TABLE 8-3 Relative Contraindications to Liver Transplantation

Age >70 yr Assess overall health of patient, but overall survival in older patients is decreased.
Other organ failure Liver transplantation is feasible only if other organ failure can be corrected.
Complicated surgical anatomy If transplant not technically feasible, must abort. If suspected to be difficult, may
need to have a backup candidate.
Poor functional status The patient needs to be able to survive the transplant and recover postoperatively.
Poor medical compliance This portends poor prognosis post transplant because pretransplant behaviors
predict posttransplant behavior.
Alcoholic hepatitis Evidence exists for good outcomes in France, but with limited resource much
controversy surrounds this area in the United States.
Extremes of BMI Survival is decreased with BMI <19 kg/m2 and in morbidly obese.

BMI, Body mass index.

TABLE 8-4 Absolute Contraindications to Liver Transplant

Severe cardiopulmonary disease Predicts death
Irreversible cerebral injury In ALF this includes elevated ICP with brainstem herniation or in other patients
CVA with irreversible deficits
Sepsis or active infection Poor outcomes when immunosuppressed post transplant
HIV/AIDS with low CD4, high viral load Poor survival post transplant
Extrahepatic malignancy Disease free for 2-5 years before transplant
Vascular Extensive portal and mesenteric vein thrombosis make transplant technically not
feasible
Psychosocial problems Active drug abuse, severe psychiatric disease, or lack of social support

AIDS, Acquired immunodeficiency syndrome; ALF, acute liver failure; CVA, cerebrovascular accident; HIV, human immunodeficiency virus;
ICP, intracranial pressure.

prohibited. In some centers cigarette smoking is also not Some centers require that a patient be under the direct
allowed. Poor compliance with medical advice, instruc- care of a mental health professional and have their disease
tions, and prescribed medications is a contraindication to well controlled before undergoing transplant evaluation.
transplantation. It is paramount that patients adhere to Patients with a history of alcohol abuse need to have
their posttransplant immunosuppression regimen, 6 months of sobriety in most programs, but this varies
because organs are a scarce resource. between countries and is beginning to change even in the
United States. Mathurin et al23 showed an excellent sur-
vival benefit in patients transplanted early for acute alco-
Relative Contraindications holic hepatitis compared to the nontransplanted group
Relative contraindications prevent optimal allograft and (77 ± 8 versus 23 ± 8%, P < .001). These patients were
patient outcome, can vary widely depending on the trans- part of a highly selective group, and the results cannot be
plant center, and are sometimes modifiable before trans- easily extrapolated to all patients with alcoholic hepatitis.
plantation.2,23,56,57 Advanced age is the most common Human immunodeficiency virus (HIV) infection was
relative contraindication with vastly different approaches previously an absolute contraindication to transplanta-
depending on the center. With an aging population, tion, but with the introduction of highly active antiretro-
many older individuals currently present for evaluation viral medications, LT in the HIV population has become
with indications for LT. In general there is heightened a risky but acceptable procedure. Several specialized cen-
concern for transplant in patients over the age of 70 years, ters perform transplants in HIV-positive patients, but it is
because mortality and the risk for malignancy are higher. not yet widespread practice. In the last decade 0.3% of
Although chronological age provides a good general liver transplants in the United States were performed in
framework from which to operate, physiological age is HIV-positive patients.59 The largest experience for HBV/
more important. Obesity is becoming a common con- HIV coinfected patients with liver transplants showed
cern, because many patients evaluated for LT are over- excellent outcomes, with 4-year patient and graft survival
weight or obese by body mass index classification. The at 100% and 85%, respectively.60 The survival for HIV/
1-year and 2-year mortality after transplantation is sig- HCV coinfected patients is less promising, with lower
nificantly higher in those with morbid obesity, and 5-year graft survival than in HCV monoinfection (71% versus
mortality is significantly higher in those defined as 86%, respectively). MELD has been validated to be an
severely obese and morbidly obese because of increased appropriate predictor of pretransplant mortality in HIV
frequency of cardiovascular events.58 Several centers have patients with liver disease.61 Cutoffs for CD4 count tar-
body mass index criteria to be eligible for listing. Psychi- gets vary by center, but a generally accepted principle is
atric disease is another relative contraindication to listing. that HIV viral load should be fully suppressed before
 8 Current Indications, Contraindications, Delisting Criteria 103

transplantation. Patients need to be referred to a trans- 3. 2009 Annual Report of the U.S. Organ Procurement and Transplan-
plant center with expertise in managing the specific issues tation Network and the Scientific Registry of Transplant Recipients:
Transplant Data 1999-2008. U.S. Department of Health and Human
related to HIV infection before and after transplantation. Services, Health Resources and Services Administration, Healthcare
Complex surgical anatomy can be a relative contrain- Systems Bureau, Division of Transplantation, Rockville, MD.
dication to transplantation. Patients with prior abdomi- 4. Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the
nal surgery and extensive portal/mesenteric vascular oesophagus for bleeding oesophageal varices. Br J Surg.
1973;60(8):646-649.
thrombosis can present difficult surgical challenges. Pre- 5. Malinchoc M, Kamath PS, Gordon FD, et al. A model to predict
transplant contrast-enhanced cross-sectional imaging poor survival in patients undergoing transjugular intrahepatic
provides a valuable tool for the surgeon for anticipating portosystemic shunts. Hepatology. 2000;31(4):864-871.
the need for vascular grafts or alternative techniques. 6. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict
survival in patients with end-stage liver disease. Hepatology.
2001;33:464-470.
7. Williams J, Said A, Holden J, et al. Model for end stage liver disease
CONCLUSION score predicts mortality across a broad spectrum of liver disease.
J Hepatol. 2004;40:897-903.
Identifying appropriate candidates for LT is a complex 8. Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver
disease (MELD) and allocation of donor livers. Gastroenterology.
process that requires a multidisciplinary approach. Medi- 2003;124:91-96.
cal and psychosocial considerations are weighed heavily 9. Wiesner RH, McDiamid SV, Kamath PS, et al. MELD and PELD:
throughout the evaluation process. The indications and application of survival models to liver allocation. Liver Transpl.
contraindications for transplant evolve over time, as do 2001;7:567-580.
our methods for allocation of livers, reflecting advances in 10. Kamath PS, Kim WR. Advanced Liver Disease Study Group. The
model for end-stage liver disease (MELD). Hepatology. 2007;45:
the understanding and ability to treat various disease pro- 797-805.
cesses. The continued goal of LT is to provide a survival 11. Hanto DW, Fishbein TM, Pinson CW, et al. Liver and intestine
benefit to those with acute or chronic liver disease and to transplantation: summary analysis, 1994-2003. Am J Transplant.
be able to provide this benefit to the most individuals 2005;5(4 Pt 2):916-933.
12. Martin AP, Bartels M, Hauss J, et al. Overview of the MELD Score
possible. and the UNOS adult liver allocation system. Transplant Proc.
2007;39(10):3169-3174.
13. Merion M, Schaubel DE, Dykstra DM, et al. The survival benefit
Pearls and Pitfalls of liver transplantation. Am J Transplant. 2005;5:307-313.
14. Dukowski P, Oberkofler CE, Bechir M, et al. The model for end-
stage liver disease allocation system for liver transplantation saves
• Early and appropriate referral for liver transplantation lives, but increases morbidity and cost: a prospective outcome
allows for time to work up and treat patients' liver dis- analysis. Liver Transpl. 2011;17:674-684.
ease in a timely fashion. 15. Pomfret EA, Freyer JP, Sima CS, et al. Liver and intestine trans-
• Organs are a limited resource, and there is a constant plantation in the United States, 1996-2005. Am J Transplant.
struggle to optimally define listing priority for liver 2007;7(5 Pt 2):1376-1389.
transplantation. 16. O’Leary JG, Lepe R, Davis GL. Indications for liver transplanta-
• Although indications and patient selection are largely tion. Gastroenterology. 2008;134:1764-1776.
standardized across centers and have undergone little 17. Murray KF, Carithers Jr RL. AASLD. AASLD practice guidelines:
change over the last few years, contraindications are Evaluation of the patient for liver transplantation. Hepatology.
2005;41:1407-1432.
more dynamic and differ between centers, based on 18. Hirschfield GM, Gibbs P, Griffiths WJ. Adult liver transplanta-
regional expertise and organ availability. tion: what nonspecialists need to know. BMJ. 2009;338:b1670.
• Model for End-Stage Liver Disease (MELD) scores 19. Alqahtani SA. Update in liver transplantation. Curr Opin Gastroen-
are a more objective and less easily manipulated meth- terol. 2012;28:230-238.
od to predict mortality on the waiting list and to assign 20. Desai NJ, Mange KC, Crawford MD, et al. Predicting outcome
priority. after liver transplantation. Transplantation. 2004:99-106:2004.
• Knowledge of MELD exceptions and the average 21. Abt PL, Mange KC, Olthoff KM, et al. Allograft survival following
MELD score at transplant in each region will allow adult-to adult living donor liver transplantation. Am J Transplant.
appropriate timing of referral and achieve maximal 2004;4:1302-1307.
22. Everhart JE, Beresford TP. Liver transplantation for alcoholic
benefit for patients. liver disease: a survey of transplantation programs in the United
• It is crucial to recognize contraindications for trans- States. Liver Transpl Surg. 1997;3:220-226.
plant so as not to cause harm in the effort to provide a 23. Mathurin P, Moreno C, Samuel D, et al. Early liver transplantation
medical or surgical treatment. for severe alcoholic hepatitis. N Engl J Med. 2011;365:1790-1800.
• As systems and medicine evolve, the overarching goal 24. Lim JK, Keeffe EB. Liver transplantation for alcoholic liver dis-
of liver transplantation remains the same: to provide ease: current concepts and length of sobriety. Liver Transpl.
a survival benefit to those with acute or chronic liver 2004;10:S31-S38.
disease and to be able to provide this benefit safely to 25. Garcia-Retortillo M, Forns X, Feliu A, et al. Hepatitis C virus
the most individuals possible. kinetics during and immediately after liver transplantation. Hepatol-
ogy. 2002;35:680-687.
26. Forman LM, Lewis JD, Berlin JA, et al. The association between
hepatitis C infection and survival after orthotopic liver transplanta-
tion. Gastroenterology. 2002;122:889-896.
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2. Brown Jr RS, Lake JR. The survival impact of liver transplantation 28. Kim WR, Poterucha JJ, Kremers WK, et al. Outcome of liver
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29. Dickson ER, Grambsch PM, Fleming TR, et al. Prognosis in 45. Vogel A, Heinrich E, Bahr MJ, et al. Long-term outcome of liver
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30. Liermann Garcia RF, Evangelista Garcia C, McMaster P, Neuber- 46. Prados E, Cuervas-Mons V, dela Mata M, et al. Outcome of auto-
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analysis of 400 patients in a single center. Hepatology. 2001;33: 1998;66:1645-1650.
22-27. 47. Ratziu V, Samuel D, Sebagh M, et al. Long-term follow-up after
31. Soetikno RM, Lin OS, Heidenreich PA, et al. Increased risk of liver transplantation for autoimmune hepatitis: evidence of recur-
colorectal neoplasia in patients with primary sclerosing cholangitis rence of primary disease. J Hepatol. 1999;30:131-141.
and ulcerative colitis: a meta-analysis. Gastrointest Endosc. 2002;56: 48. Cruz E, Ascher NL, Roberts JP, et al. High incidence of recur-
48-54. rence and hematologic events following liver transplantation for
32. Kim WR, Therneau TM, Wiesner RH, et al. A revised natural his- Budd-Chiari syndrome. Clin Transplant. 2005;19:501-506.
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34. Heimbach JK, Haddock MG, Alberts SR, et al. Transplantation 51. O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indica-
for hilar cholangiocarcinoma. Liver Transpl. 2004;10:S65-S68. tors of prognosis in fulminant hepatic failure. Gastroenterology.
35. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for 1989;97:439-445.
the treatment of small hepatocellular carcinomas in patients with 52. Bernuau J, Goudeau A, Poynard T, et al. Multivariate analysis of
cirrhosis. N Engl J Med. 1996;334:693-699. prognostic factors in fulminant hepatitis B. Hepatology.
36. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepa- 1986;6:648-651.
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adversely impact survival. Hepatology. 2001;33:1394-1403. predict outcome in adult patients with non-acetaminophen-
37. Yao FY, Hirose R, LaBerge JM, et al. A prospective study on induced acute liver failure. Liver Int. 2007;27:329-334.
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38. Kemmer N, Kaiser T, Zacharias V, Neff GW. Alpha-1-antitrypsin 55. Watt KD, Pedersen RA, Kremers WK, et al. Long-term probabil-
deficiency: outcomes after liver transplantation. Transplant Proc. ity of and mortality from de novo malignancy after liver transplan-
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39. Kowdley KV, Brandhagen DJ, Gish RG, et al. Survival after liver 56. Starzl TE, Marchioro TL, Vonkaulla KN, et al. Homotransplanta-
transplantation in patients with hepatic iron overload: the national tion of the liver in humans. Surg Gynecol Obstet. 1963;117:659-676.
hemochromatosis transplant registry. Gastroenterology. 2005;129: 57. Brown Jr RS. Transplantation for alcoholic hepatitis – time to
494-503. rethink the 6-month “rule.” N Engl J Med. 2011;365:1836-1838.
40. Brandhagen DJ, Alvarez W, Therneau TM, et al. Iron overload in 58. Nair S, Verma S, Thuluvath PJ. Obesity and its effect on survival
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Hepatology. 2000;31:456-460. United States. Hepatology. 2002;35(1):105-109.
41. Tung BY, Farrell FJ, McCashland TM, et al. Long-term follow-up 59. Kemmer NM, Sherman KE. Liver transplantation trends in the
after liver transplantation in patients with hepatic iron overload. HIV population. Dig Dis Sci. 2011;56(11):3393-3398.
Liver Transpl Surg. 1999;5:369-374. 60. Coffin CS, Stock PG, Dove LM, et al. Virologic and clinical out-
42. Medici V, Mirante VG, Fassati LR, et al. Liver transplantation for comes of hepatitis B virus infection in HIV-HBV coinfected trans-
Wilson’s disease: The burden of neurological and psychiatric dis- plant recipients. Am J Transplant. 2010;10:1268-1275.
orders. Liver Transpl. 2005;11:1056-1063. 61. Subramanian A, Sulkowski M, Barin B, et al. MELD score is an
43. Charlton MR, Burns JM, Pedersen RA, et al. Frequency and out- important predictor of pretransplantation mortality in HIV-infected
comes of liver transplantation for nonalcoholic steatohepatitis in liver transplant candidates. Gastroenterology. 2010;138:159-164.
the United States. Gastroenterology. 2011;141:1249-1253.
44. Schramm C, Bubenheim M, Adam R, et al. Primary liver transplan-
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 CHAPTER 9

Transplantation for
Hepatitis A and B
Bruno Roche • Didier Samuel

CHAPTER OUTLINE

TRANSPLANTATION FOR HEPATITIS B Posttransplantation Prevention of Hepatitis B

Indications for and Results of Liver Virus Recurrence
Transplantation Hepatitis B Virus Recurrence
Diagnosis, Mechanisms, and Risk Factors for Liver Transplantation in Patients with
Hepatitis B Virus Recurrence After Liver Hepatitis D Virus Liver Cirrhosis
Transplantation Liver Transplantation for Fulminant Hepatitis B
Prevention of Hepatitis B Virus Recurrence
TRANSPLANTATION FOR HEPATITIS A
Pretransplantation Antiviral Therapy
CONCLUSION

In the United States and Europe 5% to 10% of patients TRANSPLANTATION FOR HEPATITIS B
undergoing liver transplantation (LT) have hepatitis B
virus (HBV)-associated chronic or fulminant liver dis- Indications for and Results of Liver
ease.1,2 In Asia it is the most common indication for LT. Transplantation
Results of LT have been hampered by recurrent infec-
tion. Historically the spontaneous risk for HBV reinfec- LT should be considered when the expected median-term
tion was about 80% when related to the initial liver survival is less than 2 years. Transplantation is indicated in
disease (i.e., acute versus chronic) and to the presence of patients with a history of spontaneous bacterial peritoni-
HBV replication at the time of transplantation.3,4 Over tis, chronic encephalopathy, refractory ascites, or recur-
the last 2 decades there have been major advances in the rent variceal bleeding despite endoscopic treatments.
management of HBV transplant candidates. Using a Antiviral treatment using nucleos(t)ide analogues to sup-
combination of prophylaxis with hepatitis B immune press HBV replication may induce clinical improvement
globulin (HBIg) and nucleos(t)ide analogues, which is in a subset of patients and has led to a major decrease in
administered before and after transplantation, LT in the rate of LT for HBV cirrhosis. Actually the main indi-
patients with hepatitis B produces survival rates at 5 years cations for LT in the setting of HBV cirrhosis are hepati-
more than 80% and recurrence rates below 10% even in tis flares related to viral resistance or noncompliance with
patients with preoperative viral replication.5,6 However, antiviral therapy and hepatocellular carcinoma (HCC).1
this long-term prophylaxis is expensive and inconvenient Kim et al1 report that a number of trends in the waiting
for patients. This has led to the development of alterna- list registration for LT for HBV-related disease in the
tive strategies aiming to reduce the dose and duration of United States have occurred, including an overall reduc-
HBIg. tion in end-stage liver disease over time, along with a per-
Several effective drugs have been developed for the sistent increase in HCC. The impact of antiviral therapy
management of HBV disease on the graft so that out- on the incidence of HCC is less well established and
come of recurrent HBV infection is currently good. delayed compared with that on end-stage liver disease.
Indications for transplantation in hepatitis A are lim- Wong et al7 report that despite more advanced liver dis-
ited to fulminant hepatitis. ease and a lower rate of transplantation, intention-to-treat
In this chapter we review indications, results, and survival of patients listed for HBV cirrhosis is comparable
p­revention of recurrence of LT for HBV-related liver to those with HBV cirrhosis and HCC, possibly related to
d­isease and indications and results of LT for hepatitis A. beneficial effects of antiviral therapy.

105
106 PART II Patient Evaluation: Adult

Historically, in the absence of prophylaxis of HBV rein- This latter mechanism is probably important because
fection, the 5-year survival rate was low (between 40% and mutations in the pre-S/S genome of HBV and in the “a”
60%) and HBV-related deaths were frequent.3,4 Major determinant have been described secondary to adminis-
advances in prophylaxis and treatment of HBV recurrence tration of HBIg.14,15 Peripheral mononuclear cells may
have resulted in overall survival rates as high as 80% to be implicated in this immune pressure selection mecha-
90% at 5 years.2,5,6,8 In 206 European patients receiving nism; for example, we have shown that the HBV strain
adequate immunoprophylaxis, results of LT for HBV predominant in a patient after reinfection was the strain
infection were similar to those results achieved with other predominating in the mononuclear cells of this patient
indications, with survival rates at 1, 5, and 10 years of 91%, before LT.16 This mechanism of escape mutation is not
81%, and 73%, respectively. The 2-year patient survival exclusive because HBV reinfection with a nonmutated
increased from 85% in 1988 to 1993 to 94% after 1997 form of HBV occurs in patients receiving HBIg.15 In
(P < .05) using prevention of HBV recurrence with HBIg patients receiving antiviral monoprophylaxis, such as
and lamivudine (LAM). The 2-year recurrence rates in the LAM, HBsAg remained positive, progressively declining
two periods were 42% and 8% (P < .05).5 In the multivariate over a period of a few months after transplantation to
analysis for patient survival, only the covariates HCC and become undetectable. When reinfection occurs in com-
HBV recurrence were statistically significant. In our own pliant patients treated with antiviral monotherapy, the
series the 10-year survival rates of patients who underwent emergence of mutations of the polymerase is the cause.17
transplantation for HBV cirrhosis and hepatitis D virus Reinfection in patients on HBIg and an antiviral is related
(HDV) cirrhosis were 70.9% and 89%, respectively.9 A sim- to combined mutations in both the surface and poly-
ilar picture is seen in studies from the United States. The merase genes.18
5-year survival of HBV-infected transplant recipients has Whatever the prophylaxis used, the main risk factor
increased from 53% in the period 1987 to 1991 to 69% in for HBV recurrence is related to the pretransplant HBV
the period 1992 to 1996, to 76% in the period 1997 to 2002.6 viral load (i.e., HBV DNA > 104-105 copies/mL).8,19-23
Earlier studies used hybridization assays that had a detec-
tion limit of approximately 105 copies/mL, whereas
Diagnosis, Mechanisms, and Risk Factors recent studies use more sensitive assays (polymerase chain
for Hepatitis B Virus Recurrence After Liver reaction [PCR] or branched DNA types) that have detec-
tion limits of approximately 10 copies/mL. Thus the term
Transplantation replicative HBV infection has different meanings in differ-
Recurrence of HBV infection is commonly defined as the ent studies, depending upon the HBV DNA test used.
reappearance of circulating hepatitis B surface antigen Other factors associated with low rates of recurrence are
(HBsAg) and detectable HBV DNA after LT associated surrogate markers for low levels of viral replication and
with an increase in transaminase levels and histological include negative hepatitis B e antigen (HBeAg) status at
evidence of acute or chronic hepatitis. However, measur- listing, fulminant HBV, and HDV coinfection.8,21 Infec-
able low levels of HBV DNA in serum, liver, and periph- tion with LAM-resistant HBV virions (YMDD variants)
eral blood mononuclear cells or the presence of total increases the risk for recurrence regardless of viral
HBV DNA and covalently closed circular DNA load.24,25 Several studies have recently reported that
(cccDNA) in liver tissue could be detected transiently HCC at LT, HCC recurrence, or chemotherapy used for
after LT in the absence of a positive HBsAg, whatever the HCC are independently associated with an increased risk
prophylaxis used.9-12 The significance of these findings is for HBV recurrence.25-28
unclear but suggests that occult HBV reinfection occurs
in some HBV recipients after LT despite prophylaxis and
implies a risk for overt HBV recurrence if the prophylaxis Prevention of Hepatitis B Virus Recurrence
is stopped. Control of viral replication involves an inter-
Pretransplantation Antiviral Therapy
play of HBV and immune responses, factors that are
modified in the LT recipient by the use of antiviral pro- Until the end of the 1990s the presence of HBV replica-
phylaxis and by immunosuppressive drugs. Conversely, tion was considered a contraindication to LT by most
for the few patients who are negative for HBV DNA and centers. The goals of treatment for patients with end-
cccDNA in all compartments, the discontinuation of stage HBV liver disease are to improve liver function,
HBV prophylaxis could be discussed.13 thereby obviating the need for LT, and in patients who
HBV reinfection could be the consequence of an require a transplant to decrease the risk for HBV recur-
immediate reinfection of the graft caused by circulating rence after transplant. The major factor in achieving
HBV particles, later reinfection of the graft from HBV these goals is obtaining sustained viral suppression and
particles coming from extrahepatic sites, such as periph- reduction in hepatic activity. LAM, adefovir (ADV), and
eral blood mononuclear cells, or both. telbivudine are no longer considered as an optimal first-
In patients receiving HBIg, HBV reinfection may be line therapy related to a high rate of resistance develop-
the consequence of the following: ment, and latest recommendations suggest using entecavir
• HBV overproduction coming from extrahepatic (ETV) or tenofovir (TDF) as primary antiviral agents.29,30
sites LAM is well tolerated in decompensated cirrhosis. A
• An insufficient protective titer of anti-hepatitis B rapid viral suppression within several weeks of therapy
surface (HBs) antibodies was observed in 73% to 100% of these patients17,31-34
• The emergence of escape mutants (Table 9-1). However, clinical improvement is slow, and
 TABLE 9-1 Results of Antiviral Therapy in Patients with Decompensated HBV Cirrhosis
Duration Decrease HBV DNA HBeAg
Antiviral Patients of Therapy CTP Score in CTP ≥ 2 Undetectable Serocon- Overall Sur- Viral Break-
Author Drug (% LAM-R) (Months) at Entry Points (%) (%) version (%) LT (%) vival (%) through (%)
Villeneuve et al31 LAM 35 36 ≥8 22/23 (96%) 23/23 (100%) 6/13 (46%) 7/35 (20%) 27/35 (77%) 2/23 (9%)
Perrillo et al17 LAM 77 38 NA NA 17/22 (77%) NA NA 24/30 (80%) 3/18 (17%)
Fontana et al33 LAM 162 40 NA NA 57/71 (80%) NA 91/162 (56%) 144/162 (89%) 18/162 (11%)
Hann et al34 LAM 75 13 ≥7 23/75 (31%) 30/41 (73%) 7/36 (19%) 1/75 (1%) 64/75 (85%) 8/75 (11%)
Schiff et al36 ADV 226 (100%) 48 ≥5 NA 45/76 (59%) 7/31 (23%) 43/226 (19%) 194/226 (86%) 2/114 (2%)
Shim et al41 ETV 70 (0%) 12 ≥7 27/55 (49%) 65/70 (93%) 8/35 (23%) 3/70 (4%) 63/70 (90%) 0
Liaw et al42 ADV 91 (33%) 24 ≥7 25/91 (27%) 18/91 (20%) 5/51 (10%) 3/89 (3%) 73/89 (80%) 0 at week 48

9
6 until week 144
ETV 100 (36%) 24 ≥7 35/100 (35%) 57/100 (57%) 3/54 (6%) 11/100 (11%) 82/100 (82%) 0 at week 48

Transplantation for Hepatitis A and B

3 until week 144
Liaw et al46 ETV 22 (13%) 12 7-12 5/12 (42%) 16/22 (73%) 0/7 (0%) 0/22 (0%) 20/22 (91%) 0
TDF 45 (18%) 12 7-12 7/27 (26%) 31/44 (70%) 3/14 (21%) 2/45 (4%) 43/45 (96%) 0
TDF + 45 (22%) 12 7-12 12/25 (48%) 36/41 (88%) 2/15 (13%) 4/45 (9%) 43/45 (96%) 0
emtric-
itabine

ADV, Adefovir; CTP, Child-Turcotte-Pugh; ETV, entecavir; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; LAM, lamivudine; LAM-R, lamivudine resistant; LT, liver transplantation; NA, not
available; TDF, tenofovir.

107
108 PART II Patient Evaluation: Adult

a benefit may not be observed during the first 3 to 6 serum HBV DNA levels (-6.8 versus -6.7 log10 copies/
months of therapy. In a prospective study of 154 patients mL), the proportion of patients achieving undetectable
listed for transplantation and receiving LAM, 32 of the viremia (89% versus 78%) and the rate of HBeAg sero-
154 patients (21%) died, with most of the deaths (25 of 32 conversion (22% versus 24%) did not differ significantly
[78%]) occurring within the first 6 months of therapy.35 between the decompensated and compensated groups. In
The estimated actuarial 3-year survival of patients who the decompensated group, as reported with LAM, the
survived at least 6 months was 88%. In multivariate anal- majority of adverse outcomes occurred within the first 6
ysis an elevated serum bilirubin level, elevated creatinine months of therapy: 6 patients died as a result of liver fail-
level, and serum HBV DNA level greater than 105 cop- ure, and 3 patients underwent transplantation. These 9
ies/mL before treatment were independent predictors of patients had more severe liver failure at entry compared
6-month mortality. Thus for patients with advanced liver with the other decompensated patients (Child-Turcotte-
failure, LT remains a critical component of management, Pugh [CTP] score 10.1 versus 8.1, P = .001); however, the
irrespective of the antiviral response. The development baseline HBV DNA levels, the presence of HBeAg, and
of mutations in the HBV DNA polymerase gene is the the early response to antiviral therapy were similar. Five
main limitation of treatment with a reported incidence of patients developed HCC during the follow-up period. In
15% to 20% per year of therapy and a risk for fatal hepa- a second study, 191 patients with decompensated HBV
titis flares.17,31-34 All patients receiving LAM therapy cirrhosis (positive or negative for HBeAg and experi-
should have close monitoring of HBV DNA levels and enced or naive for treatment with nucleos[t]ide ana-
prompt institution of additional antiviral therapy when logues) were randomized to ETV (1 mg/day) or ADV
breakthrough infection occurs, related to the risk for (10 mg/day)42 (see Table 9-1). The ETV group showed a
hepatitis flares or HBV recurrence after transplant. greater change from baseline in HBV DNA at all time
ADV, a nucleotide analogue, is an effective therapy for points through week 48 and a higher proportion of sub-
patients with wild-type and LAM-resistant HBV infec- jects who achieved an HBV DNA level of less than 300
tion. In a multicenter study on 226 LAM-resistant copies/mL at week 48 (ETV, 57%; ADV, 20%;
patients awaiting transplantation, 59% and 65% achieved P < .0001). Adverse events were comparable between
an undetectable HBV DNA by PCR at weeks 48 and 96, groups. Safety of ETV in severely decompensated
respectively36 (see Table 9-1). However, 14% still died patients is poorly evaluated. A recent study showed that 5
within the first year, and at least 33% required LT for of 16 patients with decompensated HBV-related disease
long-term survival. As with LAM, the attainment of clini- (Model for End-Stage Liver Disease [MELD] score > 20)
cal benefits required survival of approximately 6 months, developed symptomatic lactic acidosis, leading to death
so for patients with advanced liver decompensation, con- in a patient with fulminant hepatitis B, after receiving
current consideration of transplantation is important. ETV for 4 to 240 days.43 The mechanisms of toxicity are
Dose reductions of ADV were required for 4% of patients unclear; however, concomitant drugs, comorbidities, and
with preexisting renal dysfunction (i.e., creatinine clear- other host factors may alter drug pharmacokinetics.
ance < 50 mL/min). Virological resistance to ADV was TDF is a nucleotide analogue and is very potent
less frequent (2% at 144 weeks).36 However, the longest against the wild-type and nucleoside analogue–resistant
follow-up studies showed a higher resistance rate: 11% at HBV strains.44 Phase III studies have shown that TDF
3 years, 18% at 4 years, and 29% at 5 years.30 Although has higher antiviral efficacy than ADV.45 It has been
antiviral drug resistance is less common with ADV than shown that TDF can control HBV replication in the
with LAM, concerns remain regarding the slow rate of majority of patients and can rescue LAM resistance or
suppressing HBV replication with ADV, as well as the nonresponse to ADV. No drug-resistant variants have
potential for dose-dependent nephrotoxicity in decom- been reported with 3 years of continuous treatment.45
pensated HBV patients. TDF could be prescribed in combination with emtric-
New nucleos(t)ides analogues (i.e., ETV and TDF) itabine, a nucleoside analogue with an antiviral activity
exhibit stronger antiviral efficacy and a lower resistance profile similar to that of LAM (Truvada).
rate. They are recommended for the treatment of HBV A recent study compared the safety and efficacy of
infection in patients with end-stage liver disease; how- TDF versus TDF plus emtricitabine versus ETV in 112
ever, experience with these drugs is more limited in this decompensated HBV patients46 (see Table 9-1). The fre-
setting.29,30 quency of undetectable HBV DNA at weeks 12, 24, and
ETV, a nucleoside analogue, is more potent in sup- 48 was comparable in the three treatment groups. How-
pressing serum HBV DNA levels than LAM in both ever, among the subjects with LAM-resistant HBV, 71%
HBeAg-positive and HBeAg-negative patients.37,38 of the 18 patients in the TDF-containing arms had unde-
Related to a high genetic barrier of resistance, this drug tectable HBV DNA at week 48 compared with 33% in
exhibits a very low resistance rate (i.e., near 1%) in LAM- the 3 ETV-treated patients. Improvements in CTP and
naive patients, even after 5 years of therapy.39 In contrast, MELD scores at week 48, rates of nephrotoxicity, and
ETV resistance occurred in more than 35% of patients patient mortality were similar in the three treatment
after 4 years of therapy in LAM-resistant patients.40 In a arms. There are growing concerns regarding the long-
recent study Shim et al41 evaluated clinical outcome and term safety of TDF in some patients, including nephro-
virological responses of 70 decompensated patients com- toxicity and metabolic bone disease.
pared with 144 compensated patients treated with ETV In summary, patients with decompensated cirrhosis
(0.5 mg/day) as first-line therapy during 1 year (see Table should be treated in specialized liver units, because the
9-1). At month 12 of therapy the mean reduction in application of antiviral therapy is complex.47 All studies
 9 Transplantation for Hepatitis A and B 109

Compensated HBV-
related cirrhosis Antiviral therapy may halt
progression to
decompensation and
decrease the risk of HCC if
General medical viral suppression can be
Decompensated HBV- maintained
management,
related cirrhosis
HCC surveillance

Early antiviral treatment:

entecavir, tenofovir, Truvada,
combination lamivudine and
adefovir
Refer for transplantation

CTP class C Long-term

MELD  15 antiviral therapy
Bilirubin levels
Creatinine levels
HBV DNA  105 copies/mL

Prioritize for transplantation

FIGURE 9-1 n Diagram of management of decompensated hepatitis B virus (HBV) cirrhosis with antiviral therapy and transplantation.
CTP, Child-Turcotte-Pugh; HCC, Hepatocellular carcinoma; MELD, Model for End-Stage Liver Disease.

emphasized the need for early treatment in patients with Patients who fail to achieve primary response, as evi-
decompensated cirrhosis. Most studies have shown a denced by less than a 2 log10 decrease in serum HBV
biphasic survival pattern with most deaths occurring DNA levels after 6 months of therapy, should be switched
within the first 6 months of treatment.35,36,41 Patients to an alternative treatment or receive additional treat-
with higher pretreatment bilirubin levels, creatinine lev- ment. Patients who develop breakthrough infection,
els, and HBV DNA levels were at greatest risk for early defined by an increase of HBV DNA levels by more than
death, whereas early suppression of HBV replication was 1 log10 from nadir, should be assessed for compliance
not associated with more favorable outcomes.35 Trans- with therapy, and a test for antiviral-resistant mutation
plantation should not be delayed in patients with CTP should be performed.
class C or a MELD score greater than or equal to 15 at
baseline or should be urgently considered in patients dis- Posttransplantation Prevention of Hepatitis B
playing suboptimal improvement in hepatic reserves after Virus Recurrence
3 months of antiviral treatment, because of our inability
to identify those patients with a poor short-term progno- Hepatitis B Immune Globulin Monotherapy
sis (Fig. 9-1). Conversely, long-term antiviral treatment A multicenter European study demonstrated a dramatic
could be done in patients who can be stabilized with anti- reduction in the rate of HBV recurrence, from 75% in
viral therapy. patients receiving no or short-term therapy with HBIg to
The oral agents that most effectively suppress HBV 33% in those receiving long-term intravenous (IV) HBIg
replication with the lowest rate of drug resistance during treatment (P < .001), which was associated with improved
prolonged use (i.e., ETV, TDF) have emerged as pre- graft and patient survival.21 Recurrence of HBV occurred
ferred first-line agents over the other available drugs in 67% of patients who underwent transplantation for
(LAM, ADV, telbivudine). Combination therapy using HBV cirrhosis, 32% of patients who underwent trans-
LAM and ADV could be used according to local health plantation for HDV cirrhosis, and 17% of patients who
policies. Decompensated HBV patients receiving oral underwent transplantation for fulminant hepatitis B. The
nucleos(t)ide analogues must undergo frequent clinical HBV recurrence rate was related to the presence of HBV
and laboratory assessment to ensure medication compli- replication, which was assessed by both HBeAg and HBV
ance and surveillance for virological and clinical response, DNA detection in serum using conventional hybridiza-
as well as drug side effects, drug resistance, and HCC. tion techniques at the time of transplantation. These
110 PART II Patient Evaluation: Adult

results were confirmed by other clinical trials in the patients with chronic hepatitis B who received a liver
United States and Europe and by long-term follow-up transplant. A total of 18 patients (22.5%) had persistent
studies.9,48,49 The administration of higher doses of HBIg HBsAg positivity after transplant without seroclearance
(adjusted to keep anti-HBs levels > 500 International (n = 8) or reappearance of HBsAg after initial seroclear-
Units/L) reduced recurrence rates in HBV DNA–positive ance (n = 10). Seventeen patients had undetectable levels
patients to 20% to 30%48,50; however, it adds greatly to of HBV DNA at the time of last follow-up. The remain-
costs. Although its mechanism of action is incompletely ing patient had a very low HBV DNA level of 217 cop-
understood, HBIg likely acts by binding to and neutral- ies/mL at 36 months after LT. Whether other antivirals
izing circulating virions and by inhibiting cell-to-cell such as TDF or a combination of antivirals without
infection. IV HBIg has been administered in two different HBIg would provide effective prophylaxis is unknown.
ways: at a frequency dictated by the maintenance of spe-
cific anti-HBs levels (e.g., 100 International Units /L) or Combination Prophylaxis
on a fixed schedule that generally “overshoots” the target The use of LAM and/or ADV before transplantation fol-
anti-HBs level. The latter approach is simpler and requires lowed by a combination of antivirals and HBIg after LT
less monitoring but is more expensive.51 HBIg has a satis- provides improved control of viral replication before
factory safety record, and adverse events observed have transplantation and complementary forms of prophylaxis
been usually minor. Evaluation of patients failing HBIg after transplantation to minimize risk for reinfection.
prophylaxis indicates that early recurrence of HBV after Dickson et al61 reported that combination LAM and
LT is typically related to insufficient dosing of HBIg and HBIg was associated with reduced requirements of HBs
is more frequent in patients with high levels of pre-LT antibody to render the sera HBsAg negative early after
HBV replication, whereas late recurrences are usually LT. Combination prophylaxis also allowed a reduction of
caused by the emergence of mutations involving the “a” the dose of HBIg required in the long term. With this
determinant of the HBV surface protein. The use of IV combination approach the HBV recurrence rate at 1 to 2
HBIg has limitations, namely, the high-cost, parenteral years after transplantation has been reduced to 0% to
administration; limited supply; need for frequent clinic 10% (Table 9-2).*
visits and laboratory monitoring; low effectiveness in Combination protocols are heterogeneous with regard
patients with high levels of HBV replication before LT; to the dosing, duration, and routes of HBIg administration
and the potential selection of HBsAg escape mutants. In (see Table 9-2). The most cost-effective regimen reported
an effort to find less costly ways of providing long-term to date is a very low IM HBIg plus LAM regimen.52,65,70
HBIg prophylaxis, alternative approaches have been stud- Combination prophylaxis with a low dose of IM HBIg
ied, including the use of low-dose intramuscular (IM) (400-800 International Units) decreases costs by more
HBIg,52 subcutaneous HBIg,53,54 and short-term HBIg in than 90% as compared with an IV regimen, with a recur-
combination with antivirals. rence rate as low as 4% at 4 years.52 Hooman et al70
reported the results of a crossover study comparing IV and
Antiviral Monotherapy IM HBIg administration in stable liver recipients taking
Lamivudine has been evaluated as a prophylactic ther- LAM or ADV more than 12 months after LT. They dem-
apy, with the drug started before transplantation and onstrated comparability of elimination pharmacokinetics
continued after transplantation without HBIg. The out- of HBIg regardless of the antibody route of administra-
come at 1 year showed a 10% recurrence rate.55 How- tion, maintenance of protective anti-HBs levels, and no
ever, with longer follow-up, rates of recurrence reached significant difference in the elimination characteristics as a
22% to 50% at 3 years after LT.17,56-58 Recurrence was function of pretransplant replication status. Taking effi-
due to the emergence of escape mutations in the YMDD cacy and cost-effectiveness into consideration, IM HBIg
motif of the polymerase gene, which were observed plus LAM seems to be superior to IV HBIg plus LAM,
mainly in patients with a high level of HBV replication although there may be a subset of patients (e.g., high HBV
before drug exposure. By reserving LAM monoprophy- DNA level before transplantation) who may benefit from
laxis for patients without viral replication at the time of the higher doses of HBIg provided by the IV route.52
LT, rates of recurrence can be lowered to less than More recently, subcutaneous regimens of HBIg have
10%.59 Because prophylactic therapy using LAM alone proven effective as well, with some advantage in tolerabil-
was associated with unacceptably high rates of reinfec- ity and possibility of self-administration by the patient at
tion in patients with a high level of viral replication home.53,54 Degertekin et al8 analyzed data from 183
before drug exposure, most transplant programs do not patients who had undergone LT between 2001 and 2007.
use LAM monotherapy for prophylaxis. Rather, a com- At transplant, 29% of patients were positive for HBeAg,
bination of HBIg and antivirals is used for prophylaxis and 38.5% had high viral load (defined as HBV DNA level
(see Combination Prophylaxis). Schiff et al36 reported 61 > 105 copies/mL). After transplant, all except 6 patients
LAM-resistant patients treated with ADV on the waiting received combination prophylaxis with antiviral therapy
list who underwent LT. Sixty percent of these patients (mostly LAM monotherapy) plus HBIg given either IV
received post-LT HBIg and ADV combination prophy- high dose (25%, 10,000 International Units monthly), IV
laxis and 40% ADV with or without LAM prophylaxis. low dose (21.5%, 3000-6000 International Units monthly),
Interestingly, no patient in either group had recurrent IM low dose (39%, 1000-1500 International Units every
HBV infection, defined as two or more positive test 1-2 months), or for a finite duration (14.5%, median
results for HBsAg or for HBV DNA. Fung et al60 inves-
tigated the efficacy of ETV as monoprophylaxis in 80 *References 5, 7, 20, 22, 25-27, 52, 62-69.
 9 Transplantation for Hepatitis A and B 111

TABLE 9-2 P
 revention of HBV Recurrence After Liver Transplantation with Antiviral
and Anti-HBsIg (HBIg)
HBV DNA
No. of Positive Follow-up HBV Risk Factors for HBV
Author Patients at LT (%) Prevention of HBV Recurrence (Months) Recurrence Recurrence

Indefinite High-Dose IV HBIg

Markowitz et al66 14 1 (7%) LAM + HBIg IV 10,000 13 0%
International Units/mo
Marzano et al62 25 0 LAM + HBIg IV 5000 Interna- 30 4%
tional Units/mo
Rosenau et al67 21 5 (24%) LAM + HBIg IV titrated to 20 9.5%
maintain anti-HBs > 200
units/L
Steinmuller et al5 206 NA LAM or Famciclovir + HBIg IV NA 8%
titrated to maintain anti-HBs
> 100 International Units/L
Faria et al26 51 21 (41%) LAM ± ADV or TDF + HBIg IV 43 6.6% HCC pre-LT
10,000 International Units/ Pre-LT HBV DNA >
mo 105 copies/mL
HBIg
monoprophylaxis
Han et al65 59 16 (27%) LAM + HBIg IV 10,000 15 0% NA
International Units/mo
Chun et al25 186 70/167 LAM + HBIg IV titrated to 35 10.2% Recurrent HCC
(42%) maintain anti-HBs > 350 Pre-LT HBV DNA >
International Units/L 105 copies/mL
LAM therapy for
>1.5 yr
Indefinite Low-Dose IM HBIg
Gane et al52 147 125 (85%) LAM + HBIg IM 400-800 17 1% 1 yr Pre-LAM HBV DNA >
International Units/mo 4% 5 yr 106 copies/mL
Zheng et al20 114 NA LAM + HBIg IM 800 Interna- 20 13.5% 1 yr Pre-LT HBV DNA >
tional Units/mo 15.2% 2 yr 105 copies/mL
Anselmo et al68 89 NA LAM + HBIg IM 1560 Interna- 29 11%
tional Units according to
HBs Ab level
Xi et al69 30 18 (60%) LAM + HBIg IM 800 Interna- NA 0% NA
90 52 (58%) tional Units according to 11%
HBs Ab level
ETV + HBIg IM 800 Interna-
tional Units/HBsAb level
Jiang et al63 254 53 (21%) LAM + HBIg IM 800 Interna- 41 2.3% 1 yr Pre-LT HBV DNA >
tional Units according to 6.2% 3 yr 105 copies/mL
HBs Ab level 8.2% 5 yr Prednisone with-
drawal time > 3 mo
Yi et al27 108 43 (40%) LAM 1 yr + HBIg IV 4000 31 13.8% Cumulative dose
International Units/mo corticoids
Systemic therapy
against HCC

ADV, Adefovir; ETV: entecavir; HBIg, hepatitis B immune globulin; HBs, hepatitis B surface; HBsAb, hepatitis B surface antibody; HBV,
hepatitis B virus; HCC, hepatocellular carcinoma; Ig, immunoglobulin; IM, intramuscular; IV, intravenous; LAM, lamivudine; LT, liver
transplantation; NA, not available; TDF, tenofovir.

duration 12 months). Cumulative rates of HBV recur- combination prophylaxis was significantly superior than
rence at 1, 3, and 5 years were 3%, 7%, and 9%, respec- antivirals or HBIg alone in preventing HBV recurrence,
tively. Multivariate analysis showed that positivity for irrespective of the HBV DNA level at transplantation
HBeAg and high viral load at transplant, but not the post- and in reducing overall and HBV-related mortality in
transplant HBIg regimen, were associated with HBV some studies. Cholongitas et al71 found that the combina-
recurrence. Among the parameters of HBIg use that were tion of HBIg and ADV with or without LAM is more
evaluated in the systematic review of Cholongitas et al,71 effective than the combination of HBIg and LAM for the
only a high dosage during the first week after LT was prevention of HBV recurrence, which developed in 2%
found to be significantly associated with HBV recurrence. to 3% and 6% to 7% of patients, respectively (P < .05).
Several meta-analyses have compared the use of HBIg, The optimal HBIg protocol is yet to be defined. Fur-
antivirals, or both.71-74 Despite methodological limita- ther research is needed to determine the dose and dura-
tions of studies included in these meta-analyses, tion of HBIg after LT, appropriate titer levels of anti-HBs
112 PART II Patient Evaluation: Adult

to prevent recurrence, and whether HBIg can be stopped. had a low titer of HBsAg in serum but was repeatedly
The role and the safety of other nucleos(t)ide analogues HBV DNA negative. Using the same protocol, Saab
(ETV or TDF) should be evaluated.69,75 et al86 switched 61 liver transplant recipients to a combi-
nation of a nucleoside (LAM or ETV) and nucleotide
Alternatives to Long-Term Combination Hepatitis B analogue (ADV or TDF). At a median follow-up of 15
Immune Globulin and Antiviral Prophylaxis months after the switch, 2 patients were HBsAg positive
Indefinite combination therapy with HBIg plus a nucleos(t) in serum but repeatedly HBV DNA negative. Drug com-
ide analogue may not be required in all liver transplant pliance during long-term antiviral therapy may be a very
recipients. The replication status of the patient before the important issue for transplant patients who feel healthy
initiation of antiviral therapy should guide prophylaxis. but have a lifelong risk for HBV recurrence.
Alternative strategies to consider, especially in patients An ultimate approach was to evaluate the safety of
without detectable HBV DNA before transplantation, are complete and sustained prophylaxis withdrawal in liver
the discontinuation of HBIg after some defined interval transplant recipients at low risk for HBV recurrence.
and continuing treatment with antivirals alone or adding Lenci et al13 evaluated a cohort of 30 patients at low risk
HBsAg vaccination or both. The high cost of long-term for recurrence (HBeAg and HBV DNA negative at LT,
HBIg and the inconvenience of parenteral administration 23% HDV coinfected) and treated with combination
prompt consideration of these other treatment approaches. HBIg and LAM (with or without ADV) for at least 3
Studies of hepatitis B vaccination as an alternative to years. Sequential liver biopsies were performed and eval-
long-term HBIg in LT recipients were conducted in uated for the presence of intrahepatic total HBV DNA
patients who were serum HBV DNA negative before LT, and cccDNA. HBIg and then antiviral therapy was with-
with a prolonged period of time from LT, who received drawn in a stepwise fashion, using the absence of intrahe-
low doses of immunosuppression and were HBV DNA patic total HBV DNA and cccDNA as a guide. After a
negative by PCR at the start of vaccination.76-81 Anti- median of 28.7 months off all prophylactic therapy, 83%
HBs titers achieved with the vaccination are highly vari- of the cohort remained without serological recurrence of
able and seem in part dependent on the vaccine adjuvant. HBV infection. Five patients had HBsAg recurrence, but
Patient populations, as well as vaccine types, doses, only 1 patient manifested evidence of HBV disease (HBV
schedules of administration, and definitions of response, DNA positive); in the other patients HBsAg positivity
differed across these studies. From these data, it seems was transient. Twenty-three of the 25 subjects without
clear that successful hepatitis B vaccination and discon- recurrence never had detectable HBV DNA in liver biop-
tinuation of HBIg are feasible only in a small group of sies, whereas all 5 patients with recurrence had evidence
selected patients, but the optimal vaccine protocols have of total HBV DNA in the liver and 1 had detected
not been established. cccDNA. However, the ability to measure total HBV
Two studies evaluated the efficacy of long-term HBIg DNA and cccDNA in liver biopsy has limitations: this
monotherapy versus HBIg followed by LAM monother- strategy needs sequential liver biopsies, and assays for
apy in patients selected on the basis of low risk for HBV quantitation of total HBV DNA and cccDNA are not
reinfection.82,83 At 1 year following the discontinuation standardized.
of HBIg, the HBV reinfection rates were not significantly The studies to date highlight several key issues to con-
different; however, HBV DNA was detected by PCR in sider with the discontinuation of HBIg after transplanta-
the serum of some patients without HBV recurrence. tion. First, the risk for HBV recurrence after cessation of
This latter finding suggests caution with this approach HBIg may increase with time off HBIg either because of
and the need for studies with longer follow-up and other the development of viral resistance or because of nonad-
antiviral therapy. Another strategy is HBIg withdrawal herence to antiviral therapy. Second, the patients with
after a defined period of combination prophy- high levels of HBV DNA at time of transplantation
laxis7,13,64,84-88 (Table 9-3). In a study of 29 patients, high- appear to be a higher-risk group for recurrence when
dose HBIg and LAM were used in the first month, and HBIg is discontinued. Third, HBV DNA persists in
then patients were randomized to receive either LAM serum, liver, or peripheral blood mononuclear cells even
monotherapy or LAM plus HBIg at 2000 International 10 years after LT in a proportion of HBV transplanted
Units IM monthly.64 None of the patients developed patients who are HBsAg negative, and these reservoirs
HBV recurrence during the first 18 months, but later may serve as a source of HBV reinfection in the future.9,10
recurrences developed in 4 patients after 5 years of Fourth, currently we lack the ability to identify patients
f­ollow-up.84 Wong et al7 reported HBV recurrence rates who may have cleared HBV after transplantation.
were 0% and 9% at 2 and 4 years after HBIg discontinu-
ation. An alternative approach is to switch from HBIg/ Guidelines and Future Prospects for Prevention of
LAM to a combination of antiviral agents that present a Hepatitis B Virus Reinfection
greater barrier to the development of resistance than The principles in strategies to prevent HBV recurrence
LAM. In a randomized prospective study, 16 of 34 should be to maximize antiviral potency while minimiz-
patients receiving low-dose IM HBIg/LAM prophylaxis ing the risk for viral resistance, costs, side effects, and
who were at least 12 months post-LT were switched to inconvenience to patients. However, improvements in
ADV/LAM combination therapy, whereas the remaining prophylactic regimens should not compromise the pre-
patients continued HBIg/LAM.85 At a median follow-up vention of disease recurrence. There is a consensus
of 21 months after the switch, no patient had disease regarding the need for lifelong prophylactic therapy
recurrence, although 1 patient in the ADV/LAM group supported by the detection of HBV DNA in both
 9 Transplantation for Hepatitis A and B 113

TABLE 9-3 P
 revention of HBV Recurrence After Liver Transplantation with HBIg Discontinuation and
Long-Term Antiviral Therapy
HBV DNA
No. of Positive Follow-up
Author Patients at LT (%) Prevention of HBV Recurrence (Months) No. of HBV Recurrences (%)
Buti et al64,84 29 0 Randomized trial 83 1/15 (6.7%) in the LAM +
LAM + HBIg 1 mo then LAM vs LAM + HBIg group
HBIg 3/14 (21.4%) in the LAM
group (poor compliance
with LAM)
Wong et al7 21 71 HBIg ± LAM (median 26 mo) then LAM 40 1/21 (4.8%)
or ADV
Neff et al87 10 0 LAM + HBIg 6 mo then LAM + ADV 31 0
Angus et al85 34 23 Randomized trial 21 0/18 in HBIg + LAM group
Low-dose IM HBIg + LAM > 12 mo 1/16 (6.2%) in ADV + LAM
then HBIg + LAM vs ADV + LAM group
Saab et al86 61 22 IM HBIg + LAM (>12 mo) then LAM or 15 2/61 (3.3%)
ETV + ADV or TDF
Lenci et al13 30 0 HBIg and LAM ± ADV were withdrawn 29 5/30 (17%)
after biopsy specimens negative for
total and cccDNA
Teperman et al88 37 47 Randomized trial at a median of 3.4 yr 22 0
post-LT, HBIg + TDF-emtricitabine 24
wk then HBIg + TDF-emtricitabine vs
TDF-emtricitabine

ADV, Adefovir; ETV, entecavir; HBIg, hepatitis B immune globulin; HBV, hepatitis B virus; IM, intramuscular; LAM, lamivudine; LT, liver
transplantation; NA, not available; TDF, tenofovir.

hepatic and extrahepatic sites in patients who are HBsAg developed graft disease.3,4 In most cases, acute lobular
negative on posttransplant HBIg and antivirals. Today hepatitis occurred with an evolution to chronic active
low-dose IM HBIg in combination with a potent hepatitis. In some cases, acute liver failure was observed.
nucleos(t)ide analogue is the most cost-effective pro- This severe evolution was probably related to the high
phylaxis. For those patients without viral replication amount of HBsAg, HBeAg, and hepatitis B core antigen
before transplant, there is no evidence that preoperative present in the nuclei and the cytoplasm of the hepato-
antiviral therapy is useful. For those patients with viral cytes, suggesting that liver injury is caused by a direct
replication before transplant, ETV, TDF, or a nucleo- cytopathic effect of the virus. A particular form of virus
side/nucleotide combination should be used in prefer- recurrence was called fibrosing cholestatic hepatitis. Antiviral
ence to LAM or ADV. treatments have dramatically improved the prognosis of
Patients with undetectable HBV DNA levels at the HBV graft reinfection. The treatment of HBV infection
time of transplant are eligible for protocols using short- is mandatory because of the severity of the liver graft dis-
term low-dose IM HBIg and antiviral then switching to ease in relation to a high viral load. HBV infection after
antiviral monotherapy or combination therapy (Fig. 9-2). LT is usually the result of failed prophylaxis, due to either
A more cautious approach to a prophylaxis regimen is noncompliance or the development of drug-resistant
necessary for those patients with high pretransplant HBV HBV infection. The availability of safe and effective anti-
DNA levels, those with limited antiviral options if HBV virals allows the majority of patients with recurrent infec-
recurrence occurs (i.e., HIV coinfection, preexisting drug tion to survive without graft loss from recurrent disease.
resistance), those with a high risk for HCC recurrence, Selection of therapy for HBV infection depends on treat-
and those with a risk for noncompliance with antiviral ments previously received by patients (i.e., no therapy,
therapy. In this group, HBIg-free prophylaxis cannot be HBIg alone, antiviral alone, or HBIg and antiviral in
recommended. combination). The optimal management strategy to
ensure long-term HBV suppression is predicted to be the
use of an antiviral with a high genetic barrier to the devel-
Hepatitis B Virus Recurrence opment of resistance, such as ETV or TDF, or the use of
Most cases of HBV reinfection occur during the first 3 combinations of antivirals. Close monitoring for initial
years after transplantation and rarely thereafter. HBV response and for subsequent virological breakthrough is
reinfection is characterized by the appearance of HBsAg essential to prevent disease progression and flares of hep-
in serum. The HBV replication level is usually high, and atitis. Patients with a suboptimal response warrant a
large amounts of HBV particles are present in the graft. change of therapy. In patients who are naive to treatment
Historically, before the advent of antivirals, HBV reinfec- or have S gene mutants, ETV or TDF are drugs of choice
tion had a major impact on graft and patient survival as single agents, but combination therapy could be con-
because almost all patients with HBV reinfection sidered. LAM or ADV would not be recommended as a
114 PART II Patient Evaluation: Adult

Time of LT Low-risk patients High-risk patients

- Undetectable HBV DNA - Detectable HBV DNA levels
levels - HBeAg positive
- HBeAg negative - Presence of drug-resistant HBV
- Fulminant hepatitis B - HIV coinfection
- HDV coinfection* - High risk of HCC recurrence
- Poor compliance to antiviral therapy

Anhepatic HBIg IV
phase and first
postoperative week

Combination prophylaxis with Combination prophylaxis with low-

Post-LT low-dose IM HBIg and antiviral(s) dose IM HBIg and antiviral(s) to
to maintain anti-HBs levels maintain anti-HBs levels >100
>100 International Units/L for a International Units/L.
finite duration then antiviral(s) Cessation of HBIg is not recommended
prophylaxis

*Shortening the duration of HBIg administration in HDV/HBV patients could have

detrimental consequences because reinfection in the case of HDV latency may lead to
chronic hepatitis B and D.
FIGURE 9-2 n Prophylaxis for prevention of hepatitis B virus (HBV) graft recurrence following liver transplantation (LT). Proposal for
guideline. HBeAg, Hepatitis B e antigen; HBIg, hepatitis B immune globulin; HBs, hepatitis B surface; HCC, hepatocellular carcinoma;
HDV, hepatitis D virus; HIV, human immunodeficiency virus; IM, intramuscular; IV, intravenous.

single agent because of a high risk for resistance. In those HBIg was 56% and 17% in HBV and HDV patients,
patients with LAM-resistant HBV, ADV or TDF in com- respectively. The use of potent antivirals against HBV
bination with LAM has been shown to be effective.36,89 In has further reduced the risk for HBV-HDV reinfec-
those patients with ADV-resistant HBV, LAM or ETV in tion.55 The lower risk for recurrence among the patients
combination with ADV has been shown to be effective.90 with HDV cirrhosis could be explained by the fact that
In summary, long-term suppression of HBV replication is 70% to 90% of patients with HDV coinfection are
essential to preventing disease progression, prior drug HBeAg negative, and most have low serum HBV DNA
exposures and achieved resistance mutations are impor- levels because of the inhibitory effect of HDV on HBV
tant in guiding drug choices, and combination antiviral replication. However, patients infected with HBV and
therapy is recommended over sequential antiviral use to HDV are at risk for reinfection by both HBV and HDV
minimize the risk for treatment failure. virus. HDV is a defective RNA agent needing the pres-
ence of HBV for its life cycle. The transplant model pro-
Liver Transplantation in Patients with vides new insights into the pathological features of HDV
and its interactions with HBV. The course of HDV rein-
Hepatitis D Virus Liver Cirrhosis fection varies depending on whether or not HBsAg is
Around 5% of the chronic carriers of HBV worldwide present. In the few cases where HBsAg reappeared, it
have serological evidence of exposure to HDV. HDV was associated with a combined HBV-HDV replication;
coinfection is associated with more severe disease and a HBV DNA and HDV RNA were present in serum, or
higher incidence of cirrhosis than HBV monoinfec- HDAg was present in the liver, or both. Acute hepatitis,
tion.91,92 Some European studies have demonstrated a followed by chronic hepatitis, developed. HBV-HDV
threefold and twofold risk increase, respectively, for recurrence is, in general, less severe than HBV recur-
developing HCC and for death in HDV patients com- rence alone.94 Ottobrelli et al95 speculate that HDV can
pared with HBV monoinfected patients.93 LT is the only cause in the grafted liver subclinical infections indepen-
treatment option for patients with end-stage liver disease, dently of an overt HBV infection. In these patients, rein-
HCC, or fulminant hepatitis due to coinfection or super- fection with HDV was shown by the intermittent finding
infection with HDV and HBV. In Europe and North of HDV RNA in sera and HDAg in the graft and the
America 2% to 3% of patients undergoing LT have liver absence of HBV markers in sera or liver. However, in
disease associated with HBV-HDV coinfection.2 most transplant recipients HBV suppression was only
With or without HBV prophylaxis, patients chroni- transitory, and the recurrence of HBV led to the intrahe-
cally infected with HBV and HDV are less at risk for patic spread of HDV and the relapse of the disease with
HBsAg reappearance after transplantation than patients typical clinical, virological, and histological patterns. In
infected with HBV alone and have better survival.21 In patients receiving long-term HBIg prophylaxis without
the European multicenter study the 3-year actuarial risk HBV recurrence, we observed in the first posttransplant
for HBV recurrence in patients receiving long-term year serum HDV RNA or liver HDAg in 88% of patients
 9 Transplantation for Hepatitis A and B 115

with histologically normal graft.94 In the long term, these Even in the absence of HBV or HDV replication, patients
markers were detectable in only 5% of the patients. remain at risk for HCC, and continued surveillance is
These data suggest that in the transplant setting HDV needed until the time of LT.
replication can be independent from that of HBV but HBIg and antiviral combination prophylaxis is the
that HDV hepatotoxicity is HBV dependent. The unex- gold standard for prevention of recurrent disease.
pected finding of HDV viremia in the absence of detect- Today low-dose IM HBIg in combination with a potent
able HBV has raised questions about the biology of HDV nucleos(t)ide analogue is the most cost-effective
in the transplantation setting. The hypotheses for prophylaxis52,65,70(see Table 9-2). In these studies the
explaining the presence of HDV replication in HBsAg- proportion of patients coinfected with HBV and HDV
negative patients are as follows: (1) HBV markers could was between 0% and 28%. Caccamo et al98 in a cohort
be present but not detectable, (2) HDV is present in the of 25 HDV-coinfected patients showed the absence of
hepatocytes in the absence of HBsAg but either cannot HBV recurrence using combined IM HBIg and LAM
replicate or has a low replication level, and (3) the level of prophylaxis. In this study the combination prophylaxis
HDV RNA in the liver is much lower in patients without was cost efficient as compared with HBIg monopro-
HBsAg than those with HBsAg, and this low level of phylaxis in the first 2 posttransplant years. HBV and
HDV may explain the absence of liver graft lesions. Sme- HDV coinfected patients are candidates for the discon-
dile et al,96 using more sensitive PCR-based assays for tinuation of HBIg after some defined interval and con-
HDV and HBV detection, showed that HBV and HDV tinuing treatment with antivirals alone (see Fig. 9-2).
were always detected coincidentally in serum following However, the latency of HDV in the graft could be a
the post-LT incubation period. This temporal associa- potential concern, because subsequent HBV superin-
tion confirmed the dependence of HDV on its helper fection may result in productive HDV infection.
HBV. HDV viremia reached maximum levels only after As in the nontransplant setting, no effective antiviral
full expression of HBV had occurred. Mederacke et al97 drugs are available for HDV graft infection treatment.
in a recent study described early HDV RNA kinetics INF is not very efficient in this setting, and there is a
during the first days after LT. They showed that HDV potential risk for precipitating graft rejection and poor
RNA becomes rapidly negative within 1 to 10 days after tolerance. There is no study reporting IFN therapy for
LT, and that the HDV RNA decline parallels almost HDV graft infection. Transplant recipients coinfected
exactly HBsAg decline. However, HDV antigen was with HBV and HDV have low levels of HBV DNA and
detectable in the graft of 6 of 26 patients up to 19 months generally do not require antiviral B therapy. In cases of
after LT in the absence of liver HBV DNA, cccDNA, advanced fibrosis on the graft (fibrosis > F3 in META-
serum HBsAg, and HDV RNA. This latency of HDV in VIR score) and presence of HBV replication, antiviral B
the graft could be a potential concern, because subse- therapy could be initiated. ETV and TDF are the drugs
quent HBV superinfection may result in productive of choice. Selection of the optimal antiviral therapy
HDV infection. The authors suggested that shortening depends on the treatment previously received and the
the duration of HBIg administration in HDV-HBV presence or absence of drug-resistant HBV species.
patients could have detrimental consequences because
reinfection in the case of HDV latency may lead to Liver Transplantation for Fulminant
chronic hepatitis D.
Patients coinfected with HBV and HDV have low lev-
Hepatitis B
els of HBV DNA and generally do not require pretrans- HBV is a common cause of fulminant hepatic failure
plant antiviral B therapy. In the study of Marzano et al,19 (FHF), which occurs in 1% to 4% of patients with acute
62 of 98 HBV (63%) and 6 of 62 HDV (9.7%) patients hepatitis B. Acute HBV infection is diagnosed by detec-
had HBV DNA levels over 105 copies/mL before LT. tion of immunoglobulin (Ig) M antibodies against hepati-
HBV recurrence was observed in 12% of HBV patients tis B core antigen because a substantial number of patients
and none of HDV patients. Treatment with nucleos(t)ide have negative HBsAg and serum HBV DNA. Coinfec-
analogues is not effective at reducing HDV replication tion with HBV and HDV, or superinfection by HDV in
but might be useful in patients with high HBV replication patients with chronic hepatitis B, can also cause FHF.
and be of potential benefit when used long term by gradu- The incidence of such coinfection is higher in IV drug
ally reducing HBsAg concentration. There is currently users. FHF following reactivation of chronic hepatitis B
no approved therapy for HDV infection. The effective- has been described mainly in patients with diverse immu-
ness of treatment of HDV infection with interferon nosuppressant conditions. Emergency LT is the treat-
(IFN)-α is limited by the need for prolonged administra- ment of choice for the most severe forms of fulminant
tion and high doses that are poorly tolerated. Even though hepatitis B. Indeed, transplantation was shown to be asso-
50% of patients present undetectable HDV RNA and ciated with survival rates of 60% to 70%, whereas only
sometimes normalization of alanine transaminase levels 5% to 10% of patients were expected to survive sponta-
with IFN, HDV relapse is frequently observed after ces- neously.99 In Europe 17% of patients undergoing LT for
sation of treatment. Pegylated interferon (PEG-IFN) has fulminant hepatitis have fulminant hepatitis B.2 In
demonstrated a better response to treatment in compari- patients with fulminant hepatitis B, the risk for HBV
son with classic IFN. Sustained virological response was reinfection is low. The European multicenter study
observed in 20% to 36% and 31% to 43% using standard showed that whatever the treatment administered, HBV
IFN and PEG-IFN, respectively.92 IFN therapy is con- infection recurred in 17% of patients undergoing trans-
traindicated in patients with decompensated cirrhosis. plantation for fulminant hepatitis B.21 In our patients
116 PART II Patient Evaluation: Adult

who underwent transplantation for fulminant hepatitis B Future research should do the following:
and were receiving long-term HBIg, the rate of HBV •  Test new protocols using lower doses and/or
reinfection was null.9 The lower recurrence rate of HBV shorter duration of HBIg in combination with anti-
infection in fulminant hepatitis B patients may be because viral agents such as ETV and TDF.
most of these patients were HBV-DNA negative at the • Identify patients in whom HBIg prophylaxis can be
time of LT. These patients are candidates for the discon- stopped safely.
tinuation of HBIg after some defined interval and con- Currently treatment of posttransplantation hepatitis B
tinuing treatment with antivirals alone (see Fig. 9-2). is a less important clinical problem than it was histori-
cally. Effective antiviral therapies exist to rescue patients
who failed initial prophylaxis. New HBV antivirals such
TRANSPLANTATION FOR HEPATITIS A as ETV and TDF are effective in viral suppression of
resistant variants.
Hepatitis A virus (HAV), a nonenveloped RNA virus, is
particularly resistant and contagious. The infection is
spread chiefly by fecal-oral transmission and is a public
health problem throughout the world. The main compli- Pearls and Pitfalls
cation of HAV infection is fulminant hepatitis (acute liver • Historically patients undergoing liver transplantation
failure with encephalopathy), which occurs in less than for hepatitis B without prophylaxis are at high risk for
1% of cases. It appears to be more frequent in adults than hepatitis B virus (HBV) recurrence and severe graft
in children.100 In the United States approximately one ­lesions.
third of adults have anti-HAV antibodies, and 100 deaths • The advent of long-term hepatitis B immune globu-
per year are attributed to fulminant hepatitis A. In Europe lin (HBIg) administration and efficient antiviral drugs
0.2% of patients undergoing LT have fulminant hepatitis used before and after transplantation as prophylaxis
A (this represents 2% of transplantation for fulminant for HBV recurrence were major breakthroughs in the
hepatitis).2 Fulminant hepatitis A is also a frequent cause management of patients.
of death due to FHF among children in developing coun- •  Pretransplant antiviral therapy should use newer
nucleos(t)ide analogues with lower resistance rates, such
tries. The mechanisms of fulminant outcome are as entecavir or tenofovir, with the goal of undetectable
unknown. Low HAV viremia was associated with a severe HBV DNA levels at the time of transplantation.
course in our series.101 This suggests that a strong • The combination of long-term antiviral and low-dose
immune response may be associated with a severe or ful- HBIg can effectively prevent HBV recurrence in more
minant course. Other factors such as age, sex, and acet- than 90% of transplant recipients.
aminophen toxicity may also play a role in the course of • Some form of HBV prophylaxis must be continued
hepatitis A.101 However, fulminant hepatitis A resolves indefinitely after transplantation. However, in patients
spontaneously more frequently than fulminant hepatitis with a low risk for HBV recurrence (i.e., HBV DNA
of other origins, and the decision to perform transplanta- levels undetectable before transplantation), it is pos-
tion or not is thus particularly difficult.100 LT has mark- sible to discontinue HBIg and maintain long-term
nucleos(t)ide analogue(s) therapy.
edly changed the prognosis of fulminant hepatitis A in • A more cautious approach to a prophylaxis regimen is
industrialized countries and is currently indicated for necessary for those patients with high pretransplant
patients with deep coma and low factor V levels.99 Because HBV DNA levels, those with limited antiviral options
of the high possibility of liver regeneration in fulminant if HBV recurrence occurs (i.e., human immunodefi-
hepatitis A, the possibility of auxiliary orthotopic LT ciency virus coinfection, preexisting drug resistance),
should be raised, particularly in young patients.102 How- those with a high risk for hepatocellular carcinoma re-
ever, as described by our group, auxiliary partial ortho- currence, and those with a risk for noncompliance with
topic LT is associated with higher morbidity and should antiviral therapy. In this group, HBIg-free prophylaxis
be reserved for patients with a low-grade coma.103 cannot be recommended.
• Currently treatment of posttransplantation hepatitis B
is a less important clinical problem than it was histori-
cally because effective antiviral therapies exist to res-
CONCLUSION    cue patients who failed initial prophylaxis.

During the past 2 decades, major advances have been

made in the management of HBV transplant candidates.
The advent of long-term HBIg administration and effi-
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54. Yahyazadeh A, Beckebaum S, Cicinnati V, et al. Efficacy and rent hepatitis B virus infection after liver transplantation: hepatitis
safety of subcutaneous human HBV-immunoglobulin (Zutectra) B immunoglobulin, antiviral drugs, or both? Systematic review
in liver transplantation: an open, prospective, single-arm phase III and meta-analysis. Transpl Infect Dis. 2009;12(4):292-308.
study. Transpl Int. 2011;24(5):441-450. 74. Loomba R, Rowley AK, Wesley R, et al. Hepatitis B immuno-
55. Grellier L, Mutimer D, Ahmed M, et al. Lamivudine prophylaxis globulin and lamivudine improve hepatitis B-related outcomes
against reinfection in liver transplantation for hepatitis B cirrho- after liver transplantation: meta-analysis. Clin Gastroenterol Hepa-
sis. Lancet. 1996;348(9036):1212-1215. tol. 2008;6(6):696-700.
56. Lo CM, Cheung ST, Lai CL, et al. Liver transplantation in Asian 75. Jimenez-Perez M, Saez-Gomez AB, Mongil Poce L, et al. Effi-
patients with chronic hepatitis B using lamivudine prophylaxis. cacy and safety of entecavir and/or tenofovir for prophylaxis and
Ann Surg. 2001;233(2):276-281. treatment of hepatitis B recurrence post-liver transplant. Trans-
57. Malkan G, Cattral MS, Humar A, et al. Lamivudine for hepatitis plant Proc. 2010;42(8):3167-3168.
B in liver transplantation: a single-center experience. Transplanta- 76. Sanchez-Fueyo A, Rimola A, Grande L, et al. Hepatitis B immuno-
tion. 2000;69(7):1403-1407. globulin discontinuation followed by hepatitis B virus vaccination:
58. Mutimer D, Dusheiko G, Barrett C, et al. Lamivudine without A new strategy in the prophylaxis of hepatitis B virus recurrence
HBIg for prevention of graft reinfection by hepatitis B: long-term after liver transplantation. Hepatology. 2000;31(2):496-501.
follow-up. Transplantation. 2000;70(5):809-815. 77. Angelico M, Di Paolo D, Trinito MO, et al. Failure of a rein-
59. Yoshida H, Kato T, Levi DM, et al. Lamivudine monoprophy- forced triple course of hepatitis B vaccination in patients trans-
laxis for liver transplant recipients with non-replicating hepatitis planted for HBV-related cirrhosis. Hepatology. 2002;35(1):
B virus infection. Clin Transplant. 2007;21(2):166-171. 176-181.
60. Fung J, Cheung C, Chan SC, et al. Entecavir monotherapy is 78. Bienzle U, Gunther M, Neuhaus R, et al. Immunization with an
effective in suppressing hepatitis B virus after liver transplanta- adjuvant hepatitis B vaccine after liver transplantation for hepati-
tion. Gastroenterology. 2011;141(4):1212-1219. tis B-related disease. Hepatology. 2003;38(4):811-819.
61. Dickson RC, Terrault NA, Ishitani M, et al. Protective antibody 79. Albeniz Arbizu E, Barcena Marugan R, Oton Nieto E, et al. Pro-
levels and dose requirements for IV 5% Nabi Hepatitis B immune phylaxis of recurrent hepatitis B virus by vaccination after liver
globulin combined with lamivudine in liver transplantation for transplant: preliminary results. Transplant Proc. 2003;35(5):
hepatitis B-induced end stage liver disease. Liver Transpl. 2006; 1848-1849.
12(1):124-133. 80. Lo CM, Liu CL, Chan SC, et al. Failure of hepatitis B vaccination
62. Marzano A, Salizzoni M, Debernardi-Venon W, et al. Prevention in patients receiving lamivudine prophylaxis after liver transplan-
of hepatitis B virus recurrence after liver transplantation in cir- tation for chronic hepatitis B. J Hepatol. 2005;43(2):283-287.
rhotic patients treated with lamivudine and passive immunopro- 81. Rosenau J, Hooman N, Hadem J, et al. Failure of hepatitis B vac-
phylaxis. J Hepatol. 2001;34(6):903-910. cination with conventional HBsAg vaccine in patients with con-
63. Jiang L, Yan L, Li B, et al. Prophylaxis against hepatitis B recur- tinuous HBIG prophylaxis after liver transplantation. Liver
rence posttransplantation using lamivudine and individualized Transpl. 2007;13(3):367-373.
low-dose hepatitis B immunoglobulin. Am J Transplant. 2010; 82. Dodson SF, de Vera ME, Bonham CA, et al. Lamivudine after
10(8):1861-1869. hepatitis B immune globulin is effective in preventing hepatitis B
64. Buti M, Mas A, Prieto M, et al. A randomized study comparing recurrence after liver transplantation. Liver Transpl. 2000;6(4):
lamivudine monotherapy after a short course of hepatitis B 434-439.
immune globulin (HBIg) and lamivudine with long-term lamivu- 83. Naoumov NV, Lopes AR, Burra P, et al. Randomized trial of
dine plus HBIg in the prevention of hepatitis B virus recurrence lamivudine versus hepatitis B immunoglobulin for long-term pro-
after liver transplantation. J Hepatol. 2003;38(6):811-817. phylaxis of hepatitis B recurrence after liver transplantation.
65. Han SH, Ofman J, Holt C, et al. An efficacy and cost-effectiveness J Hepatol. 2001;34(6):888-894.
analysis of combination hepatitis B immune globulin and lamivu- 84. Buti M, Mas A, Prieto M, et al. Adherence to lamivudine after an
dine to prevent recurrent hepatitis B after orthotopic liver trans- early withdrawal of hepatitis B immune globulin plays an impor-
plantation compared with hepatitis B immune globulin tant role in the long-term prevention of hepatitis B virus recur-
monotherapy. Liver Transpl. 2000;6(6):741-748. rence. Transplantation. 2007;84(5):650-654.
66. Markowitz JS, Martin P, Conrad AJ, et al. Prophylaxis against 85. Angus PW, Patterson SJ, Strasser SI, et al. A randomized study of
hepatitis B recurrence following liver transplantation using com- adefovir dipivoxil in place of HBIG in combination with lamivu-
bination lamivudine and hepatitis B immune globulin. Hepatology. dine as post-liver transplantation hepatitis B prophylaxis. Hepatology.
1998;28(2):585-589. 2008;48(5):1460-1466.
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86. Saab S, Desai S, Tsaoi D, et al. Posttransplantation hepatitis B 96. Smedile A, Casey JL, Cote PJ, et al. Hepatitis D viremia following
prophylaxis with combination oral nucleoside and nucleotide orthotopic liver transplantation involves a typical HDV virion
analog therapy. Am J Transplant. 2011;11(3):511-517. with a hepatitis B surface antigen envelope. Hepatology.
87. Neff GW, Kemmer N, Kaiser TE, et al. Combination therapy in 1998;27(6):1723-1729.
liver transplant recipients with hepatitis B virus without hepatitis 97. Mederacke I, Filmann N, Yurdaydin C, et al. Rapid early HDV
B immune globulin. Dig Dis Sci. 2007;52(10):2497-2500. RNA decline in the peripheral blood but prolonged intrahepatic
88. Teperman LW, Poordad F, Bzowej N, et al. Randomized trial of hepatitis delta antigen persistence after liver transplantation.
emtricitabine/tenofovir disoproxil fumarate after hepatitis B J Hepatol. 2012;56(1):115-122.
immunoglobulin withdrawal after liver transplantation. Liver 98. Caccamo L, Agnelli F, Reggiani P, et al. Role of lamivudine in the
Transpl. 2013;19(6):594-601. posttransplant prophylaxis of chronic hepatitis B virus and hepati-
89. Tan J, Lok AS. Antiviral therapy for pre- and post-liver transplan- tis delta virus coinfection. Transplantation. 2007;83(10):
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323-326. 99. Bismuth H, Samuel D, Gugenheim J, et al. Emergency liver
90. Perrillo R, Hann HW, Mutimer D, et al. Adefovir dipivoxil added transplantation for fulminant hepatitis. Ann Intern Med.
to ongoing lamivudine in chronic hepatitis B with YMDD mutant 1987;107(3):337-341.
hepatitis B virus. Gastroenterology. 2004;126(1):81-90. 100. Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a pro-
91. Rizzetto M. Hepatitis D: thirty years after. J Hepatol. spective study of acute liver failure at 17 tertiary care centers in
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92. Hughes SA, Wedemeyer H, Harrison PM. Hepatitis delta virus. 101. Rezende G, Roque-Afonso AM, Samuel D, et al. Viral and clinical
Lancet. 2011;378(9785):73-85. factors associated with the fulminant course of hepatitis A infec-
93. Fattovich G, Giustina G, Christensen E, et al. Influence of hepa- tion. Hepatology. 2003;38(3):613-618.
titis delta virus infection on morbidity and mortality in compen- 102. Bismuth H, Azoulay D, Samuel D, et al. Auxiliary partial ortho-
sated cirrhosis type B. The European Concerted Action on Viral topic liver transplantation for fulminant hepatitis. The Paul
Hepatitis (Eurohep). Gut. 2000;46(3):420-426. Brousse experience. Ann Surg. 1996;224(6):712-724, discussion
94. Samuel D, Zignego AL, Reynes M, et al. Long-term clinical and 724–716.
virological outcome after liver transplantation for cirrhosis caused 103. Azoulay D, Samuel D, Ichai P, et al. Auxiliary partial orthotopic
by chronic delta hepatitis. Hepatology. 1995;21(2):333-339. versus standard orthotopic whole liver transplantation for acute
95. Ottobrelli A, Marzano A, Smedile A, et al. Patterns of hepatitis liver failure: a reappraisal from a single center by a case-control
delta virus reinfection and disease in liver transplantation. Gastro- study. Ann Surg. 2001;234(6):723-731.
enterology. 1991;101(6):1649-1655.
 CHAPTER 10

Natural History of Hepatitis C

Stevan A. Gonzalez • Gary L. Davis

CHAPTER OUTLINE

HEPATITIS C VIRUS Protease Inhibitors

Predictors of Response
PATHOGENESIS
Adverse Events
INCIDENCE AND PREVALENCE Treatment Strategies and End-Stage Liver
PROGRESSION TO CIRRHOSIS Disease

HEPATIC DECOMPENSATION LIVER TRANSPLANTATION

HEPATOCELLULAR CARCINOMA SUMMARY
ANTIVIRAL THERAPY
Pegylated Interferon-α and Ribavirin

Hepatitis C is a major cause of chronic liver disease correct errors during replication.5 It replicates entirely
worldwide and remains the leading indication for liver within the hepatocyte cytoplasm; there is no nuclear rep-
transplantation in the United States and western Europe. lication or viral genomic integration into host DNA.
The epidemiological characteristics of chronic hepatitis HCV replicates at an extremely high rate, producing up
C infection are evolving and leading to more advanced to 1012 virions per day.6 As a result, considerable genomic
liver disease; this has significant implications for liver heterogeneity occurs. It is mathematically estimated that
transplantation. Recent trends reveal an increasing preva- every nucleic acid in the genome should mutate each day.
lence of cirrhosis and hepatocellular carcinoma associated Although most of these variants are not viable, the result-
with hepatitis C. This chapter provides an overview of the ing viral heterogeneity likely contributes to escape from
hepatitis C virus (HCV), the natural history of chronic immune surveillance, survival of the virus within the host,
infection, and key issues related to liver transplantation. and as discussed later, failure to respond to some antiviral
therapies. Over time this heterogeneity has resulted in
distinct populations of HCV known as genotypes, which
HEPATITIS C VIRUS may vary by up to 35% in nucleotide sequence.7 Cur-
rently there are six genotypes and over 100 subtypes.
Although a virus was long suspected as the cause of a form HCV genotypes differ not only in genetic composition
of hepatitis not associated with either hepatitis A or hepa- but also in geographical distribution. Genotype 1 is the
titis B, its identity was elusive and the hepatitis C virus most prevalent in North America, South America, and
was not identified until 1989.1 Nonetheless, the agent western Europe. The distribution of other genotypes
responsible for non-A, non-B hepatitis was well charac- includes genotype 2, more commonly found in the Medi-
terized before this time by careful observation of infec- terranean and Asia; genotype 3 in Southeast Asia and
tious isolates in humans and chimpanzees. The agent was India; genotype 4 in Africa and the Middle East; geno-
known to be lipid encapsidated and approximately 40 nm type 5 in South Africa; and genotype 6 in Southeast Asia
to 70 nm in size.2,3 These characteristics were suggestive and eastern Asia.7,8
of an RNA virus, most likely of the Flaviviridae family.
Eventually, blind cloning methods were able to identify a
portion of the virus and assemble the complete 9.6-kb PATHOGENESIS
RNA genome, later named hepatitis C.1,4
Several characteristics of HCV affect the natural history Early activation and mobilization of the cellular immune
of the virus and our ability to treat it. The virus is a single- response directed toward HCV is pivotal in the early host
stranded RNA virus without the ability to proofread and response to acute infection and most likely in the rate of

120
 10 Natural History of Hepatitis C 121

progression of the disease if chronic infection evolves.

TABLE 10-1 C
 haracteristics of Hepatitis C Viral
The CD4+ helper T cells appear to play a critical role in
Infection
viral clearance following acute infection, in which a vigor-
ous, multispecific, and durable CD4+ response is associ- Acute Infection
ated with a stronger likelihood of achieving spontaneous Incidence (U.S.) 16,000 cases/yr
viral eradication.9,10 This appears to be at least partly Incubation period 5-12 wk
related to polymorphisms near the IL28B gene locus Diagnosis HCV RNA by amplification
because these correlate well with spontaneous clearance Spontaneous resolution 15%-45%
of acute infection.11 Although CD8+ cytotoxic T cells also
contribute to viral clearance in the acute setting, their role Chronic Infection
is more significant after chronic infection is established, Prevalence United States: 3-4 million (1.8%)
Worldwide: 170 million (3%)
and they appear to be responsible for hepatocyte injury.9
Diagnosis Anti-HCV, confirmatory HCV
In the setting of antiviral therapy, patients with higher RNA by amplification
levels of virus-specific cellular immunity may also be more Risk for cirrhosis 20%-30% after 10-20 yr of
sensitive to the antiviral effects of IFN-α.12-15 In immuno- infection
compromised patients, particularly those with exogenous
immune suppression after transplantation, HCV repli- HCV, Hepatitis C virus.
cates without cellular immune restraint and may become
directly cytopathic to infected hepatocytes in some indi-
viduals.16,17 In these patients, virus levels are typically Because progression to chronic infection may occur in
extremely high and immunochemical stains demonstrate the majority of adults following acute exposure, chronic
large amounts of intracellular virus, resulting in a clinical HCV has emerged as a major cause of chronic liver dis-
picture of fibrosing cholestatic hepatitis. ease. The worldwide prevalence of chronic infection is
Although the majority of acutely infected persons estimated to be at least 170 million persons (approxi-
mount an antibody response to HCV within weeks of mately 3%), although the prevalence varies greatly based
exposure, the presence of antibody does not appear to on geography.30 In some regions such as West Africa,
influence the outcome of infection and in fact persists in greater than 10% of the population may be chronically
both chronic infection and after clearance of virus with infected with HCV, likely as a result of iatrogenic spread
antiviral therapy.18 The genomic heterogeneity associ- associated with cultural and medical practices.30,31 In the
ated with HCV may have a major role in allowing viral United States about 4 million individuals (approximately
escape from the humoral immune response.19,20 Other 1.8%) have chronic hepatitis C.32,33
proposed mechanisms of HCV immune evasion include The greatest prevalence of chronic HCV infection in
dysfunctional homing of activated T cells to the liver, western countries occurs within specific populations at
increased activity of regulatory T cells, impaired antigen risk. The incidence of acute HCV infection before the
presentation, viral mutational escape, or perhaps most mid-1980s was extremely high, largely because of intra-
importantly, inhibitory effects of the virus on the host venous drug use and a high risk for transfusion-associated
innate immune response.20-23 transmission.34 It has been estimated that 200,000 to
300,000 cases of acute hepatitis C occurred per year dur-
ing the 1960s, mostly attributable to blood products, in
INCIDENCE AND PREVALENCE which the incidence of acute hepatitis C following trans-
fusion was as high as 33%.35,36 The overall incidence of
Acute infection with HCV is usually asymptomatic and transfusion-associated hepatitis decreased in the 1970s
typically occurs unrecognized by the host.24 The incu- once a volunteer blood donor system was introduced in
bation period ranges from 5 to 12 weeks (Table 10-1).25 the United States and serological testing for hepatitis A
In the setting of acute infection, antibody to HCV may and B viruses became available. However, transfusions
be undetectable during the initial period of infection in continued to account for approximately 50% of reported
many patients, and assessment of serum HCV RNA cases of acute non-A, non-B hepatitis until more inten-
should be performed to confirm the diagnosis. In cohorts sive screening of donor risk factors was introduced.37 The
acutely exposed to HCV, spontaneous recovery has been practice of heat inactivation of coagulation factors in
reported in 15% to 45% of cases and appears to be 1987 and the widespread introduction of specific anti-
related to younger age, female sex, Asian ethnicity, and a body screening for HCV in potential blood donors in
favorable IL28B genotype.11,26-28 In contrast, the risk for 1992 virtually eliminated the risk for acquiring HCV
chronicity in older adults and those with unfavorable infection through blood products.1,35 Now that third-
IL28B genotypes may be as high as 80% to 85%.28 generation antibody tests are required in blood donation
Spontaneous recovery should be assumed only if serum centers, the risk for transfusion-associated HCV infec-
aminotransferase levels and HCV RNA remain normal tion may be as low as 1 per 280,000 (0.00036%) units
and undetectable for at least 6 months after acute infec- transfused in the United States.38 Nucleic acid testing in
tion. It is important to recognize that serum alanine some blood banks has reduced the risk for hepatitis C to
aminotransferase may return to the normal range and nearly zero.
HCV RNA may transiently become undetectable in Although the incidence of acute hepatitis C has fallen
some patients who nonetheless go on to develop chronic to approximately 16,000 cases per year, HCV remains the
infection.29 most common chronic blood-borne infection in the
122 PART II Patient Evaluation: Adult

United States and accounts for up to two thirds of newly strategies have evolved to more adequately identify indi-
diagnosed cases of chronic liver disease.32,39,40 Injection viduals who have yet to be diagnosed with chronic HCV,
drug use remains the most frequent means of HCV trans- most of whom were born between 1945 and 1965.32,45
mission in the United States; the seroprevalence of anti- Based on these data, the Centers for Disease Control and
body to HCV in this group may rise to over 70% within 3 Prevention (CDC) has proposed widespread screening of
to 5 years of habitual exposure.41,42 More than two thirds individuals included in this baby boomer birth cohort.47,48
of acute infections with HCV involve easily identifiable
risk factors (Table 10-2).41 Other groups known to be at
risk for exposure to HCV include hemodialysis patients, PROGRESSION TO CIRRHOSIS
hemophiliacs, and individuals infected with human immu-
nodeficiency virus (HIV).33,43 Current recommendations It has been estimated that 20% to 30% of individuals with
for identifying individuals who would benefit from hepati- chronic HCV develop cirrhosis after 10 to 20 years of
tis C screening include these groups (Table 10-3)43,44; infection (Fig. 10-1).49-52 The duration of infection with
however, it is estimated that 50% to 75% of persons with HCV is perhaps the most important factor associated with
chronic infection in the United States are not aware they progression to cirrhosis (Table 10-4).53 Most patients who
are infected.45,46 In light of these emerging data and the develop cirrhosis have had infection for more than 20
availability of more effective antiviral therapy, screening years.54 In the year 2000 approximately 30% of patients
with chronic hepatitis C had a history of infection for at
least this long.55 It is now estimated that more than half of
TABLE 10-2 E
 xposures Associated with Acute patients have had infection for more than 2 decades, a pro-
Hepatitis C in the United States portion expected to increase as the cohort with chronic
(1994-2006) infection ages. This has obvious and significant implica-
tions for the prevalence of cirrhosis in the infected popula-
Risk Factor Reported Frequency (%) tion. Mathematical models estimate that the proportion of
Injection drug use 46.7 infected patients with cirrhosis will approach 50% by 2030
HCV-positive sex partner* 10.7
Health care worker and blood
exposure 3.3 Acute hepatitis C
Multiple sex partners 3.3
Blood transfusion 1.9
HCV-positive household contact 1.5 55%-85% 15%-45%
Aggregate risk category† 3.7
No risk factor identified 29.3
Chronic hepatitis C Spontaneous resolution
Based on report from national surveillance program assessing risk
factors for exposure within 6 months of acute HCV presentation 20%-30%
(n = 2075).41
*Includes both known and suspected HCV positivity.
†Circumstances in which the individual acknowledged an exposure
Cirrhosis
risk but would not specify the category.
HCV, Hepatitis C virus.
3.9%-6.9%/yr 1.0%-5.0%/yr

TABLE 10-3 P
 ersons Recommended for Liver failure Hepatocellular carcinoma
Hepatitis C Virus Screening
Persons with elevated liver enzyme levels
Injection drug users or persons with history of injection
drug use
Persons with HIV infection Death or liver transplantation
Persons with hemophilia
Hemodialysis patients FIGURE 10-1 n Natural history of hepatitis C virus infection.
Recipients of clotting factors or other blood products
before 1987
Recipients of solid organ transplants before 1992 TABLE 10-4 R
 isk Factors for Fibrosis
Recipients of blood transfusions before 1992 Progression in Chronic Hepatitis C
Children born to HCV-positive mothers
Sexual partners of HCV-infected individuals Duration of infection
Persons with any known potential exposure via HCV-positive Degree of hepatic inflammation
blood donor, organ donor, or occupational exposure Presence of hepatic fibrosis
Persons born between the years 1945 and 1965* Heavy alcohol intake
Age greater than 40 years
Data from references 43, 44, 47. Male sex
*As proposed by the Centers for Disease Control and Prevention: Obesity
Proposed recommendations for the identification of HCV chronic Hepatic steatosis
infection among persons born during 1945 through 1965, Coinfection with HIV; CD4+ T cell counts < 500 cells/μL
reviewed and updated May 18, 2012. http://www.cdc.gov/hepati Coinfection with hepatitis B virus
tis/HCV/BirthCohortTesting.htm. Accessed June 10, 2012.
HCV, Hepatitis C virus; HIV, human immunodeficiency virus. HIV, Human immunodeficiency virus.
 10 Natural History of Hepatitis C 123

(Table 10-5), and the prevalence of complications of cir- HEPATIC DECOMPENSATION

rhosis such as liver failure and hepatocellular carcinoma
will also increase.36 In the decade from 2000 to 2010, the Although most patients who develop cirrhosis will remain
prevalence of cirrhosis and decompensation associated clinically well compensated, complications associated with
with HCV doubled and hepatocellular carcinoma increased HCV result in significant morbidity and mortality. Cur-
20-fold.56 As a consequence, annual liver-related deaths rently more than 12,000 deaths occur annually in the
attributed to chronic HCV (liver-related death and carci- United States as a result of HCV-related liver disease, and
noma) could more than nearly triple between 2000 and as many as 360,000 deaths occur annually on a global
2020 (Table 10-6). Indeed, the mortality rate attributed to scale.39,61 Decompensation occurs as a consequence of pro-
hepatitis C based on death certificate data in the United gressive hepatic dysfunction and the development of portal
States doubled over the decade from1995 at 1.09 deaths hypertension, manifested by the onset of ascites, encepha-
per 100,000 persons to 2.44 deaths per 100,000 in 2004.57 lopathy, jaundice, or variceal hemorrhage. These compli-
The rate of progression to cirrhosis is highly variable cations develop in 3% to 4% of compensated cirrhotic
and is influenced by several factors in addition to duration patients per year and are currently present in over 10%
of HCV infection (see Table 10-4). These include heavy (Table 10-7).36,62,63 Decompensation is of great prognostic
alcohol intake, fatty liver disease, obesity, male sex, age importance, even if the event is transient or easily man-
greater than 40 years, hepatitis B coinfection, and HIV aged. Only half of patients with chronic hepatitis C and
coinfection with low CD4+ T-cell counts.52 Alcohol con- cirrhosis survive 5 years after the initial episode of decom-
sumption is an important risk factor associated with a more pensation, with annual mortality rates of 15% to over 25%
rapid progression of hepatic fibrosis and is entirely pre- (Fig. 10-2).62,64 Although complications of cirrhosis can be
ventable. The relative risk for cirrhosis increases at least managed over the short term, they signal a change in prog-
threefold among regular alcohol consumers with chronic nosis and usually warrant consideration of liver transplan-
HCV.58,59 The presence of fibrosis on liver biopsy is also a tation when the first episode of decompensation occurs. In
risk factor because patients with periportal or bridging addition to hepatocellular carcinoma, several other com-
fibrosis demonstrate a more rapid progression to cirrhosis plications of cirrhosis and portal hypertension are associ-
compared to those with minimal or only portal fibrosis.51 ated with significantly increased short-term mortality risk,
Viral factors such as serum HCV RNA level or HCV geno- including hepatorenal syndrome, severe hepatopulmonary
type do not appear to contribute to disease progression.60 syndrome, and portopulmonary hypertension. As a result,
liver transplant candidates with these high-risk complica-
tions may be eligible for listing prioritization, depending
TABLE 10-5 P
 rojected Prevalence of Cirrhosis on regional organ allocation policy.
Among Persons with Chronic
Hepatitis C
Year Prevalence (%)
HEPATOCELLULAR CARCINOMA
1989 5
1998 10
Hepatocellular carcinoma (HCC) is the third most frequent
2006 20 cause of cancer death worldwide.65 Chronic HCV infection
2010 24.8 is the most common risk factor for HCC in the United
2020 37.2 States, accounting for more than 50% of cases.66 Individuals
2030 44.9 with chronic HCV have a twentyfold increased risk for
From Davis GL, Alter MJ, El-Serag H, et al. Aging of hepatitis C developing HCC compared with those who are HCV nega-
virus (HCV)-infected persons in the United States: a multiple tive, with an annual risk up to 5% per year in those with
cohort model of HCV prevalence and disease progression. HCV-related cirrhosis.66,67 HCC in patients with hepatitis
Gastroenterology. 2010;138:513-521.

TABLE 10-6 P
 rojected Impact of Chronic Hepatitis C Based on Complications and Associated
Mortality
Year
2000 2010 2020 2030

Prevalence
Chronic hepatitis C 3,560,800 3,385,700 2,805,500 1,826,000
Cirrhosis, all 413,200 838,200 1,043,300 819,100
Decompensated cirrhosis 44,900 99,700 143,800 124,100
Annual Incidence
Hepatocellular carcinoma 6,200 11,700 13,700 9,900
Liver-related deaths 10,000 21,000 29,200 24,500

Projections from Davis GL, Alter MJ, El-Serag H, et al. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple
cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521; numbers rounded to closest 100.
 124 PART II Patient Evaluation: Adult

has continued to improve. Interferon-α has remained an

TABLE 10-7 A
 nnual Risk for Complications
essential foundation of antiviral therapy; however, the
and Associated Mortality in
inclusion of ribavirin and more recently the emergence of
Compensated Cirrhosis Due
direct-acting antiviral agents, including the recently
to Chronic Hepatitis C
approved protease inhibitors (PIs), have led to the devel-
Risk for opment of regimens capable of achieving long-term clear-
Complication Decompensation (%) Risk for Death (%) ance of HCV in an increasing proportion of patients.
Compensated 3.9-6.9 (any 1.9-4.0
The goal of antiviral therapy for HCV infection is sus-
cirrhosis complication) tained virological response (SVR), which is defined as
Ascites 2.9 15.1 undetectable serum HCV 6 months after the discontinu-
Jaundice 2.0 16.6 ation of therapy; this connotes permanent eradication of
Gastrointestinal 1.0 27.7 HCV infection.73 This is possible because the HCV life
bleeding cycle occurs entirely within the hepatocyte cytoplasm and
Hepatocellular 1.0-5.0 31.5 does not include an intranuclear (integrated) component.
carcinoma Prospective studies have demonstrated clinical benefit in
patients who achieve an SVR, including histological
Data from references 62, 64, 66, 67.
improvement in those with advanced fibrosis.73-81 Regres-
sion of cirrhosis following SVR has been described based
on paired liver biopsy data73-76,82,83 in addition to reduc-
100
tions in portal hypertension,84,85 risk for developing new
esophageal varices,86 and risk for HCC.87 As a result,
Survival probability (%)

A
80
achievement of SVR in patients with cirrhosis may result
60 in a substantial decrease in liver-related mortality.80-82,88

40 B Pegylated Interferon-α and Ribavirin

20 Although treatment regimens and duration differ based
on HCV genotype, pegylated interferon (PEG-IFN)-α
0 and ribavirin remain an integral part of antiviral therapy
0 12 24 36 48 60 72 84 96 108 120 in all treatment groups. PEG-IFNs consist of standard
Months
recombinant IFN attached to a polyethylene glycol chain.
Two preparations of PEG-IFN are currently available:
Patients at risk
Peg-IFN alfa-2a (40 kD; fixed dose) and PEG-IFN alfa-
A 384 376 342 288 236 165 126 79 52 39 25 2b (12 kD; weight based). These differ in size, configura-
B 65 39 21 11 7 4 4 3 3 2 1 tion (branched versus linear), and pharmacokinetic
FIGURE 10-2 n Survival in patients with cirrhosis caused by properties (half-life 80 versus 40 hours, respectively).
chronic hepatitis C. Compensated cirrhosis is shown as line A Both are administered subcutaneously once weekly and
and decompensated cirrhosis as line B. (From Fattovich G, Gius- have similar efficacy when combined with oral ribavirin, a
tina G, Degos F, et al. Morbidity and mortality in compensated cir-
rhosis type C: a retrospective follow-up study of 384 patients. synthetic guanosine analogue, as demonstrated prospec-
Gastroenterology. 1997;112:463-472.) tively in a large randomized clinical trial.89
The mechanisms by which this combination of drugs
inhibits HCV are not clearly understood; however, IFNs
C typically occurs in the setting of cirrhosis after 20 to 30 have a key role in the host innate immune response to viral
years of chronic infection.66,68 Risk factors for HCC associ- infections, including HCV infection, by inhibiting virus
ated with chronic HCV include male sex, alcohol use, attachment and uncoating, inducing intracellular antiviral
immunocompromised state, presence of hepatitis C viremia, proteins and ribonucleases, and promotion of the cellular
history of smoking, insulin resistance, longer duration of immune response, including both innate (natural killer
infection, and decompensated liver disease.66,68,69 The over- cell) immunity and HCV-specific adaptive (T cell) activ-
all incidence of HCC has tripled in the United States over ity.10,90,91 Consequently a vigorous, durable, and multispe-
the last 30 years, and it is estimated that the number of cases cific CD4+ proliferative response and an enhanced IFN-γ
of HCC related to HCV infection will continue to increase secretory response have been reported to coincide with
in the United States for at least another decade.36,70 Although HCV clearance following IFN-based therapy.12-15
the numbers of liver transplants performed for HCV-associ- Before the availability of PIs, dual therapy with PEG-
ated liver disease appear to have reached a plateau, the pro- IFN α-2a or PEG-IFN α-2b and ribavirin was the gold
portion related to HCC has increased significantly, with the standard for the treatment of persons infected with geno-
majority of cases attributed to HCV infection (Fig. 10-3).71,72 types 1 or 4 HCV and continues to be the approved treat-
ment for genotypes 2 and 3.43,92,93 Initial pivotal trials of
combination PEG-IFN and ribavirin reported SVR rates
ANTIVIRAL THERAPY of 42% to 52% in genotype 1 infection following 48
weeks of therapy and up to 84% in genotype 2 or 3
Since the availability of antiviral therapy for chronic hepa- patients with 24 weeks of therapy (Fig. 10-4).94-96 Weight-
titis C in 1990, the efficacy of various treatment regimens based dosing of ribavirin was found to be superior to
 10 Natural History of Hepatitis C 125

3000

Hepatocellular carcinoma
Hepatitis C
2500

2000
Number of liver transplants

1500

1000

500

0
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
FIGURE 10-3 n Number of liver transplants performed yearly in the United States for the diagnoses of chronic hepatitis C and hepato-
cellular carcinoma from 1992 to 2011. (Data from U.S. Organ Procurement and Transplantation Network and Scientific Registry of Transplant
Recipients. http://optn.transplant.hrsa.gov/. Accessed April 1, 2012.)

fixed-dose in genotype 1 infection,97 whereas a higher Treatment regimens involving PIs use a response-
dose of ribavirin does not appear to improve efficacy in guided approach, in which the duration of therapy can be
genotype 2 or 3 infection.96 shortened based on achieving a rapid virological response
(undetectable HCV RNA within the first 4 weeks of triple
therapy). The treatment regimens differ slightly between
Protease Inhibitors boceprevir and telaprevir. Boceprevir therapy requires a
Although PEG-IFN and ribavirin remain the standard of 4-week lead-in phase of dual PEG-IFN and ribavirin to
care for treating genotype 2 or 3 infection, HCV-specific assess IFN responsiveness before initiating triple therapy,
PIs are now available for genotype 1. These drugs, bocepre- which may range from 24 to 44 weeks, with dual therapy
vir and telaprevir, have greatly improved the SVR rate in administered during the final 12 weeks in some cases. In
patients with genotype 1 infection by targeting the geno- contrast, telaprevir is usually initiated without a lead-in
type 1–specific HCV NS3/4A serine protease and potently phase, and triple therapy is administered for only the first
blocking viral polyprotein cleavage and HCV replication. 12 weeks, followed by PEG-IFN and ribavirin to com-
The increased efficacy of combination PEG-IFN, ribavi- plete a 24- to 48-week course (Table 10-8).
rin, and a PI in comparison with dual therapy has been
demonstrated in prospective randomized controlled trials,
with overall SVR rates of 63% for boceprevir and 75% for
Predictors of Response
telaprevir (see Fig. 10-4).98,99 Based on these data, combi- Factors associated with a poor response to IFN-based
nation therapy with PEG-IFN, ribavirin, and a PI is con- antiviral therapy include high baseline serum HCV RNA
sidered the optimal regimen for treatment of genotype 1 levels, increased age, African-American ethnicity, obesity,
chronic hepatitis C.93 PI therapy can also be considered for and the presence of advanced fibrosis or cirrhosis.94-96,102
those who previously failed therapy with PEG-IFN and Genome-wide association studies have also identified
ribavirin, including relapsers (achieved undetectable HCV single nucleotide polymorphisms located on chromo-
RNA by end of treatment), partial responders (achieved some 19 near the IL28B gene that are predictive of viro-
2-log decrease in HCV RNA within 12 weeks but not logical response associated with PEG-IFN and ribavirin
clearance), and null responders (never achieved 2-log in the treatment of genotype 1 infection.103-106 The IL28B
decrease in HCV RNA). Virological response associated gene encodes IFN-λ3, a cytokine in the IFN-λ family.107
with retreatment in those who have previously failed ther- Variations in expression of IL28B polymorphisms appear
apy varies based on prior treatment response, with the to explain in part the observed differences in virological
greatest potential for SVR in prior relapsers (69% to 83%), response based on ethnicity.103 IL28B polymorphisms are
followed by partial responders (40% to 59%), and then null among the strongest predictors of virological response to
responders (29% to 34%).100,101 treatment with IFN and ribavirin. However, IL28B and
126 PART II Patient Evaluation: Adult

100
Genotypes 2-3

84 Genotype 1

80
75
Sustained virological response (%)

63
60
42-52

40

20

0
PEG-IFN + PEG-IFN + Telaprevir + Boceprevir +
Ribavirin (24 wk) Ribavirin (48 wk) PEG-IFN + PEG-IFN +
Ribavirin (RGT) Ribavirin (RGT)
FIGURE 10-4 n Sustained virological response rates following antiviral therapy for chronic hepatitis C based on genotype and treat-
ment regimen. PEG-IFN, Pegylated interferon; RGT, response-guided therapy. (Data from references 94-96, 98, 99.)

TABLE 10-8 Treatment Regimens Involving Protease Therapy for Genotype 1 Chronic Hepatitis C
Telaprevir Boceprevir
Dose; frequency 750 mg; q 8 hr with fatty meal 800 mg; q 8 hr with food
Lead-in phase No Yes; 4 wk PEG-IFN/ribavirin
Duration of therapy 12 wk (all patients) Variable; 24-44 wk
Protease inhibitor 24 (RVR) vs 48 wk 28 (RVR) vs 48 wk
Naive 24 (RVR) vs 48 wk 36 (RVR) vs 48 wk
Relapsers 48 wk 36 (RVR) vs 48 wk
Partial responders 48 wk 48 wk
Null responders 48 wk 48 wk
Patients with cirrhosis
Response-guided therapy criteria* Undetectable HCV RNA at 4 wk and 12 wk Undetectable HCV RNA at 8 wk
Futility criteria (HCV RNA level)† >1000 International Units/mL at 4 wk, >1000 Interna- >100 International Units/mL at
tional Units /mL at 12 wk, detectable at 24 wk 12 wk, detectable at 24 wk

*Patients eligible for a shortened course of therapy with a response-guided approach include treatment-naive patients and relapsers for
telaprevir, and treatment-naive patients, relapsers, and partial responders for boceprevir. Rapid virological response (RVR) defined as
undetectable HCV RNA within 4 weeks of triple therapy involving PEG-IFN, ribavirin, and a protease inhibitor.
†Virological response and futility criteria are based on HCV RNA assay using a lower limit of quantification (25 International Units/mL) and a

lower limit of detection (10-15 International Units/mL).

HCV, Hepatitis C virus; PEG-IFN, pegylated interferon; RVR, rapid virological response.

the other aforementioned factors are all somewhat less SVR rate of about 90% after only 24 to 28 weeks of ther-
predictive in the setting of direct-acting antiviral agents apy.98,99 An inadequate virological response in the setting
such as the PIs. of PI therapy is predictive not only of treatment failure,
The initial reduction of the serum HCV RNA level but also the potential for developing drug resistance.
remains the strongest predictive factor of antiviral ther- Thus strict futility criteria are in place to guide decisions
apy and is the basis for the response-guided approach for discontinuation of treatment from time points as early
used in treatment regimens involving PIs. Achievement as 4 weeks and up to 24 weeks (see Table 10-8).
of a rapid virological response (RVR; loss of detectable In the absence of PI therapy for genotype 1 infection,
HCV RNA at week 4 of therapy) occurs in about 50% to achievement of an RVR has a positive predictive value for
60% of patients undergoing treatment with triple therapy SVR of approximately 90%.108 An early virological
(PEG-IFN, ribavirin, and a PI) and is associated with an response, defined by a greater than 2-log10 decrease in
 10 Natural History of Hepatitis C 127

HCV RNA at week 12, has a negative predictive value of of thoughtful selection of appropriate treatment candi-
approximately 100% and is used as a stopping point for dates, particularly in those with advanced fibrosis who
those who fail to meet this parameter.95,108,109 Additional have failed prior therapy.
futility criteria in this setting include the presence of Although patients with cirrhosis have the most to gain
detectable HCV RNA at 24 weeks, in which virtually no through achieving long-term clearance of HCV, they are
patients will achieve an SVR.108 the most susceptible to adverse events during therapy, par-
ticularly hematological side effects. Recent prospective
Adverse Events data involving a French cohort of 355 genotype 1 patients
with compensated cirrhosis treated with PIs have revealed
Efforts to optimize adherence to therapy are essential to poor tolerability in this population, with serious adverse
promoting viral clearance and achieving an SVR. Adher- events occurring in 48.6% and 38.4% of those treated with
ence is particularly important in the setting of PI therapy telaprevir or boceprevir, respectively.112 Significant anemia
because drug resistance can coincide with inadequate viral occurred in over 30% despite the frequent use of growth
suppression. PEG-IFN, ribavirin, and PIs have known side factors, and one quarter of patients discontinued treatment
effects that can lead to adverse events, dose reductions, and prematurely. Although prospective data are limited, main-
treatment discontinuation. Adverse events associated with taining a course of therapy in patients with decompensated
PEG-IFN include flulike symptoms, fatigue, anxiety, cirrhosis can be even more challenging. However, the
depression, exacerbation of psychiatric disease, exacerba- achievement of viral clearance at the time of liver trans-
tion of autoimmune diseases, neutropenia, and thrombo- plantation may result in a virus-free posttransplant course
cytopenia. Ribavirin is teratogenic, requiring at least two in up to 80% of patients.113 One small pilot study of patients
forms of contraception and monthly pregnancy testing in listed for liver transplantation found that more than one
women of childbearing potential during therapy and for 6 half of individuals screened were not eligible for study entry,
months after completion of therapy. Ribavirin is also asso- most often due to dose-limiting thrombocytopenia or leu-
ciated with hemolytic anemia, the development of which kopenia.114 In the 15 patients that received IFN-based
may be predictive of a successful response to therapy.110 therapy, adverse events occurred in over 85%. Although
Anemia may occur more frequently in patients with renal the most frequent events involved cytopenias, some patients
insufficiency because ribavirin is renally metabolized and experienced further clinical decompensation and infectious
excreted. Other patients susceptible to hematological side complications; it is unclear whether decompensation or
effects include cirrhosis and liver transplant recipients. If infection is any more common in treated patients than in
neutropenia, thrombocytopenia, or hemolytic anemia are others with advanced cirrhosis.114 Alternative treatment
present, dose reductions of PEG-IFN, ribavirin, or both strategies have included maintenance therapy with low-
drugs may be required and initiation of growth factors may dose PEG-IFN or using a low accelerating dose regimen of
be considered in selected cases, although their use remains IFN and ribavirin. Maintenance therapy has not been
controversial.111 PIs may cause rash, gastrointestinal symp- shown to have any long-term benefit,115-117 whereas it
toms, and an increased rate of hematological side effects, remains uncertain whether a low accelerating dose regimen
particularly anemia and neutropenia. The anemia related may have superiority over standard treatment approaches.113
to ribavirin is worsened by the addition of a PI, but the Because antiviral therapy has become more complex, costly,
dose of the PI should never be reduced. Finally, the PIs are and labor intensive for the provider, it should generally be
both substrates and inhibitors of the cytochrome P-450 managed by an experienced hepatologist. In patients with a
3A4 enzyme pathway and, as such, have numerous and sig- history of clinical decompensation, treatment should be
nificant drug-drug interactions that can limit the ability to considered only in the setting of a liver transplant center.
treat some patients.

Treatment Strategies and End-Stage LIVER TRANSPLANTATION

Liver Disease Early and proactive management of chronic hepatitis C
Among those who are the most challenging treatment that is able to eradicate infection and reduce the risk for
candidates are individuals with cirrhosis. Despite the progression and complications of cirrhosis is essential and
emergence of more effective antiviral therapy, patients will have major implications for the future health care bur-
with cirrhosis remain a difficult population to treat, with den from this disease. Indeed, chronic hepatitis C and its
overall decreased efficacy compared to those without cir- complications remain the leading indication for liver trans-
rhosis. Rates of SVR in genotype 1 patients with advanced plantation in the United States and Western Europe.71,118
fibrosis (stage 3 to 4) have been reported at 62% with At least 40% of the 16,000 individuals listed for liver trans-
telaprevir, 41% with boceprevir, and 43% to 44% with plantation annually in the United States have HCV infec-
dual PEG-IFN and ribavirin.94,95,98,99 In patients with cir- tion, and this proportion may well increase as the
rhosis who previously failed PEG-IFN and ribavirin, the complications of this disease become more common in
reported SVR following telaprevir therapy is as high as coming decades.36,71,72 Recurrence of HCV is universal in
84% in prior relapsers; however, the potential for long- liver transplant recipients with hepatitis C viremia at the
term clearance is diminished in partial responders to 34% time of transplantation and is associated with reduced long-
and is only 14% in previous null responders.100 Although term survival.119,120 Recurrent hepatitis C and its manage-
treatment should be considered in all patients with ment are discussed in detail elsewhere in this text (see
chronic hepatitis C, these data highlight the importance Chapter 79).
128 PART II Patient Evaluation: Adult

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among persons born during 1945 through 1965: Reviewed and 72. U.S. Organ Procurement and Transplantation Network and the
updated May 18, 2012. Accessed on June 10, 2012 at http://www. Scientific Registry of Transplant Recipients:Data accessed April
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48. Rein DB, Smith BD, Wittenborn JS, et al. The cost-effectiveness 73. Maylin S, Martinot-Peignoux M, Moucari R, et al. Eradication of
of birth-cohort screening for hepatitis C antibody in U.S. primary hepatitis C virus in patients successfully treated for chronic hepa-
care settings. Ann Intern Med. 2012;156:263-270. titis C. Gastroenterology. 2008;135:821-829.
49. Di Bisceglie AM, Goodman ZD, Ishak KG, et al. Long-term 74. Poynard T, McHutchison J, Manns M, et al. Impact of pegylated
clinical and histopathological follow-up of chronic posttransfu- interferon alfa-2b and ribavirin on liver fibrosis in patients with
sion hepatitis. Hepatology. 1991;14:969-974. chronic hepatitis C. Gastroenterology. 2002;122:1303-1313.
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75. Everson GT, Balart L, Lee SS, et al. Histological benefits of viro- 98. Poordad F, McCone Jr J, Bacon BR, et al. Boceprevir for untreated
logical response to peginterferon alfa-2a monotherapy in patients chronic HCV genotype 1 infection. N Engl J Med. 2011;364:
with hepatitis C and advanced fibrosis or compensated cirrhosis. 1195-1206.
Aliment Pharmacol Ther. 2008;27:542-551. 99. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for
76. George SL, Bacon BR, Brunt EM, et al. Clinical, virologic, histo- previously untreated chronic hepatitis C virus infection. N Engl J
logic, and biochemical outcomes after successful HCV therapy: a Med. 2011;364:2405-2416.
5-year follow-up of 150 patients. Hepatology. 2009;49:729-738. 100. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of
77. Veldt BJ, Saracco G, Boyer N, et al. Long term clinical outcome HCV infection. N Engl J Med. 2011;364:2417-2428.
of chronic hepatitis C patients with sustained virological response 101. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously
to interferon monotherapy. Gut. 2004;53:1504-1508. treated chronic HCV genotype 1 infection. N Engl J Med.
78. Shiratori Y, Ito Y, Yokosuka O, et al. Antiviral therapy for cir- 2011;364:1207-1217.
rhotic hepatitis C: association with reduced hepatocellular carci- 102. Muir AJ, Bornstein JD, Killenberg PG. Peginterferon alfa-2b and
noma development and improved survival. Ann Intern Med. ribavirin for the treatment of chronic hepatitis C in blacks and
2005;142:105-114. non-Hispanic whites. N Engl J Med. 2004;350:2265-2271.
79. Di Marco V, Almasio PL, Ferraro D, et al. Peg-interferon alone or 103. Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B
combined with ribavirin in HCV cirrhosis with portal hyperten- predicts hepatitis C treatment-induced viral clearance. Nature.
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80. Bruno S, Zuin M, Crosignani A, et al. Predicting mortality risk in 104. Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide associa-
patients with compensated HCV-induced cirrhosis: a long-term tion of IL28B with response to pegylated interferon-alpha and
prospective study. Am J Gastroenterol. 2009;104:1147-1158. ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41:
81. Iacobellis A, Siciliano M, Perri F, et al. Peginterferon alfa-2b and 1105-1109.
ribavirin in patients with hepatitis C virus and decompensated cir- 105. Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated
rhosis: a controlled study. J Hepatol. 2007;46:206-212. with response to chronic hepatitis C interferon-alpha and ribavi-
82. Mallet V, Gilgenkrantz H, Serpaggi J, et al. Brief communication: rin therapy. Nat Genet. 2009;41:1100-1104.
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hepatitis C. Ann Intern Med. 2008;149:399-403. IL28B is associated with chronic hepatitis C and treatment fail-
83. Shiratori Y, Imazeki F, Moriyama M, et al. Histologic improvement ure: a genome-wide association study. Gastroenterology.
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C and advanced fibrosis. Am J Gastroenterol. 2006;101:2269-2274. virological responses in chronic hepatitis C patients treated with
85. Roberts S, Gordon A, McLean C, et al. Effect of sustained viral peginterferon alfa-2a (40 KD)/ribavirin. J Hepatol. 2005;43:
response on hepatic venous pressure gradient in hepatitis 425-433.
C-related cirrhosis. Clin Gastroenterol Hepatol. 2007;5:932-937. 109. Davis GL, Wong JB, McHutchison JG, et al. Early virologic
86. Bruno S, Crosignani A, Facciotto C, et al. Sustained virologic response to treatment with peginterferon alfa-2b plus ribavirin in
response prevents the development of esophageal varices in com- patients with chronic hepatitis C. Hepatology. 2003;38:645-652.
pensated, Child-Pugh class A hepatitis C virus-induced cirrhosis. A 110. Sulkowski MS, Shiffman ML, Afdhal NH, et al. Hepatitis C virus
12-year prospective follow-up study. Hepatology. 2010;51:2069-2076. treatment-related anemia is associated with higher sustained viro-
87. Singal AK, Singh A, Jaganmohan S, et al. Antiviral therapy logic response rate. Gastroenterology. 2010;139:1602-1611:1611.e1.
reduces risk of hepatocellular carcinoma in patients with hepatitis 111. Nelson DR, Davis GL, Jacobson I, et al. Hepatitis C virus: A criti-
C virus-related cirrhosis. Clin Gastroenterol Hepatol. 2010;8:192-199. cal appraisal of approaches to therapy. Clin Gastroenterol Hepatol.
88. Bruno S, Stroffolini T, Colombo M, et al. Sustained virological 2009;7:397-414.
response to interferon-alpha is associated with improved outcome 112. Hezode C, Dorival C, Zoulim F, et al. Safety of telaprevir or
in HCV-related cirrhosis: a retrospective study. Hepatology. boceprevir in combination with peginterferon alfa/ribavirin, in
2007;45:579-587. cirrhotic nonresponders. First results of the French early access
89. McHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginterferon program (ANRS CO20-CUPIC) [abstract]. J Hepatol. 2012;
alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infec- 56(Suppl 2):S4.
tion. N Engl J Med. 2009;361:580-593. 113. Everson GT, Trotter J, Forman L, et al. Treatment of advanced
90. Peters M, Davis GL, Dooley JS. The interferon system in acute hepatitis C with a low accelerating dosage regimen of antiviral
and chronic viral hepatitis. In: Popper H, Schaffner F, eds. Prog- therapy. Hepatology. 2005;42:255-262.
ress in Liver Diseases. vol. 8. New York: Grune and Stratton; 114. Crippin JS, McCashland T, Terrault N, et al. A pilot study of the
1986:453-467. tolerability and efficacy of antiviral therapy in hepatitis C virus-
91. Gale Jr M, Foy EM. Evasion of intracellular host defence by hep- infected patients awaiting liver transplantation. Liver Transpl.
atitis C virus. Nature. 2005;436:939-945. 2002;8:350-355.
92. Dienstag JL, McHutchison JG. American Gastroenterological 115. Di Bisceglie AM, Shiffman ML, Everson GT, et al. Prolonged
Association medical position statement on the management of therapy of advanced chronic hepatitis C with low-dose peginter-
hepatitis C. Gastroenterology. 2006;130:225-230. feron. N Engl J Med. 2008;359:2429-2441.
93. Ghany MG, Nelson DR, Strader DB, et al. An update on treat- 116. Afdhal NH, Levine R, Brown Jr R, et al. Colchicine versus peg-
ment of genotype 1 chronic hepatitis C virus infection: 2011 prac- interferon alfa 2b long term therapy: Results of the 4 year COPI-
tice guideline by the American Association for the Study of Liver LOT trial [abstract]. J Hepatol. 2008;48:S4.
Diseases. Hepatology. 2011;54:1433-1444. 117. Poynard T, Colombo M, Bruix J, et al. Peginterferon alfa-2b
94. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon and ribavirin: effective in patients with hepatitis C who failed
alfa-2b plus ribavirin compared with interferon alfa-2b plus riba- interferon alfa/ribavirin therapy. Gastroenterology. 2009;136:
virin for initial treatment of chronic hepatitis C: a randomised 1618-1628.
trial. Lancet. 2001;358:958-965. 118. Muhlberger N, Schwarzer R, Lettmeier B, et al. HCV-related
95. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a burden of disease in Europe: a systematic assessment of incidence,
plus ribavirin for chronic hepatitis C virus infection. N Engl J prevalence, morbidity, and mortality. BMC Public Health.
Med. 2002;347:975-982. 2009;9:34.
96. Hadziyannis SJ, Sette Jr H, Morgan TR, et al. Peginterferon- 119. Forman LM, Lewis JD, Berlin JA, et al. The association between
alpha2a and ribavirin combination therapy in chronic hepatitis C: hepatitis C infection and survival after orthotopic liver transplan-
a randomized study of treatment duration and ribavirin dose. Ann tation. Gastroenterology. 2002;122:889-896.
Intern Med. 2004;140:346-355. 120. Watt KD, Pedersen RA, Kremers WK, et al. Evolution of causes
97. Jacobson IM, Brown Jr RS, Freilich B, et al. Peginterferon alfa-2b and risk factors for mortality post-liver transplant: results of the
and weight-based or flat-dose ribavirin in chronic hepatitis C NIDDK long-term follow-up study. Am J Transplant. 2010;10:
patients: a randomized trial. Hepatology. 2007;46:971-981. 1420-1427.
 CHAPTER 11

Transplantation for Hepatitis C

Marina Berenguer • John R. Lake

CHAPTER OUTLINE

PRETRANSPLANT HEPATITIS C VIRUS INFECTION Surgical Variables

Natural History of Hepatitis C Virus Infection Biliary Complications
Indications for Liver Transplantation Histological Variables
POSTTRANSPLANT HEPATITIS C VIRUS Biochemical Variables
INFECTION External Factors
Source of Infection PATIENT MANAGEMENT
Definition of Viral Recurrence as Opposed to Pretransplant Antiviral Therapy
Histological Recurrence Preemptive Therapy in the Early
Natural History of Hepatitis C Virus Infection Posttransplant Period
After Liver Transplantation Treatment of Hepatitis C
Factors Influencing Disease Severity and Virus-Related Graft Disease
Progression or Survival
HEPATITIS C MONITORING
Host-Related Variables
Viral-Related Variables RETRANSPLANTATION
Donor-Related Variables CONCLUSION

Advances in medical management and surgical tech- (<3 months) graft survival is not affected by hepatitis C
niques have resulted in significant improvements in recurrence. However, in the medium and long term,
posttransplant survival rates for patients with trans- survival is decreased in comparison to other nonviral
plants from both deceased and living donors, with 74% indications.
and 79% of patients, and 60% and 74% of patients, Antiviral therapy is currently the only means to
respectively, alive 5 and 10 years following transplanta- improve outcomes. When applied pretransplantation,
tion (http://unos.org). Cirrhosis secondary to chronic it may prevent HCV reinfection in those who are viro-
hepatitis C virus (HCV) infection is the most common logical responders at time of transplantation. In the
disease indication for liver transplantation among adults posttransplant setting a sustained virological response
in most European and North American centers. In the (SVR) results in improved histological findings and
United States from 1999 through 2007 the number of survival. Pegylated interferon-α (PEG-IFN-α) with
recipients with HCV increased to a peak in 2006 of ribavirin (RBV) has traditionally been the treatment of
more than one third (37% to 41%) of all recipients.1 choice with SVR achieved in only about one third of
Recurrence of HCV infection in the allograft is univer- cases. Tolerability is poor; most patients develop
sal in these patients, leading to chronic liver disease in adverse effects, particularly anemia, and frequently
most cases. The natural history of recurrent disease is require the use of growth factors and/or dose reduc-
not uniform. Whereas some patients have an acceler- tions. Triple therapy (i.e., combining PEG-IFN and
ated course leading to early allograft failure, in others, RBV with new direct-acting antivirals) is being evalu-
significant fibrosis may take years to develop. Overall, ated; interactions between these protease inhibitors
hepatitis C is significantly more aggressive in liver trans- and calcineurin inhibitors are anticipated. Retrans-
plant recipients than in patients whose immunity is plantation is the last option for those who progress to
intact, with progression to cirrhosis reported in about allograft failure. Although the results of retransplanta-
one third of patients (8% to 44%) by year 5. The tion for recurrent hepatitis C are inferior to those of
enhanced disease progression is multifactorial in etiol- primary transplantation, reasonable survival rates have
ogy and depends upon the interaction between several been achieved if patients are selected based on survival
host, donor, viral, and external factors. Short-term models.

131
132 PART II Patient Evaluation: Adult

PRETRANSPLANT HEPATITIS C VIRUS The coexistence of HCC is an increasingly frequent

INFECTION complication of HCV-related cirrhosis.3 Initially the
results of transplantation for HCC patients were disap-
Natural History of Hepatitis C Virus pointing, with high recurrence rates and dismal patient
survival because of the advanced state of disease at the
Infection time of transplant. In 1996 Mazzaferro et al defined the
HCV infection is common in most developed countries; Milan criteria (single HCC up to 5 cm; or up to three
it affects 1.5% to 2% of the general population, with at tumors, none larger than 3 cm; and without evidence of
least 2.7 million carriers in the United States and an esti- macrovascular invasion or extrahepatic spread).3 With
mated 170 million carriers worldwide. The natural his- these selection criteria, survival rates do not differ from
tory of this infection has been extensively evaluated.2 The those achieved by HCV-infected patients without
condition is characterized by a high risk for chronic infec- HCC.3,14,15 (This topic will be covered in Chapter 15.)
tion after viral exposure with progression to chronic hep-
atitis: this develops in 65% to 85% of those exposed to
the virus. The progression of chronic hepatitis C is rela- POSTTRANSPLANT HEPATITIS C VIRUS
tively slow, and the risk for developing cirrhosis ranges INFECTION
from 4% to 25% in infected persons over 20 to 30 years
of follow-up. This risk is influenced by alcohol use, age at Source of Infection
infection, sex, immune status, metabolic syndrome, and
genetics.2 The prognosis of those who progress to HCV- The most common source of posttransplant HCV infec-
related cirrhosis depends primarily on the development tion is pretransplantation infection. Recurrent infection,
of two events, clinical decompensation (e.g., development defined as the reappearance of HCV RNA in serum, is
of ascites) and hepatocellular carcinoma (HCC). Although nearly universal. A rapid decrease in HCV RNA occurs
the 10-year patient survival rate reaches 80% in the immediately after removal of the infected liver, followed
absence of these events, it drops to less than 50% once by an even sharper decline after implantation of the
complications develop.2 The risk for decompensation allograft, presumably representing virus uptake by the
unrelated to HCC has been estimated to be approxi- new liver.16-18 Selective HCV entry into recipient hepa-
mately 15% to 20% after 4 years of follow-up.2,3 The tocytes, early replication, and decreased clearance due to
annual incidence of HCC in HCV-infected cirrhotic immunosuppression and major histocompatibility com-
patients is estimated to be between 1.5% and 3.3%.2,3 plex mismatching result in a “bottleneck” or decrease in
viral diversity or quasispecies early after transplantation.
This decline is followed by a progressive increase in
Indications for Liver Transplantation serum HCV RNA levels such that pretransplantation lev-
Liver transplantation should be considered when the els are reached as soon as day 4 and increase up to tenfold
course of the disease is sufficiently advanced that medium- to twentyfold higher 1 month after transplantation.16-19
term (2 to 5 years) survival is unlikely without transplant. The virus may also be acquired from contaminated
Because the prognosis of compensated HCV-related cir- blood or donor organs. However, de novo acquisition of
rhosis is good, cirrhosis per se should not be considered HCV infection has become extremely uncommon (<1%
an indication for liver transplantation. In fact, patients of HCV-negative recipients) as a result of routine and
with compensated cirrhosis can be successfully treated by efficient screening for HCV in blood and organ donors.18
antiviral therapy, with significant but manageable side In the current era of organ shortage and given the pro-
effects.4 SVR often leads to disease stabilization and may gressive increase in the number of HCV-infected patients
even reverse cirrhosis.5 The risk for hepatic decompensa- in need of transplantation, some have advocated the use
tion or HCC development diminishes significantly but of organs from anti-HCV–positive donors. In these cases,
does not disappear in the short term,6 and hence these viral transmission to the recipient depends primarily on
patients should continue to be monitored periodically, the donor’s HCV RNA status. HCV RNA–positive
including screening for HCC. An SVR can now be donors invariably transmit HCV to recipients, whereas
achieved with the use of triple therapy (PEG-IFN in com- organs from anti-HCV–positive, HCV RNA–negative
bination with RBV and a protease inhibitor—telaprevir donors transmit infection at a much lower rate.18
or boceprevir) in approximately 45% to 65% of patients
with compensated cirrhosis; unfortunately, lower response Definition of Viral Recurrence as Opposed
rates are achieved in those who were previously nonre- to Histological Recurrence
sponders to antiviral therapy (14% in previous cirrhotic
null responders).7-10 Antibody assays for HCV are of little value after trans-
Once decompensation occurs, liver transplantation is plantation. The diagnosis of HCV reinfection should be
the treatment of choice. This is the case for patients with established by testing for HCV RNA. Levels of viremia
cirrhosis who have attained a Child-Turcotte-Pugh score after transplantation are higher than pretransplant lev-
greater than 7, Model for End-Stage Liver Disease (MELD) els.16,17,19 Viral load, although not generally associated
greater than 14, or those who have a history of spontaneous with the severity of liver disease in the nontransplant set-
bacterial peritonitis, refractory ascites or encephalopathy, ting, may help to predict outcome in liver transplant
or recurrent variceal bleeding unresponsive to traditional recipients (e.g., the development of cholestatic hepatitis,
endoscopic or radiological treatment.11,12 progressive HCV disease)16,17,19-23 as well as to predict
 11 Transplantation for Hepatitis C 133

response and monitor therapy. In addition, viral titers months of onset. Cholestatic hepatitis is likely a conse-
generally peak at the time of acute hepatitis, a finding that quence of a direct cytopathic effect of HCV on hepato-
may help to differentiate acute recurrent HCV hepatitis cytes due to massive viral replication in the context of
from cellular rejection.16,17,19 Whether higher pretrans- a relatively inept cellular immune response against
plant viremia predicts a poorer outcome after transplan- HCV.17,19,31 Indeed, such cases generally occur within
tation is less clear.17,19,24 the first year after transplant in patients overtly overim-
The diagnosis of recurrent HCV disease, in contrast munosuppressed.31,32 The histological findings include
to reinfection, is based on histological findings. Standard cholestasis, marked lobular disarray with spotty acido-
liver tests lack specificity and sensitivity in this setting and philic hepatocyte necrosis and Kupffer cell hypertrophy,
may underestimate the presence of liver damage. In par- centrizonal hepatocyte ballooning and degeneration, and
ticular, there is generally a poor correlation between the portal expansion due to prominent ductular type and
severity of histological disease and serum transaminase fibrotic type of interface activity with mild mixed or even
levels.25-30 Histologically, acute hepatitis typically devel- neutrophil-predominant portal inflammation. In 2003
ops between the second and fourth month after trans- the following diagnostic criteria were proposed by a con-
plantation, whereas changes consistent with chronic sensus conference: (1) more than 1 month posttransplant
hepatitis are usually seen after the third posttransplant (usually ≤6 months), (2) clinical cholestasis marked by
month.29,30 The usual histopathological appearance and striking elevations in serum alkaline phosphatase level
evolution of hepatitis C in liver allografts are similar to and γ-glutamyltransferase activity (more than five times
those seen in the general population, except that in the upper limits of normal levels) and bilirubin levels (>6
allografts the acute phase shows less portal inflammation, mg/dL), (3) characteristic histological features, (4) high
whereas the chronic phase less often shows portal-based serum HCV RNA levels (generally higher than 30 to 50
lymphoid aggregates, and there is more ductular type of million International Units/mL), and (5) absence of bili-
interface activity.29,30 Early liver changes seen in the acute ary complications (normal cholangiogram) or hepatic
phase include mild lobular lymphocytic inflammation artery thrombosis.33,34 Unfortunately, a recent systematic
with scattered apoptotic bodies, minimal cell swelling, review reported that only 3 of 12 studies published after
and steatosis. This lesion progresses within 2 to 4 weeks 2003 used this definition, precluding accurate study of
to a more fully developed hepatitis, with portal and lobu- this entity.35
lar inflammation of varying degrees in association with The plasma cell variant of recurrent hepatitis C usu-
hepatocyte necrosis and midzonal macrovesicular steato- ally occurs in patients maintained on low-level immuno-
sis. The portal infiltrates are typically mononuclear cells suppression and/or who are treated with IFN-based
but may be more mixed than in the nontransplant setting. therapy.29,30,36,37 This entity is characterized by very low
Fatty change, bile duct injury, and patchy parenchymal or even negative HCV RNA levels together with histo-
lymphocytic infiltrates are also common. Fatty change pathological features that mimic those of autoimmune
alone may be an early marker of recurrence. Atypical his- hepatitis (centrilobular necrosis with or without bridg-
tological findings, including marked bile duct epithelial ing necrosis and a prominent plasma cell–rich infiltrate).
injury, endotheliitis, profound cholestasis, bile duct pro- It remains controversial whether these cases represent a
liferation, and perivenular ballooning of hepatocytes, can true “autoimmune” (alloimmune) process as opposed to
mimic other entities such as acute cellular rejection, an atypical manifestation of recurrent HCV disease,
obstruction, and ischemia.29,30 Exclusion of other causes acute or chronic allograft rejection, or a combination of
such as cytomegalovirus (CMV) hepatitis, obstruction, these entities. The differential diagnosis is, however,
ischemia, or drug toxicity may require serological, immu- extremely relevant with potential risks associated with a
nohistochemical, radiological, and endoscopic studies; misdiagnosis. For instance, treatment with steroids
drug discontinuation; or serial biopsy. Immunohisto- may reduce the severity of liver inflammation in cases
chemical and in situ methods to detect HCV antigens or of “autoimmunity/alloimmunity” at the expense of
HCV RNA, or both, in liver tissue have been evaluated as enhanced viral replication.
a means of differentiating recurrent hepatitis C from A major issue in clinical practice is distinguishing
other conditions and as a predictor of disease severity. In recurrent hepatitis from rejection with hepatitis,29,30 par-
general the results are conflicting, with relatively poor ticularly at time points beyond 2 months after transplan-
correlation with histological findings. tation. However, one could argue that this dilemma has
By 6 to 12 months after transplantation, chronic hepa- not been framed appropriately. The challenge should not
titis dominates with portal and periportal changes, includ- be to differentiate recurrence of hepatitis C from rejec-
ing chronic portal inflammation, occasional portal-based tion, but rather to determine whether alloimmunity is
lymphoid aggregates, and necroinflammatory and ductu- also playing a role in posttransplant hepatitis C and how
lar type of interface activity of varying severity.29,30 Focal it should best be treated. This issue is important because
inflammatory bile duct damage and “central perivenuli- although the occurrence of acute cellular rejection does
tis" can be seen, but they are neither severe nor wide- not have an important impact on long-term outcomes in
spread, and bile duct loss is not generally a feature. HCV-negative liver recipients, this is not the case in
Atypical presentations of recurrent hepatitis C include patients who undergo liver transplantation for HCV dis-
cholestatic hepatitis and plasma cell–rich hepatitis. Cho- ease. HCV-negative recipients who experience an epi-
lestatic hepatitis is a unique and rare form of presentation sode of rejection have only half the mortality rate of
(<10%) that portends a very poor prognosis.31 Graft fail- HCV-negative recipients who do not experience an epi-
ure occurs in more than half of patients within a few sode of rejection. By contrast, HCV-positive recipients
134 PART II Patient Evaluation: Adult

Viral factors:
Viral load
Genotype
Quasispecies
Donor factors:
Age, gender, steatosis, genetic background
CH
HCV 2-6% Surgical factors:
RNA ( – ) Warming ischemic time
2% Biliary complications (LDLT, DCD)

99% 25-45% 50-98% 8-44% 42%

LT HCV acute chronic graft cirrhosis decompensated
RNA + hepatitis hepatitis in 5-7 years 1 year

Host factors:
Minimal HLA, race, sex, age,
injury genetic background
30-50%

External factors:
Immunosuppression, alcohol,
Delayed viral coinfection (HBV, HIV, CMV),
injury?? antiviral therapy
FIGURE 11-1 n Natural history of recurrent hepatitis C. CH, Cholestatic hepatitis; CMV, cytomegalovirus; DCD, donation after cardiac
death; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HLA, human leukocyte antigen; LDLT, living
donor liver transplantation; LT, liver transplantation.

have a threefold increased risk for death if they are treated 30 years in immunocompetent patients).33,34,39,40 Fibrosis
with steroids for a single episode of rejection and more can progress linearly,39 present a delayed onset of rapid
than a fivefold increased risk for death if they experience progression,41 or progress as a rapid increase in fibrosis
steroid-refractory acute cellular rejection.38 For this rea- during the first 3 years followed by slower progression
son, many centers do not treat mild acute rejection, over the long term.42 Interestingly, a recent non-Markov
defined as Banff grade I rejection, in HCV-positive recip- analysis based on 901 fibrosis measurements in 401 patients
ients, particularly when it occurs more than 2 months has shown that there is a decreasing risk for progression
after transplantation. Key features suggestive of acute and over time as duration in a specific fibrosis stage increases.
chronic rejection in HCV-positive patients include (1) a However, a longer interval to reach that stage does not
mixed inflammatory infiltrate, significant bile duct injury, appear to predict a lower risk for further progression to a
and/or biliary epithelial senescent changes and (2) termi- higher stage.43
nal hepatic vein inflammation. Features more consistent Based on published studies, by the fifth postoperative
with hepatitis C include the presence of lobular necroin- year, up to 30% of HCV recipients will progress to
flammatory activity and necroinflammatory ductular type cirrhosis.* Once cirrhosis is established, the risk for clini-
of interface activity, features that are usually minimal or cal decompensation is higher (42% versus 5% to 10% in
absent in acute and chronic rejection. 1 year among nontransplanted patients with compensated
HCV cirrhosis).46,47 Factors that predict decompensation
Natural History of Hepatitis C Virus include a Child-Turcotte-Pugh class B or C, a MELD
score above 16, a serum albumin level of less than 3.4
Infection After Liver Transplantation g/dL, and a period from transplantation to a diagnosis of
The natural history of recurrent HCV disease after liver cirrhosis of less than 1 year.46,47 Survival after decompen-
transplantation (Fig. 11-1) is highly heterogeneous.33,34,39-42 sation is less than 10% at 3 years, compared to 60% in
Besides different patterns of presentation, progression of nontransplanted patients.
fibrosis in those with a typical presentation is not uniform. Recent data have shown that the risk for severe HCV
In some patients, no or mild fibrosis progression is evident, disease after transplantation has increased, at least in
even after several years of follow-up. In contrast, others some centers.48-51 These trends have been attributed to a
progress rapidly to cirrhosis and allograft failure within change in both immunosuppression protocols and donor
months. In general the disease progresses more rapidly quality.52-55 In fact, immunosuppression and donor age
compared to the nonimmunosuppressed population, with differences by center probably explain divergent out-
a higher rate of yearly fibrosis progression (0.3 fibrosis comes in published series.†
units/yr [0.004 to 2.19] versus 0.2 fibrosis units/yr [0.09 to
0.8], P < .0001). As a consequence there is a shorter interval *References 27, 28, 33, 34, 40, 44, 45.
to the establishment of cirrhosis (9 to 12 years versus 20 to †References 27, 28, 33, 34, 40, 44, 45, 52-56.
 11 Transplantation for Hepatitis C 135

TABLE 11-1 F
 actors Influencing Disease TABLE 11-2 Immunosuppression: Effects on
Severity/Progression or Survival Viral Load and Disease Severity/
Progression
Factors Association Type of Association
Donor age Established Survival, NH Effect on Viral Effect on Disease
Load Progression
Living donor Established Learning curve
DCD donor Controversial, DCD worse Bolus Increase Detrimental
insufficient data corticosteroids
HLA-DR Controversial Steroids at Unknown None (taper
matching initiation/ slowly?)
maintenance
Donor genetic Unknown, Role of IL28B?
factors insufficient data Cyclosporine Unknown Controversial
Recipient sex Established Female: worse Tacrolimus Unknown Controversial
survival OKT3/Campath Unknown Detrimental
Recipient age Established Survival Anti–IL-2 receptor Unknown Controversial
Nonwhite Insufficient data Survival, NH antibody
Severity of Established Survival MMF Controversial None or detrimental
illness Azathioprine Unknown None or beneficial
Genotype Controversial 1b: worse mTOR inhibitors Unknown Controversial
Pre–liver Established Survival, NH
transplant IL-2, Interleukin-2; MMF, mycophenolate mofetil; mTOR, mamma-
viral load lian target of rapamycin.
Early post– Established Survival, NH
liver
transplant
viral load In the immunocompetent population the most powerful
Antiviral Established Survival, NH predictors of disease severity are those related to the host,
therapy
including age at the time of infection, sex, the existence of
DCD, Donation after cardiac death; NH, natural history. any type of immunodeficiency, and alcohol use, whereas
virus-related factors (e.g., genotype and HCV RNA) do
not appear to play a major role in determining outcome.2
The final consequence of recurrent hepatitis C is graft In the liver transplant setting the interactions are more
loss. Graft failure secondary to recurrent hepatitis C is complex, and the strongest determinants of outcome
now the most frequent cause of death, graft failure, and relate to the donor organ quality as well as the degree of
need for retransplantation in HCV-positive recipi- immunosuppression (Table 11-2).
ents.45,48,50,57 As a result, survival is significantly impaired
when compared to other indications; an overall 10% dif- Host-Related Variables
ference at 10 years has been described in large series.57 In
the most recent Organ Procurement and Transplanta- Immune Status. Several indirect findings highlight the
tion Network (OPTN)/United Network for Organ Shar- negative effect of the immunosuppressed state on recur-
ing (UNOS) report from the United States, the 3-year rent disease progression: (1) accelerated fibrosis pro-
survival was 78% among 7459 anti-HCV–positive recipi- gression in liver transplant recipients in comparison to
ents compared to 82% in 20,734 anti-HCV–negative immunocompetent patients39; (2) recent worsening of
patients (P < .0001) (http://www.unos.org). In addition, posttransplant outcome at a time when more potent
the more aggressive histological disease seen in recent immunosuppressive agents are being used for both
years is beginning to translate into a further reduction in induction and maintenance of immunosuppression†; (3)
graft survival.45,48 more aggressive course in those coinfected with the
human immunodeficiency virus (HIV) both before and
Factors Influencing Disease Severity and after transplantation59,60; and (4) worse histological and
clinical outcomes in the presence of CMV infection, a
Progression or Survival virus with immunosuppressive properties.61,62
Factors that have shown an association with disease sever-
ity/progression or survival (or both) include those related Treatment of Rejection and Hepatitis C. The use of
to the host (demographics, genetic background, immune corticosteroid boluses to treat acute cellular rejection is
status, comorbidity, hepatic function at transplantation), harmful to HCV-infected recipients‡ because it increases
the virus (genotype, HCV RNA levels, viral quasispe- serum HCV RNA concentrations 4- to 100-fold. Corti-
cies), the environment (immunosuppression, alcohol, costeroid boluses are associated with an increased fre-
viral coinfection), the donor (age, degree of hepatic ste- quency of acute hepatitis, earlier time to recurrence,
atosis, liver volume, living versus deceased, donation after increased histological severity of recurrent hepatitis,
cardiac death [DCD], genetic background), and the sur- increased graft loss, and increased mortality.
gery (ischemia time, biliary complications)* (Table 11-1).
†References45, 48, 51, 55, 58.
*References 33, 34, 40, 53, 55, 58. ‡References 25, 26, 32-34, 38-40, 42-45, 52, 53, 58.
136 PART II Patient Evaluation: Adult

Similarly, the use of lymphocyte-depleting antibodies follow-up, unadjusted graft and patient survival did not
to treat rejection is associated with a greater risk for differ between groups. However, propensity score–
aggressive recurrent disease and graft loss.32-34,40,53,58 adjusted results, which adjust for differences in recipient,
donor, and transplant characteristics and concomitant
Induction and Maintenance Immunosuppression. immunosuppression at the time of discharge, showed that
Although the impact of additional immunosuppression CSA-treated patients were at an increased risk for death,
for the treatment of rejection on hepatitis C is clear, primary graft failure, and acute rejection.
results are less conclusive regarding immunosuppressive Corticosteroids. It has long been believed that the use
agents used for induction or maintenance therapy. of corticosteroids is harmful to HCV-positive recipients.
Calcineurin Inhibitors. In vitro studies (replicon and However, the clinical evidence supporting this view is
cultured hepatocytes) have shown that cyclosporine complicated. To avoid the negative effects of steroids,
(CSA) inhibits HCV replication, an effect not seen with two different strategies have been studied: (1) use of cor-
tacrolimus (Tac).63 Whether these in vitro results trans- ticosteroid-free immunosuppressive regimens70,71 and (2)
late into differences in clinical practice is still a matter of early corticosteroid withdrawal.* Regarding early with-
debate. Most single-center, retrospective studies have drawal, several retrospective studies† did not show any
shown no differences in outcome between these two benefit, and several even suggested a negative effect of
regimens.* There are few prospective studies that have corticosteroids on hepatitis C disease progression. A sin-
examined this effect in vivo. In a study by Martin et al64 gle prospective study,73 with unfortunately a very small
79 patients were randomly assigned to CSA- or Tac- number of patients, confirmed the results of retrospective
based immunosuppression. An increase in viral load was studies. However, what constitutes “early withdrawal”
observed, which was significantly higher in patients has not been firmly established. Most studies have defined
receiving CSA when compared with those receiving Tac. early withdrawal as within 3 to 6 months of transplanta-
It is unclear whether this effect was due to the former tion. They define late withdrawal as corticosteroid dis-
patients receiving higher cumulative steroid doses. In a continuation more than 1 year after transplantation.
systematic review,65 in which a total of 366 patients were Regarding steroid-free immunosuppression protocols
included, no significant differences in mortality and graft and protocols using a rapid discontinuation of steroids
loss between CSA- and Tac-treated patients were (<7 days), studies using a variety of immunosuppression
reported. In two of the five studies no differences were protocols, as well as systematic reviews, generally show
found in the rate of cholestatic hepatitis. More recently no differences in viremia, survival, or fibrosis progression.‡
two prospective randomized studies have found discrep- Mycophenolate Mofetil. The effect of mycophenolate
ant results. In a study by Levy et al66 495 patients, 173 of mofetil (MMF) on viral replication or disease progres-
whom were HCV positive, were randomized to CSA (n = sion is also unclear. An analysis of HCV-positive recipi-
88) or Tac (n = 85) plus steroids and azathioprine. Mor- ents in the United States suggested that the use of MMF
tality and graft loss were less common in the group at discharge was associated with improved patient and
receiving CSA. However, when evaluating only HCV- graft survival. However, two large randomized trials
positive patients, mortality due to HCV and the percent- compared MMF with azathioprine in a maintenance
age of patients with mild fibrosis and viremia at 12 months immunosuppressive regimen, and neither of these stud-
were similar in both groups. The only difference between ies showed significant differences in either rates of hepa-
the groups was the time to recurrence of hepatitis, which titis C recurrence or patient or graft survival.* Finally,
was shorter in the Tac group. A similarly designed study in a recent study, which enrolled the largest number of
reported by O'Grady et al67 showed opposite results. patients to date, patients were randomized into three
After a follow-up of 3 years, the combined end point treatment arms, two with and one without MMF (Tac,
(death, retransplantation, and immunological failure) steroids [n = 80]; Tac, MMF, steroids [n = 79]; dacli-
occurred more frequently in the CSA group than the Tac zumab, Tac, MMF [n = 153]). In this study no differ-
group (34.5% versus 24%). An analysis based on HCV- ences in progression to advanced fibrosis or patient or
positive patients alone (CSA, n = 58, versus Tac, n = 46) graft survival were found.75,76
again revealed no treatment-specific differences in mor- Azathioprine. Little data exist regarding the effect of
tality or need for retransplantation. In the most recent azathioprine on HCV disease progression. In a recent
prospective randomized study, no differences in survival study,78 in which patients were randomized to Tac mono-
at 1 and 7 years, nor in any of the other end points ana- therapy (54 patients) or to triple therapy (49 patients)
lyzed (rate of acute hepatitis, cholestatic hepatitis, and using Tac, azathioprine, and prednisone, the probability
severe HCV recurrence) were found between the 136 of reaching advanced fibrosis or developing portal hyper-
patients allocated to CSA and the 117 on Tac.68 Finally, tension was lower in the triple therapy, in which azathio-
the largest study to date comparing calcineurin inhibitors prine was continued for over a year and steroids for 3 to 6
in HCV recipients is that by Irish et al69 based on the months. In this study the authors were unable to establish
retrospective analysis of the Scientific Registry of Trans- if the benefit was due to the slow withdrawal of steroids
plant Recipients (SRTR). The investigators analyzed data or a protective role of azathioprine. In a meta-analysis of
from 8809 anti-HCV–positive patients who underwent
liver transplantation and received either CSA (n = 717) or
*References 33, 34, 40, 52, 53, 58, 72, 73.
Tac (n = 8092) before discharge. At 1 and 3 years of †References 33, 34, 40, 45, 52, 53, 58, 72.
‡References 33, 34, 40, 52, 53, 58, 70, 71, 74-76.

*References 33, 34, 40, 45, 53, 58. *References 33, 34, 45, 58, 77.
 11 Transplantation for Hepatitis C 137

the use of MMF or azathioprine, it is interesting to note Race has also been found to influence outcome in
that almost all studies assessing the effect of MMF versus patients with recurrent HCV infection, with nonwhites
azathioprine showed better outcomes in azathioprine- doing worse than whites. More intriguing is a variable
containing regimen groups.79 impact based on the type of matching of donor-recipient
Antibody Induction. Data regarding antibody induc- race.33,34,40,85
tion vary based on whether the antibody used is T-cell Although a clear association between IL28B polymor-
depleting or not. Several studies using potent T-cell phisms and response to antiviral therapy exists,21,86-92 the
depletion have suggested a negative impact on outcomes. data linking this genetic background to disease recurrence
However, three randomized trials using non–T-cell are only now evolving. One study linked the expression of
depleting antibodies have shown no impact of antibody the favorable polymorphism to a delay in the biochemical
induction on recurrent HCV. In addition, in the three- recurrence of hepatitis C.86 A second study showed less
arms study mentioned earlier, the outcome was similar in allograft inflammation at later stages in recipients with this
the group in which induction was used (daclizumab, Tac, favorable IL28B polymorphism.89 In most studies, though,
MMF; n = 153) compared to the other two groups with- no association with allograft fibrosis has been observed.
out induction.75,76,80,81
Mammalian Target of Rapamycin Inhibitors. The Viral-Related Variables
impact of mammalian target of rapamycin (mTOR)
inhibitors on outcomes in HCV-positive recipients is Hepatitis C Virus Genotype. A few early studies
evolving. Because of their antiproliferative properties, it implicated genotype 1, and in particular subtype 1b,
has been proposed that these agents may decrease fibrosis with more aggressive posttransplant disease than seen
progression. Recent retrospective studies have suggested with non–genotype 1 viruses.33,34,40 Strains with differ-
a beneficial effect of mTOR inhibitors82,83 on fibrosis ing virulence but within the genotype 1b subset may be
progression in those maintained on mTOR inhibitors implicated.33,34,40 However, most studies have not dem-
compared to those treated with calcineurin inhibitors onstrated a clear impact of genotype on posttransplant
alone. For instance, in one of these nonrandomized stud- outcomes.
ies, by an intent-to-treat analysis, the sirolimus HCV
cohort (n = 172) had significantly reduced advanced Hepatitis C Virus RNA Levels. Some studies have
fibrosis (stage ≥2) compared to the HCV control group described an association between high levels of viremia
(n = 282) at year 1 (15.3% versus 36.2%, P < .0001) and before or early after transplantation19-24,93 and the develop-
year 2 (30.1% versus 50.5%, P = .001), and a multivariate ment of severe disease recurrence and reduced survival. In
analysis demonstrated sirolimus as an independent pre- the National Institute of Diabetes and Digestive and Kidney
dictor of minimal fibrosis at 1 and 2 years.83 Currently Diseases Liver Transplantation Database, the relative risk
there are no randomized studies that have adequately and for graft loss was 3.6-fold higher in patients with a pretrans-
prospectively evaluated the effect of these drugs in HCV- plant viral load greater than 1 million viral Eq/mL than in
positive recipients. those with a lower viral load, with 5-year cumulative patient
Given these confusing and occasionally conflicting survival rates of 57% and 84%, respectively (P < .001).24,93
results regarding the impact of immunosuppression on In a recent retrospective analysis of 118 HCV recipi-
the outcome of patients who undergo liver transplanta- ents,23 a peak viral load of 107 International Units/mL or
tion for HCV disease, how can one generate a unifying higher was found to be an independent predictor of
hypothesis that will help guide our use of immunosup- diminished patient and graft survival and HCV-allograft
pressive agents in this difficult population? The “classic” failure. A peak viral load in the first year after transplant
paradigm is that greater immunosuppression leads to of more than 108, 107 to 108, and less than 107 Interna-
more severe posttransplant hepatitis C. One could argue tional Units /mL was associated with a mean survival of
that it may not be simply the degree of immunosuppres- 11.8, 70.6, and 89.1 months, respectively (P ≤ 0.03).
sion that has an impact on long-term outcomes in patients High levels of viremia and intrahepatic HCV RNA
transplanted for hepatitis C but, rather, dramatic changes have been described in the setting of cholestatic hepatitis
in immunosuppression may be the factor that has a nega- and during the acute phase of recurrent hepatitis C.* This
tive impact on outcomes in patients transplanted for hep- finding suggests that during the early phase of recurrent
atitis C.* This could explain why the use of corticosteroid hepatitis C, liver damage may be due to a direct cyto-
boluses and lymphocyte-depleting antibodies for the pathic effect of HCV.17,19,32
treatment of rejection are particularly harmful to HCV-
infected patients, whereas either steroid avoidance or Hepatitis C Virus Heterogeneity. HCV heterogeneity
maintenance of low levels of corticosteroids, but not late may also play a role in the pathogenesis of progressive
steroid withdrawal, may be beneficial. HCV disease.† A high viral load before transplantation
may influence the distribution of HCV quasispecies and
Immunogenetic Background. Some, but not all, authors yield a greater chance for new and “more fit” variants to
have suggested that donor-recipient matching at the expand and dominate the viral population once cellular
human leukocyte antigen (HLA)-B locus reduces the inci- immunity is impaired by immunosuppression.‡
dence of acute cellular rejection but also promotes the
recurrence of viral hepatitis.33,34,40 *References 17, 19, 32, 33, 40.
†References 17, 19, 32, 33, 40.

*References 33, 34, 40, 45, 58, 84. ‡References 17, 19, 32, 33, 40.
138 PART II Patient Evaluation: Adult

Donor Steatosis. Hepatic steatosis is present in 15% to

TABLE 11-3 S
 uboptimal Donors in Liver
25% of potential organ donors, particularly in older liv-
Transplantation of Hepatitis C
ers. Hepatic steatosis is known to lead to faster disease
Virus–Positive Patients
progression in immunocompetent patients with chronic
Older donor age (>60 yr) hepatitis C. It is possible that the same occurs in the liver
Prolonged cold ischemia time (>12 hr) transplant setting, but the data are not entirely convinc-
Prolonged rewarming time (>90 min) ing. The use of different systems to grade the degree of
Severe steatosis steatosis together with the low prevalence of severe ste-
Donation after cardiac death atosis may explain these discrepancies. In one study,97
Living donor liver transplantation (early experience, steatosis greater than 30%, together with donor age older
learning curve) than 55 and cold ischemia times greater than 12 hours,
Older anti-HCV–positive donor (>50 yr) was significantly associated with reduced survival and
Older living donor liver donor (>45 yr) increased fibrosis.
HCV, Hepatitis C virus. Anti-Hepatitis C Virus–Positive Donors. Superinfec-
tion has been described with the use of HCV-positive
donor organs, with ultimate predominance of genotype 1
viruses in all recipient-donor pairs in which superinfec-
Donor-Related Variables (Table 11-3)
tion occurred.33,34,40 It appears, however, that both histo-
Donor Age. Donor age has been consistently shown to logical outcome and survival rates in HCV-positive
have a strong impact on disease recurrence, graft and recipients are not affected by receiving an organ from an
patient survival, and response to antiviral therapy. anti-HCV–positive donor.*
Increasing age of the donor is independently associated Given the fact that recipients infected with HCV gen-
with greater disease severity and more rapid disease pro- otypes 2 or 3 have to date had higher rates of SVR when
gression, as well as poorer graft and patient survival treated with antiviral therapy than those infected with
rates,* both when using deceased and live donors and also genotype 1, organs from anti-HCV–positive donors,
when using anti-HCV–positive donors. In an early series potentially coming from genotype 1–infected patients,
only 14% of the recipients who received an organ from a should not be used in these patients. In addition, use of
donor younger than 30 years developed cirrhosis. By con- HCV-positive grafts from older donors (age > 45 to 50
trast, 45% and 52% of those receiving an organ from years) were shown in two studies to lead to higher rates of
donors ages 31 to 59 or older than 59, respectively death and graft failure, as well as more advanced fibrosis
(P < .0001), progressed to cirrhosis.48 In an SRTR analy- than the use of HCV-negative grafts of the same age.96,99
sis including 3463 patients with hepatitis C, donor age Thus grafts from anti-HCV–positive donors older than
between 41 and 50 years was associated with a 67% 50 years of age should be used with caution.
increase in the risk for graft loss; the risk increased to
86% when donors were between 51 and 60 years of age Surgical Variables
and was more than twofold when donors were older than
60 years.94 The recent increased mean age of deceased Ischemia Time. Both cold ischemia time and prolonged
donors may in fact explain the worse outcomes described rewarming during allograft implantation have been asso-
in recent years.51 ciated with more severe recurrent disease and reduced
The mechanism by which older age is associated with graft and patient survival.† The mechanisms for these
worse outcomes in HCV-recipients is probably multifac- associations are probably multifactorial. Prolonged isch-
torial. It is known that older donor livers have a lower emia time is an independent risk factor for early allograft
tolerance for cold preservation. In addition, age-related dysfunction and biliary complications, particularly when
immune changes in liver response, liver steatosis, iron using allografts from donors older than 60 years. In these
content, preexistent fibrosis, and telomeres or replicative cases, optimal function is achieved when cold ischemia
senescence may be some of the key factors that determine times are kept to under 8 hours.97 Minimizing warm isch-
an increased susceptibility of the older liver to HCV- emia times, for instance, by using surgical techniques
related fibrosis. Interestingly, some of these features, associated with a decreased period of graft rewarming,
including moderate to severe steatosis and high iron con- such as vena cava preservation, and minimizing cold isch-
centration, have been found in some studies to be associ- emia times have become standard of practice in many
ated independently with aggressive HCV recurrence. centers in an effort to improve outcomes.
Therefore if older donor organs are used in HCV recipi-
ents, additional factors known to increase the risk for Living Donor Liver Transplantation. The potential
graft damage should be avoided. As such, ischemia times advantages of living donor liver transplantation (LDLT)
should be minimized, and those with concomitant mod- include the possibility of using antiviral therapy pretrans-
erate to severe steatosis should preferentially be targeted plantation, shorter cold ischemic time, and a younger donor
to HCV-negative recipients, in whom the expected sur- age. The potential disadvantages are HLA homology
vival may not be as compromised.94 between related donors and recipients, HCV replication in

*References 33, 34, 40, 45, 96, 98.

*References 33, 34, 39, 40, 45, 48-55, 94-96. †References 33, 34, 40, 45, 97.
 11 Transplantation for Hepatitis C 139

proliferating hepatocytes, a greater “relative immunosup- HCV recipients had significantly inferior graft survival
pression,” and in particular, more technical problems. Early compared to HCV-negative recipients ( P < .0001). How-
results from several centers suggesting worse outcomes of ever, DCD livers used in HCV-positive recipients yielded
LDLT in HCV-positive recipients may have reflected a no difference in graft survival compared to HCV-­negative
learning curve.33,34,40 More recent studies55 suggest no recipients ( P = .5170). Interestingly, graft survival in
effect on either inflammation or fibrosis after 3 to 5 years of recent years (2006-2009) was significantly better than
follow-up. that in earlier years (2002-2005) ( P = .0482).
Thus the use of DCD liver transplants for HCV-
Donation After Cardiac Death. DCD transplants are positive recipients yields satisfactory outcomes, par-
increasing largely because of a shortage of livers for trans- ticularly in centers with greater experience, and
plant. The use of liver grafts from DCD donors in HCV- provided some constraints are applied, such as not
positive patients has been addressed in a limited number exceeding 30 minutes of warm ischemic time in addi-
of studies with discrepant results. In one study the out- tion to limiting cold ischemia time to less than 8 hours
come of 37 HCV patients undergoing DCD transplants in young donors (<50 years).
was compared to that of 74 matched control HCV
patients who received donation after brain death (DBD) Biliary Complications
transplants. DCD recipients had a higher incidence of
primary nonfunction (19% versus 3%, P = .006) and sig- There is controversy about the possible influence of bili-
nificantly higher peak aspartate aminotransferase (AST) ary complications in the progression of recurrent hepati-
levels in comparison with DBD recipients, suggesting tis C. A higher rate of biliary complications may in fact be
greater ischemia-reperfusion injury. The survival rates responsible for the worse results obtained with LDLT in
were not significantly different. DCD and DBD recipi- centers with low volume or low experience. An active
ents had 1- and 5-year patient survival rates of 83% and approach to detecting and treating biliary complications
69% versus 84% and 78%, respectively (P = .75) and graft as early as possible should be pursued to minimize any
survival rates of 70% and 61% versus 82% and 74%, possible detrimental effect.
respectively (P = .24). Fibrosis progression was similar for
the two groups as were the rates of severe HCV recur- Histological Variables
rence (retransplantation or death due to recurrent hepa-
titis C and/or the development of stage 4/6 fibrosis within The histological findings observed in early liver biopsy
2 years: 8% versus 15% in DBD patients, P = .38).100 In a samples have been shown in some studies to be reliable
second retrospective study the outcomes of 77 HCV- predictors of subsequent outcome.29,30 For instance, in
positive patients who received DCD liver grafts were two studies the degree of necroinflammatory activity
compared to 77 matched HCV-positive patients who observed in the first-year liver transplant biopsy speci-
received DBD liver grafts and 77 unmatched HCV-­ men was associated with the risk for development of
negative patients who received DCD liver grafts. There ­cirrhosis. Only 3% to 10% of those with mild hepatitis
were no differences in 1-, 3-, and 5-year patient or graft contracted cirrhosis, whereas this percentage increased
survival among the groups. A comparison of the HCV- to 30% to 60% in those who showed moderate to severe
positive groups with regard to fibrosis progression based activity in the first year.24,25 Additional specific histo-
on protocol biopsy samples up to 5 years after transplan- logical features such as steatosis, ballooning degenera-
tation did not show any differences.101 By contrast, in a tion, cholestasis, and confluent necrosis may also be
third study an increased risk for severe recurrence was helpful in predicting progression to severe hepatitis or
reported in recipients of DCD allografts.102 In that study cirrhosis.*
17 recipients with HCV who received a DCD transplant Similarly, the finding of fibrosis and its severity in the
were compared with HCV-negative recipients of a DCD first-year biopsy specimen has been shown to be associ-
graft (n = 15) and with a matched group of HCV-positive ated with (1) the development of cirrhosis such that in the
recipients transplanted with a DBD graft (n = 42). Graft absence of fibrosis, progression occurs in only 9% to
survival rates were not significantly different in HCV- 11%, whereas this percentage rises to 21% to 27% in
positive patients who underwent a DCD transplant com- those with a fibrosis stage greater than or equal to 1; (2)
pared with HCV-negative patients who underwent a patient mortality (risk multiplied by 10 in the case of
DCD transplant (P = .14). However, a significant differ- fibrosis stage greater than or equal to 2; and (3) graft loss.*
ence in graft survival was seen in HCV-positive patients
who received a DCD transplant as compared to those Biochemical Variables
who received a DBD transplant (73% versus 93%,
P = .01). In addition, there was a significant increase in The peak serum AST and bilirubin levels, as well as the
HCV recurrence at 3 months (76% versus16%, P = .005) presence of biochemical cholestasis at the time of recur-
and severe HCV recurrence within the first year (47% rence of hepatitis, are associated with a higher rate of
versus 10%, P = .004) in the DCD group. Finally, Uemura progression to graft cirrhosis.†
et al103 recently analyzed the UNOS/OPTN database to
assess the effect of DCD in HCV recipients. Primary
adult DCD liver transplants (630 HCV, 1164 non-HCV) *References 24, 25, 33, 34, 40, 45.
and 54,129 DBD transplants performed between 2002 *References 24, 25, 33, 34, 40, 45, 104.
and 2009 were studied. Following DBD transplants, †References 24, 25, 33, 34, 40, 45.
140 PART II Patient Evaluation: Adult

External Factors TABLE 11-4 F

 eatures Associated With a
“Marginal Recipient”
HBV Coinfection. Patients coinfected with hepatitis
B virus (HBV) appear to have milder disease and better Marginal donor
survival than those infected with HCV alone.‡ Although Donor older than 40-50 yr
interactions between both viruses may explain this IL28B genotype TT
improved outcome, a second explanation may be the ben- “Marginal” surgery (prolonged ischemic time)
efits of passive transmission of antibodies against HCV in Preservation injury
coinfected patients receiving hepatitis B immune globu- Overimmunosuppression (HIV coinfection, retransplanta-
lin in the era before specific HCV screening of blood tion, treated rejection, CMV infection, diabetes, older)
products.105 Others
Posttransplantation diabetes, metabolic syndrome, insulin
Alcohol Intake. A substantial proportion of HCV-­ resistance
positive recipients have end-stage liver disease caused by Biliary complications (early experience)
both alcohol and chronic HCV. The histological findings “Too sick” (malnourished, renal insufficiency, high MELD)
are typically indistinguishable from those found in Contraindications to antiviral therapy
patients with HCV alone. However, the liver disease is
CMV, Cytomegalovirus; HIV, human immunodeficiency virus;
clearly more severe and accelerated in patients with con- MELD, Model for End-Stage Liver Disease.
comitant alcohol abuse and chronic HCV infection than
in those with HCV who have never abused alcohol. The
same may hold true after liver transplantation, but data recipients; using anti-HCV–positive donors only under
on this issue are surprisingly limited, and of course most specific conditions (i.e., donor age not exceeding 50 years,
recipients are counseled against posttransplant alcohol normal liver biochemistry, normal ultrasound and visual
use.33,34,40,45,106 inspection of the liver, and only into genotype 1 recipient);
effective management or prevention of metabolic syn-
Metabolic Syndrome, Diabetes, Insulin Resistance. drome; and the individualization of immunosuppression,
Metabolic syndrome occurs in 50% of HCV-infected avoiding overimmunosuppression, particularly, corticoste-
recipients within the first 12 months after transplantation roid boluses. In this regard a prospective interventional
and is associated with a greater rate of fibrosis progres- study confirmed the potential benefits of reducing overall
sion.107 In one study, posttransplant diabetes multiplied immunosuppression and avoiding abrupt variations in
the risk for developing bridging fibrosis/cirrhosis in immunosuppression. In that study the rate of severe HCV
HCV-infected recipients at 6 years more than threefold, disease was reduced from 54% to 33% when overimmuno-
with an additive effect if the donor was older than 55 suppression (steroid boluses and triple-quadruple thera-
years (risk multiplied by 8.4).108 In another study, pies at full doses) was avoided.110
increased insulin resistance (homeostasis model assess-
ment [HOMA] > 2.5) measured 4 months after transplan-
tation was associated with greater fibrosis progression, PATIENT MANAGEMENT
with an incidence of advanced fibrosis/cirrhosis at 5 years
of 43% in comparison to 21% in those without increased Although preventing HCV reinfection should be the
insulin resistance.109 major goal, there is currently no available intervention
From a practical point of view it is more the combina- to effectively prevent reinfection. A retrospective review
tion of several of these factors than the presence of one in of the use of hepatitis B immune globulin, obtained in
particular that dictates the progression and outcome of the era before routine HCV screening of blood and
recurrent hepatitis C (Table 11-4). Indeed, the use of plasma donors, in patients coinfected with HCV and
grafts from older donors together with a prolonged isch- HBV suggested that passive immunoprophylaxis might
emia time will likely result in a severe preservation injury, be effective in reducing recurrent infection.105 Unfortu-
which in turn will probably lead to a difficult early post- nately, subsequent studies showed a hepatitis C immune
transplant course, frequent changes in the immunosup- globulin preparation had no demonstrable effect on
pression, and in the medium to long term more severe HCV reinfection.111
recurrent HCV disease. One important aspect to con- Antiviral therapy with clearance of HCV is the only
sider is that early posttransplant events are likely the strategy that has shown unequivocally to improve prog-
most significant determinants of the severity of liver nosis, both histologically and clinically. Sustained viral
injury.19 One potential way to overcome the negative eradication is associated with a decreased risk for fibrosis
effect of HCV is to avoid other negative factors. Based on progression, hepatic decompensation, and graft loss, as
the associations just mentioned, strategies that may well as a decrease in portal pressure, ultimately resulting
improve posttransplant outcomes include the minimiza- in enhanced survival.112-118 This beneficial effect is more
tion of cold ischemia times over 8 hours and/or warm pronounced in patients treated before the development
ischemia time over 90 minutes; a close monitoring of, or of advanced disease.117
use of prophylaxis against, CMV; avoiding the use of liv- Three approaches to antiviral therapy can be used in
ers from donors over age 65 years for HCV-positive HCV-positive recipients (Fig. 11-2): (1) treatment of the
patient before transplantation, with the goal of suppress-
‡References 24, 25, 33, 34, 40, 45. ing viral replication so that viral reinfection is prevented;
 11 Transplantation for Hepatitis C 141

Cirrhotic patients awaiting LT

Child-Turcotte-Pugh  7 Child-Turcotte-Pugh  8 or MELD  14

Genotype 2, 3, or 4 Genotype 1 No treatment

(Future: interferon-free regimens/
Future combinations)
Naive
Nonresponder
relapser Naive, relapser, partial responder Null responder

PEG-IFN + RBV No treatment CV > 1 log10 after lead-in CV < 1 log10 after lead-in

PEG-IFN + RBV + TVP/BOC

Liver transplantation

No posttransplant viral response FCH Posttransplant maintained viral response

Fibroscan ± noninvasive
index every 4-6 months
Stable LFTs
Fibroscan < 8 kPa Liver biopsy ± HVPG at one year
Benlloch index: Z < -1.386
F = 0 or F = 1 + Mild activity
HVPG < 6 mm Hg PEG-IFN + RBV +/- TVP/BOC
3-MALG < 2 Fibroscan > 8 kPa (based on genotype, prior therapies, patient characteristics)
Benlloch index: Z > 1.386
F = 2-4 or F = 1 + severe activity
HVPG > 6 mm Hg
No treatment Progressive disease
(follow-up) 3-MALG > 2
FIGURE 11-2 n Treatment of hepatitis C virus infection before or after liver transplantation. BOC, Boceprevir; CH, cholestatic hepatitis;
CV, F, fibrosis; FCH, fibrosing cholestatic hepatitis; HVPG, hepatic venous pressure gradient; LFTs, liver function tests; LT, liver trans-
plantation; 3-MALG, MELD, Model for End-Stage Liver Disease; PEG-IFN, pegylated interferon; RBV, ribavirin; TVP, telaprevir.

(2) preemptive early posttransplant antiviral therapy and a short-term approach beginning 3 to 4 months before
before histological damage has occurred in an attempt to the estimated date of transplantation, with the aim of
avoid the development of histological hepatitis or prevent achieving HCV-RNA negativity before transplanta-
its progression; and (3) treatment of established disease. tion.121-123 The results with either approach are similar;
Retransplantation is the last option for those progressing prevention of HCV reinfection is possible in about 20%
to allograft failure. of treated patients, which is 10% of HCV-positive patients
on the waiting list. In a first study by Everson et al,120 124
patients with a relatively good functional status (mean
Pretransplant Antiviral Therapy Child-Turcotte-Pugh score of 7.4, 45% class A , 36% B,
Antiviral therapy may be attempted before transplantation 18% C; mean MELD score of 11) were treated with a
to eliminate the virus and prevent recurrence. However, combination of IFN alpha-2b and RBV starting at low
the currently available antiviral agents (IFN, RBV, and dosing with gradual dose increases as tolerated, maintain-
the recently approved protease inhibitors) are difficult to ing the treatment for the standard duration (24 weeks for
use in patients with decompensated liver disease because genotypes 2 and 3 and 48 weeks for genotypes 1 and 4). An
of the risk for further decompensation, development of SVR was achieved by 24% of treated patients, with very
bacterial sepsis, or dangerous cytopenias.119-123 Some low rates among genotype 1 patients, the most common
reports of success with this approach have been pub- genotype in liver transplant candidates in the West (13%
lished.120-123 However, the patients treated to date repre- versus 50% in genotypes 2 and 3). HCV reinfection was
sent a highly selected group, and most HCV-positive prevented in all almost all patients who achieved SVR.
patients on the waiting list do not meet criteria for initia- More recent studies have evaluated the short-term
tion of treatment. Two strategies have been used: a long- approach using full doses of antiviral agents. In one
term approach to achieve SVR before transplantation120 study 51 patients (80% genotype 1; MELD score 12;
142 PART II Patient Evaluation: Adult

complication in the antiviral treatment group. In the mul-

TABLE 11-5 Pretransplantation Antiviral
ticenter U.S. study, where the median Child-Turcotte-
Therapy: Factors Associated With
Pugh score of those treated was 7 and the median MELD
Prevention of Hepatitis C Virus
score 11, a greater percentage of treated patients experi-
Reinfection
enced adverse events (98% versus 70%) and serious
HCV genotype 2 or 3 adverse events (75% versus 50%), but mortality rates
Low baseline viral load between treated and untreated patients were similar (14%
HCV RNA negative in liver explant versus 15%).123
Duration of dual therapy before liver transplantation more Data on triple therapy with either telaprevir or
than 16 weeks boceprevir in combination with PEG-IFN and RBV in
Ability to tolerate dual or triple therapy patients with cirrhosis are very limited. In phase III stud-
Child-Turcotte-Pugh < B7 or MELD score < 14 ies the proportion of cirrhotic patients was low, around
Albumin levels > 3.5 g/dL 7%.7-10 These studies demonstrated high efficacy rates
Platelet count > 100,000/mm3 among some subgroups, particularly treatment-naive
patients (71% to 92% with telaprevir, 42% with bocepre-
HCV, Hepatitis C virus; MELD, Model for End-Stage Liver Disease. vir) and relapsers (84% with telaprevir, 50% to 83% with
boceprevir) but significantly less in treatment-experi-
enced patients (34% and 14% for partial and null
Child-Turcotte-Pugh class A 45%, B 43%, C 6%) were responders re-treated with telaprevir-based triple ther-
treated with PEG-IFN alfa-2a (180 mcg/wk) and RBV apy, 30% to 46% for partial responders re-treated with
(800 to 1000 mg/day) for an average duration of 15 weeks. boceprevir-based triple therapy). Furthermore, tolerabil-
A control group of 51 patients on the transplant list with ity was poor in these patients. As expected, side effects
similar baseline characteristics received no treatment.121 were similar to those previously reported with dual ther-
The efficacy was similar to that obtained with daily admin- apy, including anemia that frequently required the use of
istration of standard IFN, with 15 patients (29%) HCV- erythropoietin or transfusions, as well as liver decompen-
negative at the time of transplant and 10 (20%) remaining sation. These results, though, come from trials where
HCV-negative after transplant. Factors predictive of only selected F4 patients were included. Real-life data
virological response were non-1 genotype (virological are accumulating and show that indeed these regimens
response 67% versus 21% in genotype 1) and rapid decline can be effective in cirrhotic patients and the inclusion of
in viral load (>2 log10 at week 4) (93% versus 28%). Impor- a protease inhibitor in the treatment regimen is associ-
tantly, none of the patients with poor liver function ated with an enhanced rate of early serum HCV RNA
(Child-Turcotte-Pugh class C or MELD > 18) had a viro- negativity, but their use is associated with high rates of
logical response. In the most recent and to date only ran- serious adverse events and treatment discontinuation.124
domized study, the length of time on therapy before In a large cohort of treatment-experienced cirrhotic
transplantation had a significant impact on the percentage patients treated in France (n = 485) (median MELD
of patients who were HCV RNA negative at transplanta- score 8, range 6 to 28, a third fulfilling phase III trials
tion and the percentage of patients remaining HCV-­ exclusion criteria), 40% of 295 telaprevir-treated patients
negative after transplantation.123 In that U.S. study, two and 41% of 190 boceprevir-treated patients achieved an
thirds of patients treated for 10 weeks or more were HCV SVR.124 Importantly, the majority (65% to 81%) were
RNA negative at the time of transplant. However, relapse HCV RNA negative after only 8 to 16 weeks of therapy,
rates were high in patients treated for less than 15 weeks. a relevant end point when trying to prevent HCV rein-
The likelihood of being HCV negative after transplanta- fection. Serious adverse events were common (about half
tion was highest for those with the greatest duration of of treated patients), resulting in treatment discontinua-
treatment (>15 weeks)—44% overall (25% for genotype tion in 14% to 21% of patients. Factors independently
1/4/6 and 63% for genotype 2/3)123 (Table 11-5). Unfor- associated with poor outcome (defined as severe infec-
tunately, antiviral therapy before transplantation is fre- tions, hepatic decompensation, and death) were a platelet
quently associated with side effects, the most common count below 100,000/mm3 and albumin levels of less
being asthenia/fatigue and cytopenias; this results in pre- than 3.5 g/dL.124
mature discontinuation in 13% to 43% of patients and These study results suggest the following:
dose reductions in 0% to 60% despite the use of erythro- 1. A large proportion of patients awaiting transplan-
poietin (5% to 67%) and granulocyte colony-stimulating tation (about 50%) will not benefit from antiviral
factor (33% to 45%). One potentially severe complication therapy due to contraindications, particularly throm­­
is bacterial infections. In the first U.S. multicenter study bocytopenia, neutropenia, or advanced liver
to evaluate pretransplant antiviral therapy, life-threaten- insufficiency.
ing infection ultimately led to early termination of the 2. Awareness of the potential complications is impor-
study.120 In the study by Carrión et al,122 the likelihood of tant when treating the small proportion who meet
bacterial infection was higher in the treated group than in the initiation criteria. Use of growth factors and
the control group, with most episodes occurring in Child- antibiotic prophylaxis may be helpful to avoid side
Turcotte-Pugh class B-C patients. Poor liver function effects and complete the course of therapy.
(Child-Turcotte-Pugh ≥7 or MELD ≥ 14) and antiviral 3. Pretransplantation treatment is feasible in
treatment were independently associated with the risk for selected patients; in particular, in well-compen-
infection. Prophylaxis with norfloxacin prevented this sated cirrhotic patients on the waiting list for
 11 Transplantation for Hepatitis C 143

TABLE 11-6 S
 tudies Evaluating Preemptive Therapy in Hepatitis C Virus–Positive Liver
Transplant Recipients
Time to Treatment
Number in Treatment/Con- Since Liver Trans-
Author Treatment Arm Control Arm trol Arms plantation (wk)
Sheiner et al195 IFN2b Control 35/46 2
Singh 98 IFN-α Control 12/12 2
Reddy 02 IFN2b + RBV Control 21/11 2-4
Mazaferro 03 IFN-RBV/IFN Control 22 & 21/20 4
Chalasani et al126 PEG-IFN alpha-2a Control 26/28 3
Shergill et al128 IFN + R IFN 22/22 2-6
Bzowej et al129 PEG-IFN + RBV Control 54/48 10-26

IFN, Interferon; PEG-IFN, pegylated interferon; RBV, ribavirin.

transplantation. The expected benefits associated 14% to 100% in genotype 2 or 3). Whether preemptive
with triple therapy need to be balanced with the therapy is helpful in delaying and/or reducing the sever-
risks for severe adverse events, particularly in ity of recurrent disease is still a matter of debate. In one
prior null responders or those with a platelet study, preemptive therapy was associated with a delay in
count below 100,000/mm3 and albumin levels subsequent HCV therapy for moderate to severe disease
below 3.5 g/dL. The patients who may benefit (fibrosis score ≥ 2 or moderate necroinflammatory
from this approach are compensated cirrhotic activity), with a median time of 36.3 months versus 20.3
patients, often with coexistent HCC. In these months in the preemptive and nonpreemptive groups,
patients, triple therapy can achieve a virological respectively (P = .004).130
response in a higher proportion of patients and at
an earlier stage of treatment than dual therapy. Treatment of Established Hepatitis C
4. 
Reinfection can be prevented if HCV RNA is
absent at the time of transplantation; it is always
Virus–Related Graft Disease
prevented in patients who have previously achieved The most widely used strategy involves initiating antivi-
an SVR. ral therapy once the histological consequences of HCV
reinfection are detected on a liver biopsy. Treatment of
Preemptive Therapy in the Early recurrent HCV disease with IFN or RBV as single agents
yielded poor results.* As in the nontransplant setting, the
Posttransplant Period results improved with combination therapy and the
Preemptive therapy with IFN (standard or pegylated) pegylation of IFN.† Until recently, treatment was based
either alone or in combination with RBV in the early on a combination of PEG-IFN and RBV over 48 to 72
posttransplant period has also been used in an attempt weeks. Due to the lack of studies comparing different
to reduce the incidence or severity (or both) of recur- treatment regimens, it is not possible to define whether
rent hepatitis C125-130 (Table 11-6). It is generally it is preferable to begin treatment with full or reduced
administered during the first 2 to 7 weeks after trans- dose and increase as tolerated, or whether it is beneficial
plantation, before there is clinical evidence of liver to individualize treatment according to the response
damage. Benefits and limitations of this strategy are kinetics. Three systematic reviews described rates of
similar to those of pretransplant therapy. First, the SVR averaging 35%, ranging from 27% to 41%.136-138
applicability is very low due to the multiple complica- SVR rates have improved with time, possibly because of
tions that occur in the first weeks after transplantation, more aggressive approaches to treatment adherence as
particularly since the introduction of the MELD system well as treating patients at less advanced stages of fibro-
and transplantation of patients with a greater degree of sis,117,153,159 where the chances of achieving an SVR
illness. In a single-center study, only 41% of 124 con- appear to be higher. When a first course of antiviral ther-
secutive liver transplant patients were determined to be apy fails, retreatment with PEG-IFN and RBV may result
candidates for preemptive therapy.128 Reasons for ineli- in SVR in one third of cases, particularly in previous
gibility were persistent anemia, renal or neurological relapsers and in those in whom adherence is reinforced
dysfunction, or generally poor health. Patients trans- during retreatment.159 Adverse events with dual therapy
planted with lower MELD scores were more frequently are very common, resulting in treatment discontinuation
eligible to start therapy. In addition, poor tolerability is in approximately 25% of cases; dose reductions, particu-
a marked limitation, with frequent need for dose reduc- larly of RBV, in more than half; and frequent use of
tions and/or premature treatment discontinuation. As a growth factors.* Whether these adjunctive therapies
consequence, SVR rates have been generally low, rang-
ing from 8% to 9% with monotherapy to 18% to 43% *References 33, 34, 40, 131, 132.
with combination therapy (with significant differences †References 33, 34, 40, 112-118, 125, 133-159.
between genotypes: 5% to 33% in genotype 1 versus *References 33, 34, 40, 118, 125, 133-159.
144 PART II Patient Evaluation: Adult

should be used empirically to allow for full dosing from

TABLE 11-7 P
 redictors of Sustained Viral
the start is still a matter of debate. Among side effects,
Response With Pegylated
hematological toxicity, particularly anemia, is the most
Interferon and Ribavirin
frequent complication of antiviral therapy in the trans-
plant setting. In one study based on 164 transplant recipi- Viral-Related Factors
ents treated with PEG-IFN and RBV, almost 70% of Infection with HCV genotype non-1
patients developed anemia (defined by a hemoglobin level Low pretreatment viral load (<800,000 International
of less than 10 g/dL), a percentage significantly higher Units/mL)
than the 30% reported in immunocompetent patients.
Recipient-Related Factors
Importantly, the reduction of hemoglobin was greater
IL28B genotype CC (rs129789860)
than 5 g/dL in 41% of treated patients.160 As a conse-
Male sex
quence, the use of erythropoietin was very frequent in
Absence of cirrhosis
transplant recipients (60% compared to only 15% in
immunocompetent patients). Factors independently Donor-Related Factors
associated with the development of anemia were renal Donor age < 60 yr
insufficiency, high baseline viremia, CSA-based immuno- IL28B genotype CC (rs129789860)
suppression, low baseline hemoglobin values, and use of Immunosuppression-Related Variables
MMF. In fact, it is likely that renal impairment, present Cyclosporine versus tacrolimus
in a large proportion of transplant patients, possibly
Treatment-Related Factors
explains the higher incidence of this complication com- Posttransplant naive or relapsers versus null responders
pared to those who are immunocompetent. Given the Rapid viral response (week 4)
strong influence of renal function on the development of Early viral response (week 12)
anemia, experts recommend adjusting RBV doses based Treatment adherence
on calculated creatinine clearance.
In addition, IFN has immunomodulatory properties HCV, Hepatitis C virus.
resulting in a broad range of immune-related disorders,
including chronic rejection (1%), acute cellular rejection
(6%), and “de novo” autoimmune (alloimmune) hepatitis predictive values (PPVs) and negative predictive values
(3% to 7%),36,37 each associated with reduced patient and (NPVs) of a rapid 1-month viral response and absence of
graft survival. In one study, risk factors associated with early 3-month viral response are also confirmed in the
these immune-mediated complications were no prior transplant patient.* In fact, stopping therapy may be con-
PEG-IFN therapy (odds ratio = 5.3; P < .0001), therapy sidered in patients without a virological response after 12
with PEG-IFN alpha-2a (odds ratio = 4.7; P = .03), and weeks of therapy, in particular if treatment is poorly tol-
immune features (mainly plasma cell hepatitis) on pre- erated and/or there is no biochemical response. Whether
treatment liver biopsies (odds ratio = 3.9; P = .005). Those therapy should be maintained in those without virologi-
experiencing immune-mediated complications had lower cal response but the presence of biochemical response is
long-term patient (61.5% versus 91.3% of controls) and still under investigation because some authors have
graft (38.5% versus 85.6% of controls) survival and described some benefit in this setting.116,162,163 Several
higher rates of retransplantation (34.6% versus 6.7% of studies have documented improved rates of viral response
controls) (all, P < .0001), without increases in SVR.37 The if therapy is initiated at low stages of fibrosis, with par-
risk for rejection is also dependent on the posttransplant ticularly poor results, both in terms of efficacy and toler-
interval and the immunosuppressive drug levels. HCV ability, in those with bridging fibrosis and allograft
clearance improves hepatic microsomal function, result- cirrhosis. In a single-center study where an overall SVR
ing in a decrease in CSA and Tac trough levels.161 Two was achieved in 33.5% of patients, worse results were
important recommendations are hence not to reduce observed in those treated in more recent years (2001-
excessively the immunosuppression during and after 2003: n = 27, 46.5%; 2004: n = 23, 43.5%; 2005: n = 21,
treatment and to perform a liver biopsy in case of 35%; 2006 to January 2007: n = 36, 24%; P = .043).
increased liver enzyme levels to exclude acute or chronic Potential causes for this trend were the increase in donor
rejection or alloimmune hepatitis. These immune-related age and a greater proportion of patients being treated at
entities can occur even after achieving an SVR, therefore advanced stages of disease, variables in turn associated
strict graft monitoring is also mandatory after antiviral with lower rates of viral clearance. More specifically, only
treatment. 4 of 22 patients with baseline cirrhosis (18%) achieved an
An understanding of factors predictive of viral res­ SVR compared to 41% of patients without baseline
pon­se is important to improving the efficacy of antiviral cirrhosis.157 A follow-up from that center showed improved
therapy. In general, factors predictive of SVR with dual rates of viral response after changing the center policy to
therapy are similar to those described in the immune- start therapy at less advanced stages of fibrosis. A more
competent patient, including infection with non-1 geno- aggressive approach, particularly regarding doses of RBV,
types, absence of prior posttransplant null response to also contributed to the improved results.117 Furthermore,
antiviral therapy, good adherence, and low baseline vire- tolerability is also compromised if therapy is started in
mia116-118,136-159 (Table 11-7). Older donor age has also patients with advanced disease. In one study, tolerability
been found in some studies to predict a lack of response
to antiviral therapy.117,118,142,153 In addition, the positive *References 117, 118, 142, 143, 147, 148, 152, 153, 155, 157, 159.
 11 Transplantation for Hepatitis C 145

decreased in those with fibrosis stage 3 or higher on base- challenging, because initial treatment attempts have
line liver biopsy. A total of 20% of these patients died or been in “difficult-to-treat” patient populations (prior
were retransplanted because of liver failure as opposed to nonresponders, advanced fibrosis or cholestatic hepati-
1% of patients who had fibrosis stage below 3.153 tis, high baseline HCV RNA), improved SVR rates are
The role of baseline immunosuppression in viral expected based on preliminary virological data. Indeed,
response in those treated with dual therapy is still under high rates of viral response, approximately 80% at week
debate. CSA has demonstrated in vitro activity against 12 (68% to 100%) and 60% at weeks 24 to 48 (50% to
HCV.166 In addition, in a study where detailed analyses of 65%), have been reported in the first weeks of therapy,
early viral kinetics of HCV during PEG-IFN alpha-2a with no significant differences between boceprevir- and
and alpha-2b treatment were performed in eight patients telaprevir-based therapy. As in the cirrhotic population,
on Tac-based and eight patients on CSA-based immuno- high rate of adverse events, particularly infections (9%
suppression, compared to that of three nontransplant to 18%), hematological toxicity, and renal dysfunction,
patients, viral clearances were shown to be delayed in likely reflecting drug-drug interactions, are being
liver transplant patients with no significant differences reported.176-179 In particular, anemia occurs almost
between those treated with PEG-IFN alpha-2a and invariably and results in an extremely frequent need for
alpha-2b. Interestingly, patients on CSA with delayed erythropoietin and ribavirin dose reductions, as well as
monophasic declines were still able to achieve an SVR frequent transfusions.
despite unfavorable or absent early viral load declines.165 One limitation when using protease inhibitors in
Finally, some but not all studies suggest that SVR is more transplant recipients is the drug-drug interactions with
likely achieved on CSA than on Tac. The rates of viral calcineurin inhibitors. Boceprevir and telaprevir both
response, however, differ substantially between centers, significantly downregulate the cytochrome P-450 3A
and although some authors report rates of only 14% with system and lead to slower metabolism of CSA, Tac,
Tac, others achieve rates as high as 56% in patients with everolimus, and rapamycin.176-181 Emerging data sug-
the same baseline immunosuppression. Likewise, SVR gest that the area under the curve for these immunosup-
rates ranging from 14% to 73% have been achieved in pressive agents is markedly increased when given with
patients taking CSA as their main immunosuppressive telaprevir or boceprevir. This is particularly true for
agent. These discrepant results, based on retrospective Tac when using telaprevir. Clinical data show, however,
studies, may reflect the existence of as-yet unidentified that these interactions can be managed successfully with
factors predictive of response or, most likely, differences strict and frequent monitoring of immunosuppressive
in the study population or treatment management. In the drug levels. When protease inhibitors are started, calci-
only randomized pilot study published to date, unfortu- neurin inhibitor doses need to be reduced to avoid tox-
nately based on a small sample size, the authors did not icity, whereas increasing the doses to pretreatment or
find significant differences in SVR between 20 patients even higher doses is required once protease inhibitors
on Tac and 18 on CSA (35% versus 39%, P = .8).156 are discontinued in order to avoid rejection episodes.
The pattern of response to IFN-based therapies in In summary, based on preliminary findings, it is
individuals who have been treated before transplantation expected that triple therapy will result in a 30% increase
may change in some cases. In one study the authors found in SVR in liver transplant recipients. As expected, and
a change in the pattern of response in about 25% of given that PEG-IFN-RBV is still needed, concerns
patients.166 Importantly, some null responders became remain regarding safety and toxicity issues. Finally,
responders after transplantation, suggesting that the new drug-drug interactions need to be acknowledged but
virus environment and graft response to IFN play a sig- can be managed through strict immunosuppressive
nificant role in treatment response. In fact, polymor- trough level monitoring. Future studies should focus on
phisms in the region of the IL28B gene strongly influence identifying predictors for nonresponse to avoid unnec-
the rate of SVR in immunocompetent patients and may essary treatment and associated toxicities. As in the non-
partially explain these observations. Indeed, the IL28B transplant setting, there is great hope for non–IFN-based
genetic background of both donor and recipient seem to therapies, which might result in greater efficacy but
influence the antiviral treatment outcomes,86-92 and thus mostly promise less toxicity and fewer significant drug-
optimal graft-recipient matching depending on IL28B drug interactions.178,179,182,183
alleles may improve sensitivity to antiviral therapy after In conclusion, each of the antiviral strategies has
transplantation. A donor with an IL28B CC genotype advantages and disadvantages. Prophylactic therapy while
may restore partially the sensitivity to IFN-α in an unfa- the patient is awaiting transplantation is the best theoreti-
vorable IL28B genotype recipient. Based on these find- cal approach. It is, however, limited by the low tolerabil-
ings, it is clear that a lack of response to antiviral treatment ity of antiviral agents. It is unlikely that current IFN-based
before transplantation should not prevent an attempt to regimens used with this approach will have a major impact
re-treat HCV recurrence in the same patient, particularly on posttransplant recurrence of HCV, because only a
if the donor IL28B genotype is different from that of the relatively small proportion of patients will qualify for
recipient. therapy. In addition, treatment with new oral antivirals
Following the improved response rates achieved with may result in the selection of more virulent or resistant
triple therapy in immunocompetent genotype 1 infected viral strains and ultimately lead to a more aggressive
patients,7-10 some authors have begun evaluating the use course of the disease or to a posttransplant situation in
of triple therapy with PEG-IFN RBV, and protease which no effective antivirals are available if needed. Dra-
inhibitors in the transplant setting.167-176 Although matic changes are expected with IFN-free regimens,
146 PART II Patient Evaluation: Adult

which will likely be administered before transplantation of 8.7 kPa, the sensitivity and NPV for significant fibro-
and hopefully prevent HCV reinfection. sis (F ≥ 2) and portal hypertension (HVPG ≥ 6 mm Hg)
Preemptive posttransplant therapy is also attractive. were ≥ 0.90. The best cutoff values for detection of
However, HCV RNA levels increase rapidly after trans- patients with fibrosis stage 2 or higher have varied in
plantation, so the window for initiation of treatment with different studies between 7.9 and 10.1 kPa, all of them
a low viral load is narrow. In addition, a significant pro- with high PPVs (65% to 86%) and NPVs (88% to
portion of patients are not candidates for IFN-based 94%).189-194 For a diagnosis of cirrhosis the cutoff values
therapy in the early posttransplant period, and tolerabil- used in deceased donor transplants have ranged from 12
ity of full doses of IFN and RBV is unlikely. With the to 12.5 kPa with 50% to 74% PPV and 99% to 100%
currently available IFN-based treatments, the wait-and- NPV, whereas in LDLT these values have been 26.5
treat approach is probably the most cost-effective option kPa with 83% PPV and 100% NPV. The cutoff value to
(see Fig. 11-2). The tolerability is better, and treatment is estimate the existence of portal hypertension (HVPG >
offered only to patients in whom progressive disease 6 mm Hg) was 8.7 kPa with a PPV of 81% and NPV of
develops or is predicted. In that sense, strict monitoring 90%. One advantage of elastography is the potential for
of disease progression is of paramount importance to repeated measurements of liver stiffness at short inter-
identify early histological changes that herald an aggres- vals, potentially allowing discrimination between rapid
sive course, and in these cases, therapeutic interventions and slow "fibrosers." Indeed, in one study slow and rapid
may be implemented at less advanced stages when a fibrosers could be early identified. Median liver stiffness
response appears to occur more frequently, with both (in kilopascals) at months 6, 9, and 12 were significantly
dual and triple therapy. higher in rapid fibrosers (9.9, 9.5, 12.1) than in slow
fibrosers (6.9, 7.5, 6.6) (P < .01, all time points).194 All
these noninvasive tools, however, should not be consid-
HEPATITIS C MONITORING ered a substitute for the liver biopsy but rather should
be complementary (see Fig. 11-2).
To target antiviral therapy to patients with progressive
disease, strict disease monitoring is mandatory. Both
invasive and noninvasive means of monitoring fibrosis RETRANSPLANTATION
progression are available in the liver transplant setting.
Liver biopsy continues to be the standard of care, par- With the continued increase in the number of HCV-
ticularly before IFN therapy is considered. Noninvasive infected recipients potentially in need of retransplanta-
tools to monitor fibrosis progression, particularly elas- tion, it has become imperative to determine whether
tography, commonly used in the immunocompetent some or all patients with graft failure as a result of recur-
patient, are also being evaluated in the transplant popu- rent HCV disease are candidates for retransplantation.
lation.184 Simple noninvasive mathematical indexes to To date there is reluctance to accept these patients for
predict fibrosis in HCV-infected liver transplant recipi- retransplantation, particularly those in whom recurrent
ents have also been developed.185,186 In one study the disease leading to graft failure develops over a short
multivariate analysis identified four variables as inde- period. Concern regarding retransplantation in this pop-
pendent predictors of fibrosis stage: prothrombin time ulation relates to four issues: (1) early reports suggesting
(PT), albumin/total proteins ratio (PALB), AST levels, a worse outcome after retransplantation in these patients
and time from liver transplantation (TFLT); [1 / 1+e than in those undergoing retransplantation for other
12.698 + 0.097 (PALB) − 1.356 (PT) − 0.004 (AST) − indications195,196; (2) uncertainty regarding the natural
0.02(LTLB)].185 Direct markers of fibrogenesis have history of recurrent hepatitis C in the second graft,197
also been assessed.187,188 In one study, serum fibrosis particularly in nonresponders to antiviral therapy; (3) fre-
markers, including hyaluronic acid, amino-terminal quent comorbidities in those receiving prolonged immu-
propeptide of type-III-procollagen, and tissue inhibitor nosuppression; and (4) the ever-present organ shortage.
of matrix metalloproteinase type 1, measured during the However, recent reports have indicated improved out-
first months after transplantation, particularly after the comes, particularly when retransplantation is performed
sixth month, identified patients with mild as opposed to before the development of infectious and renal complica-
those with aggressive hepatitis C recurrence.188 The tions198-208 or the occurrence of advanced allograft dys-
best results though have been obtained with elastogra- function as indicated by MELD score. Some consensus
phy. Several studies have shown a very good correlation regarding this issue is urgently needed, because retrans-
between liver stiffness and the histological stage of plantation on a large scale for recurrent hepatitis C would
fibrosis. In an early study a cohort of 124 liver transplant have a significant impact on outcomes, resource utiliza-
recipients with HCV infection underwent 169 liver tion, and perhaps even donation.200 Until a consensus is
biopsies and 129 liver hemodynamic studies, paired with reached, maximum equity and optimization of organs
liver stiffness measurements.189 There was an excellent require that retransplantation be offered to patients who
congruence between the fibrosis stage determined by have at a minimum a greater than 60% chance of survival
liver biopsy and liver stiffness. The area under the at 1 year.200,202 There are many variables that can influ-
receiver operating characteristic (ROC) curve for diag- ence patient survival after retransplantation: bilirubin
nosis of significant fibrosis (F ≥ 2) and portal hyperten- level, serum creatinine level, age, experience of the cen-
sion (hepatic venous pressure gradient [HVPG] ≥ 6 mm ter, or the time between the first transplantation and
Hg) was 0.90 and 0.93, respectively. Using a cutoff value recurrence of HCV, among others.198-208 Based on these
 11 Transplantation for Hepatitis C 147

factors, predictive models of survival after retransplanta- therapies to prevent recurrence, (8) limited but poten-
tion have been created and can be used in clinical prac- tially enhanced efficacy of current antivirals in the treat-
tice.198,202-208 Retransplantation of highly selected ment of posttransplant HCV disease, and (9) unacceptable
patients based on these models has resulted in improved survival rates when retransplantation is performed on
results. unselected patients.
A number of important issues remain to be investi-
gated, including (1) optimal management of HCV-
CONCLUSION infected patients awaiting liver transplantation, in
particular, decreasing waiting list mortality with the use
There are a certain number of proven concepts regarding of HCV-infected organ donors or antiviral drugs (or
HCV infection in the setting of liver transplantation, both) before transplantation; (2) expansion of the donor
including (1) a progressive increase in the number of pool; (3) improved understanding of the long-term out-
patients infected with HCV who are in need of a first or come of HCV-positive liver transplant recipients and the
second transplant, (2) universal viral reinfection, (3) variables associated with outcome; (4) improved manage-
extremely low risk for de novo HCV infection, (4) recur- ment of recurrent hepatitis C, particularly with regard to
rence of chronic hepatitis C in the majority of patients immunosuppression; (5) evaluation of new approaches to
with progression to cirrhosis in a substantial proportion the prevention or treatment (or both) of HCV reinfec-
of these over time, (5) variable natural history of disease tion; (6) definition of the outcome of HCV-positive
ranging from minimal damage to cholestatic hepatitis, (6) patients undergoing transplantation with DCD livers;
acceptable graft and patient survival with short- and and (7) development of a consensus regarding retrans-
medium-term follow-up, but inferior to that of unin- plantation in patients with allograft failure secondary to
fected controls, (7) lack of effective prophylactic recurrent HCV disease.

Pearls and Pitfalls

• Despite the recent advances in antiviral therapy, hepatitis C • Antiviral therapy before liver transplantation, either with
virus (HCV)-related liver disease continues to be the first dual (non-1 genotype) or triple therapy (genotype 1)
indication for liver transplantation in most transplant cen- should be used with caution only in patients with Child-
ters. Turcotte-Pugh score less than 8 and/or MELD score
• The accelerated nature of fibrosis progression in recurrent less than 18. The combination of platelet count less than
hepatitis C results in 20% to 54% of liver transplant recipi- 100,000/mm3 and albumin levels less than 3.5 g/dL should
ents developing bridging fibrosis-cirrhosis within the first preclude the use of triple therapy in this setting.
5 years after transplantation. • Antiviral therapy after transplantation with pegylated inter-
• The profile of an HCV-infected liver transplant recipient feron and ribavirin results in greater sustained viral eradica-
at risk for aggressive recurrent disease is that of a woman, tion and less frequent complications if started at mild stages
transplanted with a graft from an older donor, who devel- of fibrosis. Preliminary data with triple therapy suggest that
ops early recurrent disease and additional complications the same holds true with triple therapy.
such as cytomegalovirus infection, insulin resistance, and • Preliminary experience with triple therapy with protease
frequent need for immunosuppressive modifications. inhibitors (boceprevir/telaprevir) and pegylated interferon
• Frequent assessment of fibrosis progression, with protocol with ribavirin in patients with recurrent hepatitis C (HCV
liver biopsies in addition to noninvasive tools, is essential genotype 1) shows improved efficacy (about 60% sustained
in the transplant setting to determine the degree of liver virological response [SVR] rates) but also greater toxicity
fibrosis and necroinflammation to timely indicate antiviral (particularly hematologic) than dual therapy (SVR rates
therapy of about 35%). Drug-drug interactions with immunosup-
• Successful antiviral therapy is the only confirmed means pressive agents are relevant but can be easily managed with
to improving long-term posttransplant survival in HCV-    frequent monitoring of drug levels.

infected liver transplant recipients.

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110. Berenguer M, Aguilera V, Prieto M, et al. Significant improve- 131. Gane EJ, Lo SK, Riordan SM, et al. A randomized study compar-
ment in the outcome of HCV-infected transplant recipients by ing ribavirin and interferon alfa monotherapy for hepatitis C recur-
avoiding rapid steroid tapering and potent induction immunosup- rence after liver transplantation. Hepatology. 1998;27:1403-1407.
pression. J Hepatol. 2006;44(4):717-722. 132. Terrault NA, Berenguer M. Treating hepatitis C infection in liver
111. Schiano TD, Charlton M, Younossi Z, et al. Monoclonal anti- transplant recipients. Liver Transpl. 2006;12:1192-1204.
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tion for HCV: results of a phase 2 randomized study. Liver nation of interferon alfa and ribavirin as therapy of recurrent
Transpl. 2006;12(9):1381-1389. hepatitis C after liver transplantation. Hepatology.
112. Berenguer M, Palau A, Aguilera V, et al. Clinical benefits of anti- 1997;26:500-504.
viral therapy in patients with recurrent hepatitis C following liver 134. Lavezzo B, Franchello A, Smedile A, et al. Treatment of recurrent
transplantation. Am J Transplant. 2008;8(3):679-687. hepatitis C in liver transplants: Efficacy of a six versus twelve
113. Picciotto FP, Tritto G, Lanza AG, et al. Sustained virological month course of interferon alfa 2b with ribavirin. J Hepatol.
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tion after liver transplantation. J Hepatol. 2007;46:459-465. 135. Samuel D, Bizollon T, Feray C, et al. Interferon-alfa 2b plus riba-
114. Bizollon T, Pradat P, Mabrut JY, et al. Benefit of sustained viro- virin in patients with chronic hepatitis C after liver transplanta-
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2008;8(11):2183-2184. feron and ribavirin in liver transplant candidates and recipients
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120. Everson GT, Trotter J, Forman L, et al. Treatment of advanced plus ribavirin for recurrent hepatitis C infection after liver trans-
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121. Forns X, García-Retortillo M, Serrano T, et al. Antiviral therapy 142. Berenguer M, Palau A, Fernandez A, et al. Efficacy, predictors of
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389-396. Transpl. 2006;12:1067-1076.
 11 Transplantation for Hepatitis C 151

143. Oton E, Barcena R, Moreno-Planas JM, et al. Hepatitis C recur- 163. Walter T, Scoazec JY, Guillaud O, et al. Long-term antiviral
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2009;15:782-789. telaprevir: A single center experience. Hepatology. 2012;56
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Liver Transpl. 2008;14:1766-1777. limus based immunosuppression. Hepatology. 2012;56(suppl):720.
154. Al-Hamoudi W, Mohamed H, Abaalkhail F, et al. Treatment of 175. Burton Jr JR, O’Leary JG, Verna EC, et al. A multicenter study of
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156. Firpi RJ, Soldevila-Pico C, Morelli GG, et al. The use of cyclo- boceprevir and immunosuppressive therapy in liver transplant
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157. Berenguer M, Aguilera V, Prieto M, et al. Worse recent efficacy 178. Mutimer D. Understanding the switchbacks: the impact of direct
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158. Lee WC, Wu TJ, Chou HS, et al. Flexible and individualized and challenges associated with their use in the liver transplant set-
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770-777. pharmacokinetics of cyclosporine and tacrolimus. Hepatology.
159. Berenguer M, Roche B, Aguilera V, et al. Efficacy of retreatment 2011;54:20-27.
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sive approach (LT-12-335). Liver Transpl. 2013;19(1):69-77 between the hepatitis C virus protease inhibitor boceprevir and
2013. cyclosporine and tacrolimus in healthy volunteers. Hepatology.
160. Giusto M, Rodriguez M, Navarro L, et al. Anemia is not predic- 2012;56:1622-1630.
tive of sustained virological response in liver transplant recipients 182. Fontana RJ, Hughes EA, Appelman H, et al. A case report of suc-
with hepatitis C virus who are treated with pegylated interferon cessful peginterferon, ribavirin, and daclatasvir therapy for recur-
and ribavirin. Liver Transpl. 2011;17(11):1318-1327. rent cholestatic hepatitis C following liver retransplantation.
161. Kugelmas M, Osgood MJ, Trotter JF, et al. Hepatitis C virus Liver Transplant. 2012;18:1053-1059.
therapy, hepatocyte drug metabolism, and risk for acute cellular 183. Fontana RJ, Hughes EA, Bifano M, et al. Sofosbuvir and Daclatasvir
rejection. Liver Transpl. 2003;9:1159-1165. Combination Therapy in a Liver Transplant Recipient With Severe
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185. Benlloch S, Heredia L, Barquero C, et al. Prospective validation 196. Rosen H, O’Reilly P, Shackleton C, et al. Graft loss following
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virus-infected liver transplant recipients. Liver Transpl. plantation. 1997;62:1773-1776.
2009;15:1798-1807. 197. Berenguer M, Prieto M, Palau A, et al. Severe recurrent hepatitis
186. Cross TJS, Calvaruso V, Foxton MR, et al. A simple, non-invasive C following liver retransplantation for HCV-related graft failure.
test for the diagnosis of liver fibrosis in patients with hepatitis C Liver Transpl. 2002;9:228-235.
recurrence after liver transplantation. J Viral Hepat. 2010; 198. Rosen HR, Madden JP, Martin P. A model to predict survival fol-
17:640-649. lowing liver retransplantation. Hepatology. 1999;29:365-370.
187. Pungpapong S, Nunes DP, Krishna M, et al. Serum fibrosis mark- 199. Busuttil RW, Shaked A, Millis JM, et al. One thousand liver trans-
ers can predict rapid fibrosis progression after liver transplanta- plants. The lessons learned. Ann Surg. 1994;219:490-499.
tion for hepatitis C. Liver Transpl. 2008;14:1294-1302. 200. Biggins SW, Beldecos A, Rabkin JM, et al. Retransplantation for
188. Carrión JA, Fernández-Varo G, Bruguera M, et al. Serum fibrosis hepatic allograft failure: Prognostic modeling and ethical consid-
markers identify patients with mild and progressive hepatitis C erations. Liver Transpl. 2002;8:313-322.
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2010;138:147-158. liver retransplantation: a European single-center experience. Sur-
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diagnosis of advanced fibrosis and portal hypertension in patients 202. Carrión JA, Navasa M, Forns X. Retransplantation in patients
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190. Rigamonti C, Donato MF, Fraquelli M, et al. Transient elastog- 203. Ghabril M, Dickson R, Wiesner R. Improving outcomes of liver
raphy predicts fibrosis progression in patients with recurrent retransplantation: an analysis of trends and the impact of hepatitis
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191. Corradi F, Piscaglia F, Flori S, et al. Assessment of liver fibrosis in 204. Doyle HR, Morelli F, McMichael J, et al. Hepatic retransplanta-
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transient elastography. Dig Liver Dis. 2009;41:217-225. plantation. 1996;61:1499-1505.
192. Harada N, Soejima Y, Taketomi A, et al. Assessment of graft fibrosis 205. Markmann JF, Gornbein J, Markowitz JS, et al. A simple model to
by transient elastography in patients with recurrent hepatitis C after estimate survival after retransplantation of the liver. Transplanta-
living donor liver transplantation. Transplantation. 2008;85:69-74. tion. 1999;67:422-430.
193. Adebajo CO, Talwalkar JA, Poterucha JJ, et al. Ultrasound-based 206. Ghobrial RM, Gornbein J, Steadman R, et al. Pretransplant
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tion: A systematic review and meta-analysis. Liver Transpl. 2012 207. Azoulay D, Linhares MM, Huguet E, et al. Decision for retrans-
Mar;18(3):323-331. plantation of the liver: an experience-and cost-based analysis. Ann
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 CHAPTER 12

Transplantation for Fulminant

Hepatic Failure
John O’Grady

CHAPTER OUTLINE

PATIENT POPULATIONS DONORS, GRAFTS, AND WHEN TO PROCEED TO

TRANSPLANTATION
LISTING FOR LIVER TRANSPLANTATION
POSTOPERATIVE MANAGEMENT
PROGNOSTIC MODELS
General Models RESULTS
Radiological and Histological Assessment

Data from the Scientific Registry of Transplant Recipi- The improved survival was seen in acetaminophen
ents (SRTR) and the European Liver Transplant Registry patients and in patients with drug-induced liver injury
(ELTR) indicate comparable levels of liver transplanta- and hepatitis A or B. However, the improved survival was
tion for fulminant hepatic failure (FHF), representing not seen in patients with seronegative hepatitis or FHF of
around 8% of overall organ utilization.1,2 A single-center indeterminate cause.3
(King’s College Hospital) experience of 2095 patients The efficacy of liver transplantation was never estab-
with FHF and at least grade 2 encephalopathy had a 19% lished in a randomized controlled trial or even a carefully
transplantation rate, but this increased to 53% of nonac- constructed case comparison study. In 1990 an argument
etaminophen cases and 35% of acetaminophen cases by was made for a “controlled trial between specialist units…
the end of the study period in 2004-2008 (Table 12-1).3 to establish the role of emergency hepatic transplantation
The application of liver transplantation also varied with in patients with fulminant hepatic failure,” but this fell on
cause and in the United States was notably lower at only deaf ears then and is unlikely to be received with any great
8% in patients with acetaminophen-related FHF as com- enthusiasm over 20 years later.23 The arguments in sup-
pared with about 40% of cases with other causes.4 port of such a trial were scientifically sound but were
It is frequently stated that liver transplantation is the silenced by counterarguments that careful selection of
only effective treatment for FHF. This statement has patients with the worst prognosis would deliver survival
some credibility in that liver transplantation is the inter- benefit well beyond that which need to be demonstrated
vention that has made the single most visible contribu- in a randomized controlled trial. This view continues to
tion to the improvement in survival in patients with FHF, dominate the evaluation of the role of liver transplantation
particularly in those with clear-cut evidence of an inher- in the management of FHF.
ent poor prognosis. The concept of replacing a failing
liver in a young patient with only a few days to live is a
graphic illustration of the power of liver transplantation, PATIENT POPULATIONS
especially because the outcomes proved to be very accept-
able with respect to survival and long-term rehabilitation. In the context of liver transplantation, patients with FHF
The concept was initially applied in the early 1980s, and can be divided into the following groups:
by 1995 the feasibility of liver transplantation had been 1. Patients considered to have a reasonable prospect
established in a series of patient with survival rates of survival without liver transplantation
­peaking at over 90% at 1 year.5-22 2. Patients with a poor prognosis but with medical
Although liver transplantation was a revolution, a par- contraindications to liver transplantation
allel evolution of advances in critical care, by means of 3. Patients with a poor prognosis but with psychoso-
small steps rather than quantum leaps, also contributed cial contraindications to liver transplantation
to improved survival rates without transplantation. In the 4. Candidates for wait-listing for transplantation
King’s College Hospital series, nontransplant survival The prognosis in FHF is variable and often counter-
increased from 16.7% at baseline to 48% (Fig. 12-1). intuitive, and consequently an understanding of the

153
154 PART II Patient Evaluation: Adult

90
TABLE 12-1 L
 aboratory Tests with Prognostic Baseline
Value in Fulminant Hepatic Failure 80 2004-2008
Widely Utilized 70
Coagulation parameters (prothrombin time, INR, factor V
levels) 60
Serum bilirubin
Serum transaminases 50
Serum creatinine
40
Arterial pH
Serum lactate 30
Restricted Utilization
α-Fetoprotein 20
Ammonia
10
Arterial ketone body ratio
Galactose elimination 0
Gc globulin All Grade >1 Transpl. Nontranspl.
Serum phosphate
FIGURE 12-1 n Improvement in survival from baseline (1984-
M30 (marker of apoptosis) 1993) to end of study (2004-2008) in over 3300 patients treated at
King’s College Hospital.
INR, International normalized ratio.

30 Survived
LISTING FOR LIVER TRANSPLANTATION
Died
Alive after transplant The principles driving selection processes are the accu-
25 Died after transplant rate identification of those in need of and those who will
benefit from liver transplantation. Broadly, there are two
approaches to listing patients with FHF for liver trans-
20 plantation. The first is to use some set of indicators of a
poor prognosis to discriminate for the purposes of wait-
15
listing; the second is to list all eligible patients and defer
the decision until a donor organ becomes available. The
first approach requires the selection process to have a
10 high level of confidence that each individual patient would
benefit from a liver transplant. In this context, failure to
list a patient for liver transplantation who subsequently
5 dies is a visible and regrettable event. The potential for
“unnecessary transplantation” is greatest for acetamino-
0 phen-related FHF. In one series from the United States
Listed for transplantation
59% of patients wait-listed for transplantation but not
transplanted survived (Fig. 12-2), whereas the survival
FIGURE 12-2 n Outcome of 72 patients with acetaminophen-
related fulminant hepatic failure who were listed for liver trans-
rate in those receiving transplants was 78%.4 The second
plantation in a prospective U.S.-based study. (From Larson AM, approach favors the individual patient but risks unneces-
Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver fail- sary transplantation, which is a less visible but also regret-
ure: results of a United States multicenter, prospective study. Hepa- table outcome given that a scarce organ could have been
tology. 2005;42:1364-1372.) better used. These clinical tensions are reflected in how
prognostic models are used and evaluated with respect to
sensitivity and specificity.
issues that determine outcome is fundamental to the
appropriate delivery of liver transplantation to this
patient population. Analyses of different etiological
cohorts have identified survival rates that range from
PROGNOSTIC MODELS
10% to 90% by category. Spontaneous survival is much
better for patients with FHF associated with acetamino-
General Models
phen, pregnancy, or hepatitis A (>50% to 90%) than The King’s College criteria (KCC) were described in
with seronegative hepatitis, idiosyncratic drug reac- 1989 and were the first to differentiate between acet-
tions, or Wilson’s disease (<10% to 20%). Patients aminophen-induced and other causes of FHF.24 The
under the age of 30 to 40 years and those with the rap- parameters tested were basic clinical and laboratory data
idly evolving variant hyperacute liver failure (interval with the result that the resulting models were considered
from jaundice to encephalopathy within 7 days) also to be simple to use and widely applicable. The nonacet-
have better spontaneous survival rates. aminophen criteria are still used in the United Kingdom
 12 Transplantation for Fulminant Hepatic Failure 155

as originally described. In acetaminophen patients there

TABLE 12-2 Disease-Specific Prognostic
have been a number of modifications to reflect the
Models
improved survival in patients presenting with a severe
acidosis that responded rapidly to aggressive fluid resus- Disease Parameters Utilized
citation and to try to reduce the 17% to 20% of patients
Acetaminophen Serum lactate
who died without fulfilling the definition of a poor prog-
Mushroom poisoning INR, prothrombin time
nosis.25 The KCC were intended for application early in
Hepatitis A ALT, serum creatinine
the disease course and therefore were as independent as
Hepatitis B α-Fetoprotein
possible from clinical parameters of advancing disease
Pregnancy-related Serum lactate
(e.g., grade of encephalopathy). The KCC were also
designed as a dynamic model rather than a one-off evalu- ALT, Alanine aminotransferase; INR, international normalized ratio.
ation; the practice of administering prophylactic frozen
plasma limited their use in this way.
The performance of the KCC has been evaluated in a history of FHF mentioned earlier. One of three studies
number of comparative studies and in two meta-analyses. found that MELD outperformed the KCC in selecting
One involved 18 studies and 1105 patients and yielded an patients for transplantation.30-32 A recently described
overall specificity of 82% and sensitivity of 68%.26 Speci- variation of the MELD theme was to replace bilirubin
ficity increased to 93% in patients with more advanced with a marker of cell injury (cytokeratin 18), which
encephalopathy and to 88% when the criteria were yielded peak sensitivity and specificity indices of 81% and
applied dynamically, as was originally intended. The 82%, respectively, in a series of 68 patients with liver
reduced sensitivity was most apparent in acetaminophen- ­failure of mixed causes.33
induced FHF. The second meta-analysis involving 1960 The most recently described prognostic model called
patients in 14 studies yielded a specificity of 95% and a the Acute Liver Failure Study Group index combines three
sensitivity of 58%, but again the sensitivity was consid- classes of variables: clinical (coma grade), laboratory
ered to have been reduced by nondynamic application.27 (INR, serum bilirubin, phosphorus), and a marker of
The Clichy criteria, which are used mainly in France, apoptosis (M30).34 This was considered to outperform
were also defined in the 1980s, initially for hepatitis both the KCC and MELD in identifying patients most
B–related disease but were subsequently used for other likely to need transplantation, with a sensitivity of 86%,
causes of FHF.28 A feature of these criteria is that they but it also had a specificity of only 65%. The applica-
apply only to patients with at least grade 2 encephalopa- tion of this model will depend on the introduction of
thy, and there is an adjustment of the discriminating factor assays for M30 into routine laboratory testing for
V level determined by an age of 30 years. The common patients with FHF.
ground between the Clichy criteria and the KCC was the
central role of parameters of coagulation and the recogni-
tion that the prognosis of FHF was worse in older patients.
Radiological and Histological Assessment
Other criteria have subsequently been described spe- The role of liver biopsy in the assessment of patients with
cifically for FHF or applied to this condition. One study FHF is controversial. It should be considered in patients
from India identified six parameters—age above 50 years, with apparent FHF who have clinical or radiological evi-
jaundice to encephalopathy time greater than 7 days, dence of hepatomegaly to exclude malignant infiltration
grade 3-4 encephalopathy, cerebral edema, prothrombin of the liver and acute alcoholic hepatitis, which are con-
time greater than 35 seconds, and serum creatinine level traindications to emergency liver transplantation. Spe-
greater than 1.5 mg/dL—with any three of these factors cific diagnoses of autoimmune hepatitis and Wilson’s
indicating a poor prognosis.29 This is a hybrid model that disease may be confirmed by liver histological study, but
combines early indicators of prognosis with specific later institution of conventional therapy for these diseases is
complications that confirm the anticipated poor outcome likely to be too late in patients with encephalopathy.
(i.e., advanced encephalopathy and cerebral edema). It is Assessing the volume of viable hepatocytes may have
likely that future prognostic models will develop this con- prognostic value, with the critical mass suggested as being
cept by becoming more time dependent and specific to the associated with a good prognosis calculated at 25% to
different stages of the evolving disease. A number of dis- 40%, but there is considerable scope for sampling error.
ease-specific prognostic models have also been described, A small liver on clinical or radiological assessment, or
and the parameters used are shown in Table 12-2. more particularly a liver that is found to be shrinking rap-
Model for End-Stage Liver Disease (MELD) scores idly, is a poor prognostic indicator. This feature is espe-
were introduced and validated for use in prognostication cially useful in subacute liver failure when the degree of
in chronic liver disease but have been used in assessing encephalopathy and the severity of the derangement of
prognosis in non–acetaminophen-related FHF. The use coagulation may not be particularly marked. In Japan,
of MELD in this way is not surprising given that the computed tomography scanning has been used to assess
three components of MELD (bilirubin level, interna- both the size of the liver and the functional reserve, and
tional normalized ratio [INR], serum creatinine level) fig- this was useful in determining prognosis. Serial ultrasono-
ure strongly in other prognostic models. However, a graphic assessments of liver size are commonly used to
disadvantage of relying on MELD as the prognostic detect changes in liver size, but the ease with which this can
model of choice is that it does not capture the three very be done has to be weighed against the relatively subjective
important clinical characteristics affecting the natural assessment of liver volume with this technique.
156 PART II Patient Evaluation: Adult

DONORS, GRAFTS, AND WHEN TO TABLE 12-3 C

 linical Situations When
Proceeding to Liver
PROCEED TO TRANSPLANTATION Transplantation May Be Futile
Donor organ allocation systems prioritize patients with • Patients with evidence of compromised brainstem
FHF, and in many systems the majority of patients receive function
transplants within 48 to 72 hours of registration. In the • Patients with confirmed invasive fungal infection
United States the waiting-list mortality was 18.7% for all • Patients with rapidly escalating inotrope or pressor
causes of FHF and 28% for acetaminophen cases.1,4 In requirements
Europe the average donor age was 41 years, and 89.6% of • Patients with severe pancreatitis (usually in acetaminophen-
organs came from brain-dead donors.2 related FHF).
Living related donation is well established in Asia, • Patients who are clinically unstable and the liver allocated
is steatotic, non–ABO identical or split
where deceased-donor donation is limited, but in Europe
just less than 1% of transplants occurred after living FHF, Fulminant hepatic failure.
donation. About 70% of organs were ABO identical, and
about 5% were incompatible.2 Waiting times influence
policy on the use of ABO-mismatched grafts, steatotic antibiotic therapy. However, confirmed systemic fungal
livers, livers from non–heart-beating deceased donors, infection should contraindicate liver transplantation. Ino-
and other suboptimal potential grafts. In Europe the peak trope or pressor requirements are a good surrogate
period for auxiliary transplantation was 1994 to 1998, marker of disease severity, and both absolute levels and
when it accounted for 4% of activity, but this figure has the rate of change in dose often inform the decision about
subsequently fallen to 2%.2 The concept of auxiliary proceeding to surgery once an organ becomes available.
transplantation as a bridge to survival without the need These contraindications to transplantation are age sensi-
for lifelong immunosuppression is exciting, especially for tive, with younger patients being more resilient and more
acetaminophen-related FHF, but enthusiasm for this likely to recover after liver transplantation. Although
approach has remained confined to a few centers. some risk scenarios are outlined (Table 12-3), in most
Some patients deteriorate clinically and become too programs a pragmatic case-by-case evaluation of the risk-
sick to benefit from transplantation. The identification of benefit profile is employed.
these patients is difficult but important in order to mini-
mize wastage of a valuable resource. Insight into some
issues that correlate with outcome has emerged from two POSTOPERATIVE MANAGEMENT
studies: an analysis using the United Network for Organ
Sharing (UNOS) database of 1457 patients and 310 Patients undergoing liver transplantation for FHF stay
patients listed at King’s College Hospital.35,36 These stud- longer in intensive care environments and have higher
ies identified five clinical factors that correlate with out- requirements for renal replacement therapy. Some of the
come: body mass index of greater than 30, serum creatinine clinical challenges in the management of FHF are carried
level of greater than 2 mg/dL, recipient age above 45 to over into this phase of the posttransplant course. Cere-
50 years, the need for inotropes, or the need for life sup- bral edema is a case in point, and continued monitoring
port. Taken in isolation these parameters are not clinically of intracerebral pressure and cerebral perfusion pressure
useful in identifying patients too ill to benefit from liver may be needed for 48 hours after transplantation, or even
transplantation. The parameters performed better when longer when graft function is suboptimal. Infection is
grouped, and in the United States cohort the survival rate another example, and antimicrobial regimens are usually
when none were present was 81% as compared with 42% more complex and for longer duration than after elective
when four were present. The latter outcome was the only transplants. In particular, these patients are among the
survival rate lower than 50% (the commonly accepted high-risk groups for fungal infection and often receive
threshold to justify organ allocation), and this subgroup prophylactic systemic antifungal therapy.
was found in only 2% of the overall population. There- Immunosuppressive strategies balance the higher risk
fore, although these risk stratification studies give some for rejection characteristic of this younger patient popu-
insight, they have not generated practical clinical end lation with the need to recover from infection and renal
points to assist decision making in most individual cases. failure. Recurrence of hepatitis B is a risk, particularly in
Failure of recovery of neurological function after liver patients who were not hepatitis B virus DNA negative at
transplantation was a feared outcome, but this has become the time of transplantation, and consequently most cen-
less common. Nevertheless, objective evidence of brain- ters adopt immunoprophylaxis regimens as used in
stem injury with established fixed and fully dilated pupils patients with chronic hepatitis B infection. In theory a
should preclude liver transplantation. Contrary to some subgroup with de novo hepatitis B infection will have
suggestions, there are no validated cerebral perfusion or cleared the virus by the time of transplantation and should
intracranial pressure thresholds that automatically exclude not require long-term immunoprophylaxis. These are
patients from transplantation. In theory, “active sepsis” recognizable by stable anti–hepatitis B surface antigen
contraindicates liver transplantation, but this is often a (HBsAg) antibody levels as the interval between hepatitis
difficult diagnosis to make or refute. The pragmatic B immunoglobulin levels are gradually extended (usually
approach is not to contraindicate transplantation on the under cover with an antiviral drug, e.g., lamivudine or
basis of bacterial infection after 48 hours of appropriate tenofovir).
 12 Transplantation for Fulminant Hepatic Failure 157

RESULTS 5. Tan KC, Mondragon RS, Vougas V, et al. Liver transplantation for
fulminant hepatic failure and late-onset hepatic failure in children.
Br J Surg. 1992:1192-1194.
The overall 1-year patient survival rate in Europe between 6. Ringe B, Lubbe N, Kuse E, et al. Total hepatectomy and liver
2004 and 2009 was 79%, while the equivalent graft sur- transplantation as two-stage procedure. Ann Surg. 1993;218:3-9.
vival rate was 73%.2 The 1-year patient survival rate in 7. Munoz SJ, Moritz MJ, Martin P, et al. Liver transplantation for
fulminant hepatocellular failure. Trans Proc. 1993;25:1773-1775.
the United States was very similar at 78.6% using 8. Makin AJ, Wendon J. Williams R. A 7-year experience of severe
deceased donors but numerically higher at 87% using liv- paracetamol induced hepatotoxicity (1987-1993). Gastroenterology.
ing donors.1 A notable feature of the extended survival 1995;109:1907-1916.
curves is the slower rate of decline when compared with 9. Rakela J, Perkins JD, Gross JB, et al. Acute hepatic failure: the
emerging role of orthotopic liver transplantation. Mayo Clin Proc.
the other main patient cohorts undergoing liver trans- 1989;64:424-428.
plantation. This presumably reflects younger age and the 10. Brems JJ, Hiatt JR, Ramming KP, et al. Fulminant hepatic failure:
limited scope for recurrence of the original disease. the role of liver transplantation as primary therapy. Am J Surg.
The factors that influence outcome after liver trans- 1987;154:137-141.
plantation are multiple. The cause of the underlying dis- 11. Lidofsky SD. Liver transplantation for fulminant hepatic failure.
Gastroenterol Clin North Am. 1993;22:257-269.
ease did not correlate with outcome in the overall analysis 12. Emond JC, Aran PP, Whitington PF, et al. Liver transplantation in
of the ELTR data, but acetaminophen patients had a the management of fulminant hepatic failure. Gastroenterology.
24% increase in the risk for death. Seronegative hepatitis 1989;96:1583-1588.
or FHF of no definable cause was associated with a higher 13. Peleman RR, Gavaler JS, Van Thiel DH, et al. Orthotopic liver
transplantation for acute and subacute hepatic failure in adults.
risk for primary graft nonfunction or early graft dysfunc- Hepatology. 1987;7:484-489.
tion. Survivors of liver transplantation for acetamino- 14. Vickers C, Neuberger J, Buckels J, et al. Transplantation of the
phen-related FHF received the graft about 2 days sooner liver in adults and children with fulminant hepatic failure. J Hepa-
than those who succumbed (day 4 after drug ingestion tol. 1988;7:143-150.
versus day 6, respectively).8 This may reflect the role of 15. Bismuth MD, Samuel D, Gugenheim J, et al. Emergency liver
transplantation for fulminant hepatitis. Ann Intern Med.
sepsis in propagating the continued deterioration in these 1987;107:337-341.
patients and the inability of liver transplantation to 16. O’Grady JG, Alexander GJM, Thick M, et al. Outcome of ortho-
­positively influence this complication. topic liver transplantation in the aetiological and clinical variants of
acute liver failure. Q J Med. 1988;258:817-824.
17. Devictor D, Desplanques L, Debray D, et al. Emergency liver
transplantation for fulminant liver failure in infants and children.
Pearls and Pitfalls Hepatology. 1992;16:1156-1162.
18. Castells A, Salmeron JM, Navasa M, et al. Liver transplantation for
• Fulminant hepatic failure is not a condition but rather acute liver failure: analysis of applicability. Gastroenterology.
an umbrella term for a collection of variable clinical 1993;105:532-538.
scenarios and outcomes. 19. Gallinger S, Greig PD, Levy G, et al. Liver Chapman, R W, For-
• The “sickest” patients with defined causes and hyper- man, D, Peto, R, Smallwood, R Liver transplantation for acute
hepatic failure? Lancet. 1990;335:32-35.
acute patterns of disease have the highest spontaneous
20. Iwatsuki S, Stieber AC, Marsh JW, et al. Liver transplantation for
recovery rates. fulminant hepatic failure. Transplant Proc. 1989;21:2431-2434.
• Patients with the less dramatic clinical syndrome of 21. O’Grady JG, Wendon J, Tan KC, et al. Liver transplantation after
subacute liver failure and indeterminate cause are least paracetamol overdose. BMJ. 1991;303:221-223.
likely to survive without liver transplantation. 22. Ascher NL, Lake JR, Emond JC, Roberts JP. Liver transplantation
• The ideal prognostic model delivering high sensitivity for fulminant hepatic failure. Arch Surg. 1993;128:677-682.
and specificity levels has not yet been described. 23. Chapman RW, Forman D, Peto R, Smallwood R. Liver transplan-
• The use of prognostic models that are strong on speci- tation for acute hepatic failure? Lancet. 1990;335:32-35.
ficity may result in avoidable deaths. 24. O’Grady JG, Alexander GJ, Hallyar KM, Williams R. Early indica-
tors of prognosis in fulminant hepatic failure. Gastroenterology.
• The use of prognostic models that are strong on sensi-
1989;97:439-445.
tivity may result in unnecessary transplantation. 25. Neuberger J, Gimson A, Davies M, et al. Selection of patients for
• The type and quality of donor organ used do affect the liver transplantation and allocation of donated livers in the UK. Gut.
outcome. 2008;57:252-257.
• The survival rates are not yet as good as for elective 26. McPhail MJW, Wendon JA, Bernal W. Meta-analysis of perfor-
liver transplantation, but the clinically relevant indica- mance of King’s College Hospital Criteria in prediction of out-
   tors of futility have not yet been defined. come in non-paracetamol-induced acute liver failure. J Hepatol.
2010;53:492-499.
27. Craig DGN, Ford AC, Hayes PC, Simpson KJ. Systematic review:
prognostic tests of paracetamol-induced acute liver failure. Aliment
Pharmacol Ther. 2010;31:1064-1076.
REFERENCES 28. Bernuau J, Gordeau A, Poynard T, et al. Multivariate analysis of
1. Freeman BR, Steffick DE, Guidinger MK, et al. Liver and intestine prognostic factors in fulminant hepatitis B. Hepatology.
transplantation in the United States, 1997-2006. Am J Transplant. 1986;6:648-651.
2008:958-976. 29. Dhiman R, Jain S, Maheswari U, et al. Early indicators of progno-
2. Germani G, Theocharidou E, Adam R, et al. Liver transplantation sis in fulminant hepatic failure: an assessment of the MELD and
for acute liver failure in Europe: outcomes over 20 years from the King’s College hospital criteria. Liver Transpl. 2007;13:
ELTR database. J Hepatol. 2012;57:288-296. 814-821.
3. Bernal W, Hyyrylainen A, Gera A, et al. Lessons from look-back in 30. Yantorno SE, Kremers WK, Ruf AE, et al. MELD is superior to
acute liver failure? A single centre experience of 3,300 patients. King’s College and Clichy’s criteria to assess prognosis in fulmi-
J Hepatol. 2013;59:74-80. nant hepatic failure. Liver Transpl. 2007;13:822-828.
4. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced 31. Schmidt LE, Larsen FS. MELD score as a predictor of liver failure
acute liver failure: results of a United States multicenter, prospec- and death in patients with paracetamol-induced liver injury. Hepa-
tive study. Hepatology. 2005;42:1364-1372. tology. 2007;45:789-796.
158 PART II Patient Evaluation: Adult

32. Zaman MB, Hoti E, Qasim A, et al. MELD score as a prognostic 35. Barshes NR, Lee TC, Balkrishnan R, et al. Risk stratification of
model for listing acute liver failure patients for liver transplanta- adult patients undergoing orthotopic liver transplantation for ful-
tion. Transplant Proc. 2006;38:2097-2098. minant hepatic failure. Transplantation. 2006;81:195-201.
33. Bechmann LP, Jochum C, Kocabayoglu P, et al. Cytokeratin 36. Bernal W, Cross JS, Auzinger G, et al. Outcome after wait-listing
18-based modification of the MELD score improves prediction of for emergency liver transplantation in acute liver failure: a single
spontaneous survival after acute liver injury. J Hepatol. centre experience. J Hepatol. 2009;50:306-313.
2010;53:639-647.
34. Rutherford A, King LY, Hynan LS, et al. Development of an accu-
rate index for predicting outcomes of patients with acute liver fail-
ure. Gastroenterology. 2012;143:1237-1243.
 CHAPTER 13

Transplantation for
Primary Biliary Cirrhosis
Mohamad H. Imam • Jayant A. Talwalkar

CHAPTER OUTLINE

EPIDEMIOLOGY AND ETIOLOGY Living Donor Liver Transplantation

Health-Related Quality of Life Following
CLINICAL FEATURES
Liver Transplantation for Primary Biliary
Diagnosis Cirrhosis
Presymptomatic Disease MELD Scores in Patients with Primary Biliary
Symptomatic Disease Cirrhosis
Extrahepatic Autoimmune Diseases
POSTTRANSPLANT ISSUES IN PRIMARY
Disease-Related Complications BILIARY CIRRHOSIS
Natural History and Prognosis Recurrent Primary Biliary Cirrhosis After Liver
Medical Treatment of Primary Biliary Transplantation
Cirrhosis Metabolic Bone Disease After Liver
Liver Transplantation Transplantation for Primary Biliary Cirrhosis
Outcomes of Liver Transplantation for
Primary Biliary Cirrhosis CONCLUSION

Primary biliary cirrhosis (PBC) is a chronic cholestatic and 1995 was 2.7 cases per 100,000 person-years, whereas
liver disease of unknown etiology characterized by lym- in women the incidence was 4.5 per 100,000 person-years
phocytic cholangitis and segmental destruction of intra- as compared to 0.7 per 100,000 person-years in men.12
lobular bile ducts within the liver. Patients with PBC may Similar data have emerged from European studies as well.
progress gradually to cirrhosis, liver failure, and ulti- These data suggest that an estimated 3500 new cases of
mately death or liver transplantation (LT). Survival free PBC may exist within the United States each year. In addi-
of liver transplantation can be prolonged by ursodeoxy- tion, a recent systematic review suggests that prevalence
cholic acid (UDCA) in the majority of patients receiving rates of PBC are increasing with time.13
therapy. However, in patients not responding to UDCA Case-control epidemiological studies have also identi-
therapy the need for LT is more likely. Furthermore, LT fied several risk factors associated with PBC, including
not only prolongs survival in patients with PBC but also cigarette smoking, family history of PBC, tonsillectomy,
helps improve health-related quality of life. Although dis- prior urinary tract infections, and a previous history of
ease recurrence in the transplanted liver may occur, the obstetric cholestasis.14,15
data showing a significant clinical burden from recurrent Current evidence suggests that PBC develops from an
PBC are lacking to date. immune-mediated pathogenetic process. This hypothe-
sis is supported by the presence of serum antimitochon-
drial antibodies (AMAs) in patients with PBC.16-19 The
EPIDEMIOLOGY AND ETIOLOGY E2 subunit of the pyruvate dehydrogenase complex is
targeted by AMAs in most patients with PBC.20 How-
PBC is not limited to a certain geographical distribution or ever, it remains unclear how detectable immunological
a specific race. European studies have estimated the inci- abnormalities are responsible for the histological changes
dence rate of PBC at 0.33 to 5.8 cases per 100,000 person- that occur with PBC.
years with prevalence rates varying from 0.5 to 39 cases per Cross-reactivity between self and microbial antigens,
100,000 person-years.1-11 Conversely, population-based also referred to as molecular mimicry, has also been pro-
studies on the epidemiology of PBC remain scarce world- posed as a pathogenetic mechanism for PBC. The associa-
wide. In Olmsted County, Minnesota, the overall inci- tion between PBC and recurrent urinary tract infections is
dence (adjusted for age and gender) of PBC between 1975 supportive of this hypothesis. T-cell clones from PBC

159
160 PART II Patient Evaluation: Adult

patients can be activated by Escherichia coli peptides that PBC include antinuclear antibodies, anti–smooth muscle
are analogous to the pyruvate dehydrogenase complex E2 antibodies, and anticentromere antibodies.
subunit.21 Helicobacter pylori and Chlamydia may also make Typical features of PBC on liver histological exami-
a similar contribution to disease pathogenesis.22 This con- nation include lymphocytic cholangitis, portal tract
cept remains a theory that requires further study and edema, and in rare cases ductopenia. The presence of
confirmation. granulomatous cholangitis (also termed the florid duct
Several environmental triggers may also be involved in lesion) is pathognomonic for stage 1 PBC.35Although
the pathogenesis of PBC. This is further supported by liver biopsy is not required for diagnosis in most patients,
many epidemiological studies showing clustering of the it does provide information on disease stage. The Batts-
disease on genetic and geographical basis. In New York, Ludwig staging system is most commonly used for
PBC cases were found to occur increasingly around toxic PBC.36 Recent advances, including elastography imag-
waste disposal sites.23 In England the majority of PBC ing, can also provide information on disease stage and
cases in Sheffield shared a water reservoir,24 whereas an prognosis in PBC.37
increase in PBC cases was attributed to former coal mining
activities within the region adjacent to Newcastle.10,14,25,26
Hence it is plausible to consider that environmental fac-
Presymptomatic Disease
tors, whether infectious, toxic, or chemical, may play a role Isolated elevations of serum alkaline phosphatase level in
in disease pathogenesis. the absence of symptoms are the most common presenta-
Recent work has also further elucidated the genetic tion in patients with PBC. Recent studies with prolonged
predisposition for developing PBC. Screening asymp- follow-up of PBC patients have shown that when symp-
tomatic family members of PBC patients using serum toms develop in patients with asymptomatic disease, the
AMA has demonstrated a 2% to 4% rate of seropositivity, course of the disease becomes similar to patients who are
with daughters of PBC patients having 60 times the risk symptomatic at baseline.9,38 This contradicts findings of
for developing PBC as compared to unrelated con- earlier studies that showed improved outcomes in asymp-
trols.27-29 Furthermore, the concordance rate of PBC in tomatic patients.2 The results of early studies may be
identical twins is among the highest reported for any attributed to lead-time bias, in which the diagnosis was
autoimmune disease.30 Initial studies, including candidate made relatively early in asymptomatic patients as com-
and genome-wide association studies, among patients pared to patients with symptoms. This is also reasonable
with PBC and controls have identified a number of single because of the natural history of the disease, whereby
nucleotide polymorphisms that could have functional presymptomatic patients usually develop symptoms after
associations with molecular pathways associated with 2 to 4 years of follow-up.
PBC development.31
Symptomatic Disease
The relative frequency of symptoms and signs at presen-
CLINICAL FEATURES tation is given in Table 13-1. Fatigue is the most com-
Diagnosis mon symptom reported, and its frequency may be as high
as 70%. Alterations in central neurotransmitters and
The diagnosis of PBC requires meeting at least two of the release of corticotropin hormone are hypothesized to
following three criteria: (1) a cholestatic serum liver bio- play a role in the development of fatigue in PBC patients.39
chemistry profile for a minimum of 6 months, (2) serum Sleep disturbances resulting from itching or other causes,
AMA positivity, and (3) liver histological examination including depression, may also influence fatigue.
results consistent or compatible with features associated Pruritus occurs in 30% to 50% of subjects and is most
with PBC. The majority of patients typically meet the often a presenting symptom before diagnosis. Pruritus in
first two criteria, and liver biopsy when performed dem- PBC has several proposed mechanisms, including endog-
onstrates nonsuppurative inflammation of the bile ducts. enous opioids and serum bile acid levels.40,41 The severity
Elevation of serum alkaline phosphatase level is the of pruritus often increases at nighttime and is unrelated to
biochemical hallmark of PBC. Serum alanine amino-
transferase and aspartate aminotransferase levels are usu-
ally elevated as well, but at levels that are less than five TABLE 13-1 P
 resenting Signs and Symptoms
times the upper limit of normal. Conversely, serum bili- in Primary Biliary Cirrhosis
rubin levels are normal at diagnosis but often rise once
cirrhosis develops. Feature Prevalence (%)
Serum AMA positivity occurs in 90% to 95% of patients No symptoms 40
with PBC. In the absence of a cholestatic liver biochemistry Fatigue 70
profile, serum AMA positivity can also be seen in patients Pruritus 30-50
with autoimmune hepatitis and less commonly in primary Hepatomegaly 25
sclerosing cholangitis. The presence of clinical features Hyperpigmentation 25
without AMA positivity is referred to as AMA-negative Splenomegaly 15
PBC.32-34 Limited data suggest that the natural history and Jaundice 10
treatment response for AMA-negative PBC is similar to Xanthelasma 10
classic PBC. Other serum autoantibodies in patients with
 13 Transplantation for Primary Biliary Cirrhosis 161

histological stage of the disease. Notably, it appears that

the pruritus severity resolves as the disease progresses.42
Natural History and Prognosis
Late-stage disease characterized by jaundice is uncom- Historically the clinical course for PBC resulted in the
mon at initial presentation. As the disease advances, com- development of cirrhosis and liver failure in the absence
plications related to portal hypertension such as variceal of effective medical therapy. The median survival in
bleeding, ascites, and hepatic encephalopathy may occur. patients with early-stage disease (stage 1 to 2) was 10 to
15 years from the time of diagnosis as compared to 8
Extrahepatic Autoimmune Diseases years for patients with late-stage disease (stage 3 to 4).63
Further reductions in median survival at 2 years from
Autoimmune diseases occurring outside the liver are com- diagnosis were observed for patients with serum total
mon in 70% of patients with PBC.43 Keratoconjunctivitis bilirubin levels above 8 mg/dL at diagnosis.63
sicca may occur in 75% of patients and constitutes dry eyes Several mathematical models have been developed to
and xerostomia from secondary Sjögren’s syndrome.44,45 estimate the projected survival in PBC.64 The most vali-
Other disorders include arthritis in 10% to 40%, thyroid dated prognostic model is the Mayo PBC risk score,65-67
disease (mainly Hashimoto’s thyroiditis) in 15% to 20%, which has been useful for predicting survival and timing
and scleroderma or CREST (calcinosis cutis, Raynaud’s for LT among groups of individuals at varying stages
phenomenon, esophageal dysfunction, sclerodactyly, and of PBC.
telangiectasia) syndrome in 10% of patients.46-48
Medical Treatment of Primary
Disease-Related Complications Biliary Cirrhosis
Metabolic bone disease is an important complication in UDCA is the only drug therapy approved by the U.S.
patients with PBC that can lead to increased morbidity Food and Drug Administration for the treatment of PBC.
and decreased quality of life.49 This occurs because of In addition to improving liver biochemistry profiles,
reduced bone mass rather than defective bone mineral- UDCA has been shown to improve survival free of LT in
ization (osteomalacia).50 Cholestasis in addition to female patients with PBC.68-73 UDCA also reduces the risk for
sex (related by PBC) and lower weight and height are risk developing esophageal varices and cirrhosis.74 Several
factors for osteoporosis.51 Furthermore, it has been mechanisms of action have been associated with UDCA,
recently shown that the severity of liver disease may affect including apoptosis inhibition, improving mitochondrial
the risk for osteoporosis in patients with PBC.52 Standard dysfunction through replacing endogenous hydrophobic
definitions for osteopenia (T score between −1 and −2.5 bile salts, decreased cytokine production, and cell mem-
on dual-energy x-ray absorptiometry [DEXA] scanning) brane stabilization.75,76
and osteoporosis (T score <−2.5) are used for assessing Normalization of serum liver test results occurs in an
bone disease in PBC. Available therapies, including cal- estimated 30% of patients with PBC. An additional 30%
cium, vitamin D, and bisphosphonates, are also used in to 40% of subjects have near normalization of serum
subjects with PBC.53 liver biochemistry profiles. Thus an estimated 30% of
Hypercholesterolemia and hyperlipidemia can be patients are incomplete responders to UDCA. It should
found in 85% of patients with PBC.54 Early-stage dis- be noted that biochemical responses can be preserved for
ease commonly involves lipoprotein abnormalities, with up to 15 years in patients with biochemically nonad-
elevated levels of high-density lipoproteins rather than vanced PBC.77
low-density lipoproteins.54 Conversely, as the disease Several observational cohort studies have determined
progresses, this ratio may reverse. Despite the signifi- that patients with early-stage PBC who are complete
cant abnormalities in lipid profiles, there has been no responders to UDCA have a prognosis similar to that of
published evidence suggesting an increased occurrence the general population. Improved prognosis may also
of atherosclerotic disease in PBC.54,55 However, the use occur in patients with late-stage PBC who respond to
of pharmacological therapies, including statins, may be UDCA as compared to incomplete responders or
advised in patients with other risk factors for coronary untreated patients.78 In turn, the frequency of LT for
artery disease. PBC has declined in recent years following the availabil-
Abnormalities in bile acid delivery and inadequate ity of UDCA therapy.79
micellar concentrations in the small intestine lead to ste- Several other therapeutic options have been assessed
atorrhea and malabsorption of fat-soluble vitamins in for incomplete responders to UDCA. Agents such as cor-
some patients with PBC.56,57 Steatorrhea in PBC can be ticosteroids, immunosuppressants, antifibrotic agents, and
further attributed to the coexistence of celiac disease, colchicine alone or in combination with UDCA have not
exocrine pancreatic insufficiency, and bacterial over- shown clinical efficacy. Recent data suggest that the novel
growth (especially in patients with scleroderma).57 bile acid obeticholic acid may have efficacy in subjects
Hepatocellular carcinoma also develops in patients with with incomplete responses to UDCA, but further studies
cirrhosis from PBC.58-60 Hepatocellular carcinoma sur- are required.
veillance with abdominal ultrasonography and determina-
tion of serum α-fetoprotein levels every 6 to 12 months is
advised. Furthermore, an increased risk for extrahepatic
Liver Transplantation
cancers such as breast and pancreatic cancers remains a PBC remains one of the most common indications for
matter of controversy.58,61,62 LT in the United States.80 Traditional indications for LT
162 PART II Patient Evaluation: Adult

in PBC include hepatic encephalopathy, refractory asci- probability of favorable and poor outcomes following LT
tes, spontaneous bacterial peritonitis, and hepatorenal in patients with PBC. However, it is important to realize
syndrome resulting from portal hypertension. Disabling that variations in natural history among individual
fatigue and intractable pruritus are also indications for patients not captured by risk models may be stronger pre-
LT in PBC. However, these indications are more com- dictors of timing of LT and eventual outcomes.81,86 The
monly addressed with living donor LT (LDLT), given effect of pretransplant disease severity on short-term out-
the disparity in available deceased donor livers compared comes probably reflects existing multisystem organ dys-
to the number of patients on the waiting list. function that increases the risk for mortality and
morbidity perioperatively.87-90
Outcomes of Liver Transplantation for
Primary Biliary Cirrhosis Living Donor Liver Transplantation
An initial report by Markus et al81described the effective- The first LDLT operation was performed in 1989 on a
ness of LT in improving outcomes by comparing actual 2-year-old girl who received a portion of her mother’s
patient survival to expected survival (using the Mayo nat- liver at the University of Chicago Medical Center. This
ural history model) following LT in 161 patients with was followed by a published study in 1989 of 56 children
PBC between 1980 and 1987. The median duration of from 1 month to 13 years of age receiving LDLT and
follow-up was 25 months, after which transplanted showing excellent patient survival (89% at 2 years).91
patients were found to have significantly better (P < .01) Since then a number of centers have developed expertise
2-year survival (74%) as compared to nontransplanted in LDLT for adult patients with end-stage liver disease,
patients (31%). including PBC. To date, excellent outcomes in patients
In a subsequent report published in 1998, 143 PBC with PBC receiving LDLT have been reported. For
patients who underwent LT between 1987 and 1994 at example, among 81 PBC patients receiving LDLT fol-
Mayo Clinic and Baylor University Medical Center were lowed for a mean of 6.2 years, a 5-year survival rate of
followed up for a median period of 36 months.82 Actual 80% was observed.92,93 An analysis of the United Net-
survival of patients from the 1980s and 1990s following work for Organ Sharing (UNOS) database aimed at com-
liver transplant as compared to survival predicted by natu- paring outcomes in cholestatic patients receiving living
ral history was compared. Results were noted for an donor and deceased donor livers concluded that following
improved survival in patients undergoing LT in the 1990s, adjustment for the Model for End-Stage Liver Disease
where at 1 year and 3 years 93% and 88%, respectively, (MELD) score and age, the donor type is not significant
survived as compared to 75% and 72% for the patients in determining outcomes.94 Persistent ascites before
transplanted in the 1980s. This could be attributed to the LDLT, mismatch between donor and recipient in terms
shorter time to transplantation because the group from of human leukocyte antigen (HLA)-A, HLA-B, and HLA-
the 1990s had better predicted survival even before LT. DR, and old age (>50 years) of the donor were identified in
Interestingly, patients from the 1980s had a larger gain in a multivariate analysis of 50 PBC patients undergoing
survival following LT as compared to patients from the LDLT as factors significantly associated with early death
1990s. Another study of 400 PBC patients transplanted following liver transplant.95 Patients with PBC may need
between 1983 and 1999 and followed up for a mean of 56 prolonged steroid therapy following LT, and steroid
months also showed that LT is a successful treatment for withdrawal may pose a challenge to patient management.
patients with advanced PBC; patients undergoing LT had It is worth noting that LDLT was associated with higher
1-, 5- and 10-year survival rates of 83%, 78%, and 67%, success in corticosteroid withdrawal after transplant in a
respectively.83 Excellent long-term outcomes have also study of 1032 liver transplants in patients with PBC.96
been shown in PBC patients undergoing LT at Mayo With LDLT the majority of donors are often geneti-
Clinic with an actuarial overall patient survival at 1, 5, 10, cally related to the transplant recipient, which has raised
15, and 20 years of 93%, 90%, 79%, 66%, and 49%, questions about the possibility of disease recurrence. In
respectively.84 2001 the first report of recurrent disease in PBC patients
Pretransplant disease severity appears to have a direct receiving LDLT was published by Hashimoto et al.97
effect on survival following LT for PBC. Patients with Recurrence of PBC following LDLT can develop in a
higher Mayo PBC risk scores (>7.8) from both studies significant number of patients; however, this recurrence
demonstrated a tendency for worse outcomes regardless has not been shown to affect the quality of life or the need
of the era of transplantation. Furthermore, patients who for hepatic retransplantation.98 It has been shown that
are malnourished and chronically ill in the preoperative patients with PBC, unlike those with primary sclerosing
period were less likely to experience favorable short-term cholangitis (PSC), do not suffer adverse outcomes related
outcomes after LT.81 Neuberger et al85 also reported that to disease recurrence associated with blood relative
patients with an increased risk for poor outcomes after donors. In a study of 50 patients with PBC and 28 patients
LT (predicted survival of <4 months and median serum with PSC undergoing LDLT between 1994 and 2004,
bilirubin level of 27.3 mg/dL) have lower survival rates the recurrence rate 1 year after transplant was 29% in
(50%) after transplant as compared to survival rates patients with PBC and 59% in those with PSC. An
(78%) in lower-risk patients (i.e., predicted survival of >9 increase in adverse outcomes such as death, graft failure,
months and median serum bilirubin level of 4.9 mg/dL). cirrhosis, and retransplantation was seen with recurrent
The available data suggest that natural history mod- PSC, whereas in the patients having recurrent PBC such
els such as the Mayo PBC risk score can predict the outcomes did not develop in any of the patients.99
 13 Transplantation for Primary Biliary Cirrhosis 163

Health-Related Quality of Life Following The clinical and biochemical features seen in de novo
Liver Transplantation for Primary Biliary PBC are not usually present with the development of
recurrent PBC.110 For example, a number of cases have
Cirrhosis been diagnosed on protocol liver biopsies when serum
The NIDDK-QA form is a reliable and valid instrument liver biochemistry profiles were within normal limits.
for assessing the quality of life in patients with PBC.100 Furthermore, serum AMA levels may fluctuate between
This involves four areas: liver symptoms, physical func- positive and negative in patients with or without recur-
tioning, health satisfaction, and overall wellbeing. Intui- rent PBC. Thus the identification of histological features,
tively, an increase in disease severity will lead to a worsened including granulomatous cholangitis, is crucial to helping
quality of life. This, however, can be recovered by insti- diagnose recurrence after LT.111
tuting LT. The NIDDK-QA questionnaire was com- Several investigations to date have identified risk fac-
pleted by 157 adult patients with cholestatic liver disease, tors for recurrent PBC after LT. These include donor
including PBC, before and 1 year after LT. Results were age, HLA profile, and the use of tacrolimus as immuno-
noted for significantly improved health-related quality of suppressive therapy.82-84,112,113 Although cyclosporine and
life ratings after LT compared to scores recorded before tacrolimus are associated with the development of recur-
LT. Improvements were noted in symptoms, function, rent PBC, the time to developing recurrent disease is sig-
health satisfaction, and overall quality of life. Further- nificantly shorter with tacrolimus than with
more, the health-related quality of life at 1 year after LT cyclosporine.96,98,100 Withdrawal of azathioprine or corti-
was not associated with pre-LT clinical factors.100,101 costeroids is not convincingly associated with an increased
chance of recurrent PBC. Notably, the presence or
MELD Scores in Patients with Primary absence of acute cellular rejection and pre-LT UDCA use
do not influence the probability of recurrent PBC.98
Biliary Cirrhosis Little is known regarding the optimal management of
The MELD score was adopted in February 2002 by recurrent PBC after LT. There is no evidence that the
UNOS to guide organ allocation policies.102,103 The exclusive use of cyclosporine will reduce the risk for
MELD score involves three readily available laboratory recurrent disease. Similarly, the continuation of cortico-
values: serum total bilirubin, creatinine, and international steroids for long-term immunosuppressive management
normalized ratio (INR). The original MELD score was is unproven. Few studies have examined the role of
based on a predictive survival model described for patients UDCA therapy for recurrent PBC. In a recent study
receiving transjugular intrahepatic portosystemic shunt.104 from the Mayo Clinic, the normalization of liver enzyme
In this cohort the MELD score was associated with a very levels after UDCA therapy occurred in 52% of patients
high discriminative value of 0.87 (95% confidence interval with recurrent PBC as compared to 22% among
[CI], 0.71-1.00) for mortality at 3 months that remained at untreated patients.98 However, there was no significant
the same (0.87) value when assessing 1-year mortality. difference in histological progression, need for retrans-
Subsequent analysis demonstrated that the MELD score plantation, and death. These results should be inter-
was equivalent to the Mayo PBC risk score for predicting preted with caution because therapy was not allocated by
survival in PBC patients. randomization.
It should be noted that the original MELD study rec- Although recurrent PBC is uncommon, it does not
ognized that patients with cholestatic liver disease had appear to create an extensive burden in terms of hepatic
improved predicted survival as compared to other types of retransplantation to date. From a retrospective study on
liver disease. However, the influence of liver disease cause the rates and causes of graft loss in 1840 consecutive
on MELD score was eliminated from the model when adults receiving a primary liver transplant between 1982
UNOS implementation was undertaken.105,106 With over and 2004, patients undergoing LT for PBC had only a
a decade of experience using the MELD score for LT, 5% risk for graft loss.114
there are questions about PBC having a disadvantage in
terms of waiting list time as compared to non–cholestatic
liver disease. Although this has been demonstrated for Metabolic Bone Disease After Liver
PSC,107 there are no specific data examining this issue Transplantation for Primary Biliary
with respect to PBC to date. Cirrhosis
In the postoperative period following LT, bone mineral
POSTTRANSPLANT ISSUES IN PRIMARY density may decline by as much as 20%, resulting in an
BILIARY CIRRHOSIS increased risk for peripheral and vertebral bone fractures.115
Moreover, patients with PBC are predisposed to bone frac-
Recurrent Primary Biliary Cirrhosis tures following LT because of the high prevalence of
osteopenia and osteoporosis before LT.116
After Liver Transplantation The management of bone disease after LT is consis-
Recurrent disease after LT may occur in patients with an tent with strategies used in the pre-LT setting. Adequate
initial diagnosis of PBC. The first case of recurrent PBC calcium intake (1000 to 1200 mg daily) with oral vitamin D
was described by Neuberger et al108 in 1982, and recent supplementation when deficiency is present are the cor-
studies estimate the cumulative incidence of recurrent nerstones of therapy. Weight-bearing exercises may be
PBC at approximately 20% to 25% at 10 years.109 helpful as an adjunctive measure.117 Little data exist
164 PART II Patient Evaluation: Adult

regarding the use of hormone replacement therapy after 7. Boberg KM, Aadland E, Jahnsen J, et al. Incidence and prevalence
LT, and the emergence of other nonhormonal therapies of primary biliary cirrhosis, primary sclerosing cholangitis, and
autoimmune hepatitis in a Norwegian population. Scand J Gastro-
has rendered this option less common.118 The estrogen enterol. 1998;33:99-103.
analogue raloxifene has a minimal side effect profile and 8. Eriksson S, Lindgren S. The prevalence and clinical spectrum of
may be used following LT. Oral and intravenous primary biliary cirrhosis in a defined population. Scand J Gastroen-
bisphosphonates (risedronate, alendronate, etidronate) terol. 1984;19:971-976.
9. Metcalf JV, Bhopal RS, Gray J, et al. Incidence and prevalence of
have been safely used after LT and may be as efficacious primary biliary cirrhosis in the city of Newcastle upon Tyne, Eng-
when used in the non-LT setting.119 Conversely, the land. Int J Epidemiol. 1997;26:830-836.
role of calcitonin remains unclear, and its use is not 10. James OF, Bhopal R, Howel D, et al. Primary biliary cirrhosis
recommended.120 once rare, now common in the United Kingdom? Hepatology.
1999;30:390-394.
11. Baldursdottir TR, Bergmann OM, Jonasson JG, et al. The epide-
miology and natural history of primary biliary cirrhosis: a nation-
CONCLUSION wide population-based study. Eur J Gastroenterol Hepatol.
2012;24:824-830.
LT is a valuable therapeutic advance in the management 12. Kim WR, Lindor KD, Locke 3rd GR, et al. Epidemiology and
natural history of primary biliary cirrhosis in a US community.
of patients suffering from PBC. Despite the effectiveness Gastroenterology. 2000;119:1631-1636.
of UDCA therapy in reducing disease progression, there 13. Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary
will still be patients with PBC who require LT for pro- sclerosing cholangitis and primary biliary cirrhosis: a systematic
gressive disease. The significance of LT in improving review. J Hepatol. 2012;56:1181-1188.
survival is reflected through mathematical models that 14. Prince MI, Ducker SJ, James OF. Case-control studies of risk fac-
tors for primary biliary cirrhosis in two United Kingdom popula-
have reliably predicted patient outcomes. Patients with tions. Gut. 2010;59:508-512.
PBC may benefit from LDLT as well, and it is expected 15. Parikh-Patel A, Gold EB, Worman H, et al. Risk factors for pri-
that further studies will be done examining the long-term mary biliary cirrhosis in a cohort of patients from the United
outcome of LDLT for PBC. States. Hepatology. 2001;33:16-21.
16. Van de Water J, Ansari AA, Surh CD, et al. Evidence for the tar-
geting by 2-oxo-dehydrogenase enzymes in the T cell response of
primary biliary cirrhosis. J Immunol. 1991;146:89-94.
Pearls and Pitfalls 17. Leung PS, Chuang DT, Wynn RM, et al. Autoantibodies to
BCOADC-E2 in patients with primary biliary cirrhosis recognize
•  Primary biliary cirrhosis (PBC) should be considered a conformational epitope. Hepatology. 1995;22:505-513.
as a diagnosis when patients have the following clinical 18. Maeda T, Loveland BE, Rowley MJ, Mackay IR. Autoantibody
features: against dihydrolipoamide dehydrogenase, the E3 subunit of the
• Positive serum antimitochondrial antibodies 2-oxoacid dehydrogenase complexes: significance for primary
• Liver serum test results reflecting cholestasis biliary cirrhosis. Hepatology. 1991;14:994-999.
19. Mori T, Ohira H, Kuroda M, et al. Characterization of autoan-
• Compatible liver histological features
tibodies against the E1alpha subunit of branched-chain 2-oxo-
• Therapy with low doses of ursodeoxycholic acid (UDCA; acid dehydrogenase in patients with primary biliary cirrhosis.
13 to 15 mg/kg/day) for a minimum period of 6 months Int J Hepatol. 2012;2012:369-740.
is recommended to achieve a reduction in serum alkaline 20. Gershwin ME, Rowley M, Davis PA, et al. Molecular biology of
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­upper limit of normal. antibodies. Prog Liver Dis. 1992;10:47-61.
• The Model for End-Stage Liver Disease (MELD) score 21. Shigematsu H, Shimoda S, Nakamura M, et al. Fine specificity of
is used for prioritizing PBC patients for deceased donor T cells reactive to human PDC-E2 163-176 peptide, the immuno-
liver transplant. dominant autoantigen in primary biliary cirrhosis: implications
for molecular mimicry and cross-recognition among mitochon-
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drial autoantigens. Hepatology. 2000;32:901-909.
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90. Doyle HR, Marino IR, Jabbour N, et al. Early death or retrans- 109. Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cir-
plantation in adults after orthotopic liver transplantation. Can rhosis. Hepatology. 2009;50:291-308.
outcome be predicted? Transplantation. 1994;57:1028-1036. 110. Silveira MG, Talwalkar JA, Lindor KD, Wiesner RH. Recurrent
91. Piper JB, Whitington PF, Woodle ES, et al. Living related liver primary biliary cirrhosis after liver transplantation. Am J Trans-
transplantation in children: a report of the first 58 recipients at the plant. 2010;10:720-726.
University of Chicago. Transpl Int. 1994;7(suppl 1):S111-113. 111. Neuberger J. Recurrent primary biliary cirrhosis. Liver Transpl.
92. Kaneko J, Sugawara Y, Tamura S, et al. Long-term outcome of liv- 2003;9:539-546.
ing donor liver transplantation for primary biliary cirrhosis. Transpl 112. Neuberger J. Recurrent primary biliary cirrhosis. Liver Transpl.
Int. 2012;25:7-12. 2001;7:596-599.
93. Fournier V, Foureur N, Rari E. The ethics of living donation for 113. Neuberger J, Gunson B, Hubscher S, Nightingale P. Immuno-
liver transplant: beyond donor autonomy. Med Health Care Philos. suppression affects the rate of recurrent primary biliary cirrhosis
2012. after liver transplantation. Liver Transpl. 2004;10:488-491.
94. Kashyap R, Safadjou S, Chen R, et al. Living donor and deceased 114. Rowe IA, Webb K, Gunson BK, et al. The impact of disease recur-
donor liver transplantation for autoimmune and cholestatic liver rence on graft survival following liver transplantation: a single
diseases–an analysis of the UNOS database. J Gastrointest Surg. centre experience. Transpl Int. 2008;21:459-465.
2010;14:1362-1369. 115. Eastell R, Dickson ER, Hodgson SF, et al. Rates of vertebral bone
95. Morioka D, Egawa H, Kasahara M, et al. Impact of human leuko- loss before and after liver transplantation in women with primary
cyte antigen mismatching on outcomes of living donor liver trans- biliary cirrhosis. Hepatology. 1991;14:296-300.
plantation for primary biliary cirrhosis. Liver Transpl. 116. Newton J, Francis R, Prince M, et al. Osteoporosis in primary
2007;13:80-90. biliary cirrhosis revisited. Gut. 2001;49:282-287.
96. Campsen J, Zimmerman M, Trotter J, et al. Liver transplantation 117. Neuhaus R, Kubo A, Lohmann R, et al. Calcitriol in prevention
for primary biliary cirrhosis: results of aggressive corticosteroid and therapy of osteoporosis after liver transplantation. Trans-
withdrawal. Transplant Proc. 2009;41:1707-1712. plant Proc. 1999;31:472-473.
97. Hashimoto E, Shimada M, Noguchi S, et al. Disease recurrence 118. Crippin JS, Jorgensen RA, Dickson ER, Lindor KD. Hepatic
after living liver transplantation for primary biliary cirrhosis: a osteodystrophy in primary biliary cirrhosis: effects of medical
clinical and histological follow-up study. Liver Transpl. treatment. Am J Gastroenterol. 1994;89:47-50.
2001;7:588-595. 119. Riemens SC, Oostdijk A, van Doormaal JJ, et al. Bone loss after liver
98. Hashimoto E, Taniai M, Yatsuji S, et al. Long-term clinical out- transplantation is not prevented by cyclical etidronate, calcium and
come of living-donor liver transplantation for primary biliary cir- alphacalcidol. The Liver Transplant Group, Groningen. Osteoporos
rhosis. Hepatol Res. 2007;37(suppl 3):S455-461. Int. 1996;6:213-218.
99. Haga H, Miyagawa-Hayashino A, Taira K, et al. Histological 120. Valero MA, Loinaz C, Larrodera L, et al. Calcitonin and bisphos-
recurrence of autoimmune liver diseases after living-donor liver phonates treatment in bone loss after liver transplantation. Calcif
transplantation. Hepatol Res. 2007;37(suppl 3):S463-469. Tissue Int. 1995;57:15-19.
 CHAPTER 14

Transplantation for
Sclerosing Cholangitis
Anil Seetharam • Jeffrey S. Crippin

CHAPTER OUTLINE

ISSUES BEFORE TRANSPLANTATION POSTTRANSPLANT SURVIVAL

Ductal Stricturing/Bacterial Cholangitis POSTTRANSPLANT COMPLICATIONS
Pruritus Acute Cellular and Chronic/Ductopenic
Hepatic Osteodystrophy Rejection
Inflammatory Bowel Disease Inflammatory Bowel Disease Following
Gallbladder Disease Transplantation
Cholangiocarcinoma Recurrent Disease and Biliary Strictures
Prognostic Models SUMMARY
TRANSPLANT SURGERY

Sclerosing cholangitis is characterized by chronic biliary Trials evaluating ursodeoxycholic acid (UDCA) have
duct inflammation, subsequently resulting in fibrotic shown improvement in serum liver test results but not in
stricturing and duct obliteration. Biliary cirrhosis fol- symptoms and, more importantly, no difference in mor-
lows, with progression to complications of end-stage tality, progression to cirrhosis, or liver transplantation.5
liver disease, liver failure, and the need for liver trans- There is evidence that UDCA used at even higher doses
plantation. Primary sclerosing cholangitis (PSC) is likely than typically given in other cholestatic diseases may
an immune-mediated chronic and progressive cholestatic result in adverse outcomes when used in PSC.6 Cortico-
liver condition characterized by inflammation and fibro- steroids and other immunosuppressive therapies have
sis of both intrahepatic and extrahepatic bile ducts. Sec- not been shown to be effective; however, they may have
ondary sclerosing cholangitis is characterized by a similar utility in overlap syndromes (e.g., features of both PSC
multifocal biliary stricturing process that is due to identi- and autoimmune hepatitis). Surgical therapies or endo-
fiable causes such as long-term biliary obstruction (from scopically placed stents may relieve obstruction associ-
previous biliary duct surgery, choledocholithiasis, and ated with a dominant stricture, but there is no long-term
congenital biliary tract abnormalities), infection, inflam- effect on survival or disease progression. Thus liver
mation, or ischemia—which in turn leads to destruction transplantation ultimately remains the only option for
of bile ducts. patients with PSC who have developed complications of
In addition to biliary duct injury and the typical chol- end-stage liver disease or recurrent episodes of bacterial
angiographic findings, PSC has a number of other char- cholangitis caused by chronic biliary obstruction.
acteristics. A strong association between PSC and
inflammatory bowel disease (IBD) exists, with the overall
prevalence of IBD in PSC approximately 70%. The most ISSUES BEFORE TRANSPLANTATION
common form of associated IBD is ulcerative colitis;
however, Crohn’s disease (typically with colonic involve- The general criteria for liver transplantation are no differ-
ment) can occur.1 Males are more commonly affected ent for PSC than for other chronic liver diseases. Further-
with the disease and the course is progressive in nature.2-4 more, the Model for End-Stage Liver Disease (MELD)
Presentation is usually at the time of symptoms and score calculation is identical to that used for patients on
fibrotic bile ductular changes, with little in the way of the waiting list with other diseases. Timing of transplan-
hope for medical management. Multiple medical thera- tation is difficult to predict because of variability of disease
pies have been studied; however, trials of bile acid ther- course in any individual patient. Disease-specific compli-
apy and immunosuppressive agents have not led to cations may arise and lead to a request for additional
prolonged survival or improvement in quality of life. MELD points from the regional review board.

167
168 PART II Patient Evaluation: Adult

• Liver transplantation remains an extreme option;

Ductal Stricturing/Bacterial Cholangitis however, the current MELD prioritization system
The presence of fibrotic stricturing resulting in impaired does not give exception points for pruritus unless
bile flow may lead to recurrent episodes of bacterial chol- approved by a regional review board.
angitis. A “dominant stricture” has been defined as a ste-
nosis with a diameter of 1.5 mm or less in the common Hepatic Osteodystrophy
bile duct or of 1 mm or less in the hepatic duct system.7 It
is a frequent finding and occurs in 45% to 58% of patients Hepatic osteodystrophy, a common complication of cho-
during follow-up cholangiographic studies.8 Dominant lestatic liver disease, can lead to vertebral body compres-
strictures should raise the suspicion of a cholangiocar- sion fractures resulting in severe, immobilizing back pain
cinoma (CCA), because this malignant complication and atraumatic fractures of the axial skeleton.15 The inci-
presents as a stenotic ductal lesion. Cholangiographic dence of osteoporosis in PSC is between 4% and 10%.
evaluation may identify a dominant stricture amenable to The incidence increases with decreasing body mass index,
balloon dilation. Before any attempt at endoscopic ther- increasing duration of disease, and with age; however,
apy, brush cytology and/or endoscopic biopsy should be hepatic osteodystrophy does not necessarily correlate with
obtained to help exclude a superimposed malignancy. the severity of the liver disease.16 Bone density should be
The best therapeutic endoscopic approach for PSC is measured in all patients with PSC being evaluated for a
still a subject of debate, with multiple techniques evalu- liver transplant. Calcium and vitamin D supplementation,
ated, including sphincterotomy, catheter or balloon dila- particularly in deficient patients, should be instituted,
tion, and stent placement. Of these, only endoscopic although evidence that this actually improves bone density
biliary sphincterotomy and balloon dilation with or in patients with PSC is lacking. The use of antiresorptive
without stent placement are of value.9 However, diffuse agents (such as bisphosphonates or calcitonin) or hormone
involvement of the intrahepatic biliary tree not amena- replacement therapy in postmenopausal or oophorecto-
ble to stenting can lead to recurrent episodes of cholan- mized women is also not of proven benefit, although these
gitis and biliary sepsis. Broad-spectrum antibiotic therapies are frequently used. Debilitating bone disease
coverage for gram-negative bacteria and Enterococcus was once considered an indication for transplantation;
usually leads to improvement, but hepatic abscesses may however, the worsening of bone density over the course of
develop in the face of obliterated bile ducts. Recurrent the first 3 postoperative months, with as many as one third
episodes should prompt referral to a transplant center, of patients with PSC suffering pathological fractures, has
even in the absence of complications of end-stage liver historically led some transplant centers to consider this a
disease. contraindication to transplantation.17

Pruritus Inflammatory Bowel Disease

Pruritus is a common complication of cholestatic liver IBD may be diagnosed at any time during the course of
disease. Although dilation of a dominant stricture may PSC. In many cases the diagnosis of IBD precedes that of
lead to improvement or resolution, some patients may PSC; however, IBD and PSC are sometimes diagnosed
complain of pruritus in the absence of jaundice or a domi- concomitantly.18 It is now recognized that the onset of
nant stricture. This is likely related to an increase in cen- IBD can also occur years after the diagnosis of PSC, and
tral opioid receptors.10 Treatment may range from the de novo IBD may present after liver transplantation.19,20
simple to the bizarre: The common association of IBD with PSC often raises
• Antihistamines and topical lotions rarely provide management issues before transplantation. The potential
relief, but there is no contraindication. for colonic malignancy in patients with ulcerative colitis
• Cholestyramine has historically been the treatment should result in a screening colonoscopy during the ini-
of choice. tial evaluation. If colonic dysplasia is present, a practical
• UDCA is helpful in a small percentage of patients. issue regarding management may be problematic.
• Rifampin, in a dose of 150 to 300 mg twice a day, Although colonic resection in the face of end-stage liver
can decrease pruritus.11 If decompensation occurs disease may be associated with increased morbidity and
in a patient using rifampin therapy who has other- even mortality, the issue of delaying resection until a suit-
wise stable PSC, the patient may have rifampin able time after the transplant is plagued by the concern
hepatotoxicity. that malignancy may be present and, if so, its behavior
• Opiate antagonists, such as naltrexone in a dose of may be altered by immunosuppression. Each case must
25 to 50 mg daily to twice a day, can lead to imme- be considered individually, with careful assessment of
diate resolution of pruritus.12 potential risks and benefits. Medical management of the
• Serotonin uptake inhibitors decreased symptoms in patient with active colitis should be no different from that
one small study.13 for any other patient with ulcerative colitis; however,
• Plasmapheresis can lead to transient resolution of severe cases should be controlled before the patient
symptoms if medical therapy does not lead to assumes a position at the top of the list. Attempts to mini-
improvement.14 However, plasmapheresis should be mize immunosuppressive therapy in a patient at the top
used only for patients with severe symptoms, such as of the list to reduce the chance of an opportunistic infec-
soft tissue abscesses related to skin excoriations or tion should be carefully weighed against the potential for
suicidal ideation. a disease flare.
 14 Transplantation for Sclerosing Cholangitis 169

the absence of metastatic disease.33 Thus liver transplan-

Gallbladder Disease tation is an accepted therapy for CCA in highly selected
PSC is frequently associated with gallbladder abnormali- patients with pretransplant neoadjuvant chemoirradia-
ties. Patients may be prone to the development of stones in tion. Although no widely accepted guidelines exist, it is
both the gallbladder and the biliary tract. In one large ret- reasonable to annually screen PSC patients for CCA.
rospective review the incidence of gallstones in PSC Most transplant centers screen with MRCP, though
patients was estimated at 25%, and mass lesions in the ERCP with brushings is a consideration. Unfortunately,
gallbladder were found in 6% of cases.21 In one series eval- data supporting either technique are limited.
uating the gallbladders of 72 patients with PSC (6 obtained
before and 66 at the time of transplant), 37% revealed dys- Prognostic Models
plasia and 14% harbored adenocarcioma.22 Given the
potentially high risk for malignancy of polyps in PSC, it is Because no effective treatment for PSC exists beyond
reasonable to follow gallbladder lesions with serial imag- liver transplantation, a number of prognostic models have
ing and evaluate for a cholecystectomy regardless of size, if been developed to predict outcome. Although prognostic
clinical suspicion warrants. models may have applicability in cohort populations, their
ability to precisely predict outcomes in any individual
patient are limited. Current guidelines recommend
Cholangiocarcinoma against the use of prognostic models for predicting clini-
The risk for CCA is increased in patients with PSC, cal outcomes in individual patients because there is no
occurring in 10% to 20% of cases.23 One study estimated consensus on the optimal model to apply.34
the 10-year cumulative incidence to be 10%.24 Numer-
ous risk factors have been associated with development of
CCA, including alcohol25 and tobacco abuse,26 duration TRANSPLANT SURGERY
of concurrent IBD,27 and polymorphisms of the NKG2D
gene (encoding a protein involved in natural killer cell The principles of liver transplant surgery for sclerosing
activity).28 Of note, the duration of PSC may not be a risk cholangitis differ little from those for other liver diseases.
factor for the development of CCA. In fact, in approxi- Any remaining recipient biliary duct tissue is at risk for the
mately half of patients with PSC plus CCA, the malig- subsequent development of fibrotic changes, if not already
nancy is detected at the time of PSC diagnosis or within present, so it is standard surgical practice to avoid the use
the first year. of native duct tissue. A Roux-en-Y choledochojejunos-
Ideally a serum tumor marker would allow early detec- tomy is the procedure of choice. Although the optimal
tion of CCA, but results have been less than perfect. The length of the jejunal limb has not been established, 40 cm
cancer antigen (CA) 19-9 has been the most widely studied of defunctionalized jejunum is routinely used. The impor-
biomarker of CCA. Using a cutoff of 130 units/mL, the tance of a Roux limb of adequate length is illustrated by a
sensitivity and specificity is 79% and 98%, respectively.29 single case report of a patient with PSC and intrahepatic
Most studies examining CA 19-9 were performed in strictures after liver transplantation.35 Although recurrent
cohorts where CCA suspicion was high. Thus far no study PSC in the liver allograft was considered, the presence of
to date has demonstrated value in CA 19-9 levels as a partially digested vegetable matter embedded in a severely
screening tool in asymptomatic patients with PSC. inflamed duct was thought to be responsible, presumably
Magnetic resonance cholangiopancreatography (MRCP) the result of food refluxing up the 20-cm jejunal limb and
is a less invasive method of evaluating the biliary tree, but across the biliary-enteric anastomosis. Transplant surgery
to date no evidence exists of any effect on early detection. may be complicated by previous biliary surgery, although
Mass lesions with characteristic imaging features (delayed this is much less common currently because of the decrease
venous enhancement) in a backdrop of PSC are highly in attempts at surgical management.
specific for a diagnosis of CCA; however, mass lesions are
unusual in early stages of CCA, and the positive predic-
tive value of MRCP for CCA diagnosis is approximately POSTTRANSPLANT SURVIVAL
40%.30 Endoscopic retrograde cholangiopancreatogra-
phy (ERCP) with conventional brush cytology may be Patient and allograft survival following transplantation for
attempted for diagnosis of CCA in PSC. ERCP with PSC are excellent. A recent retrospective analysis of the
brushings appears to have limited sensitivity (20% to United Network for Organ Sharing (UNOS) database for
40%) but excellent specificity.31 Fluorescence in situ patients transplanted with PSC was performed.36 PSC
hybridization (FISH) of brush cytology specimens evalu- patients receiving deceased donor organs had 1- and
ating for polysomy (duplication of chromosomes) in more 5-year survival rates of 93% and 87.5%, respectively. Liv-
than five cells may improve the diagnostic yield.32 ing donor recipients had 1- and 5-year survival rates of
If the diagnosis of CCA is made, surgical resection is 97.2% and 95.4%, respectively. The 1- and 5-year allograft
often impossible in the face of PSC, particularly in survival rates among deceased and living donors were 87%
advanced stages. Chemotherapeutic options are generally and 79.2%, and 89.6% and 87.1%, respectively. The most
ineffective; however, transplantation appears lifesaving in common cause of death remains infection, with rates as
highly selected patients. A study from the Mayo Clinic high as 26% in one older series.37
reported results in which liver transplantation was per- CCA clearly affects survival rates, particularly in patients
formed after a neoadjuvant chemoirradiation protocol in with tumors found incidentally. A study of 169 patients
170 PART II Patient Evaluation: Adult

undergoing transplantation over a 9-year period found a over a 19-year period.43 Patients with concurrent IBD
10.6% incidence of CCA.38 Although the 1-year survival (n= 74, 67%) versus 36 with PSC alone before transplant
rate was not different for patients with CCA versus were studied. IBD developed (flare of IBD or de novo) in
patients without, the 5-year survival of patients with PSC 39 cases post transplant. The cumulative risk for IBD at
alone was 75.8%, whereas 26.7% of those with malignant 1, 2, 5, and 10 years was 16%, 24%, 38%, and 72%,
changes survived the same period. More of those with respectively. IBD flares occurred in 33 patients with a
CCA known before the transplant died than those with mean time to flare of 30 ± 28 months. De novo IBD
incidental tumors at 2 years (26.7% survival versus 54.6% occurred in 6 patients (all ulcerative colitis). Mean time to
survival), although the small numbers prevented this diagnosis was 29 ± 25 months. Regression analysis identi-
from reaching statistical significance. Overall, incidental fied active IBD at the time of transplantation as a signifi-
CCAs are found in 1.5% to 8% of cases.38,39 cant predictor of allograft failure post LT and smoking at
A recent analysis of predictors of recurrence of CCA post the time of transplantation and subsequent cessation pre-
transplant found a statistically significant association with dictive of recurrent IBD post transplantation.
an elevated CA 19-9 level, portal vein encasement and
residual tumor in the explant.40 Recurrent Disease and Biliary Strictures
The presence of biliary strictures following liver trans-
POSTTRANSPLANT COMPLICATIONS plantation may be secondary to any number of problems.
In the patient who undergoes transplantation for PSC,
Other sections of this book address the general compli- the question of disease recurrence in the transplanted liver
cations seen in liver transplant recipients. Patients under- must be considered. Isolated strictures at the biliary-enteric
going transplantation for PSC have disease-specific anastomosis may be a technical complication, occurring in
complications that may lead to increased morbidity and approximately 5% of patients. Nonanastomotic biliary
mortality. strictures can occur as well and have been associated with
multiple factors, including prolonged ischemia time, dona-
Acute Cellular and Chronic/Ductopenic tion after cardiac death, cytomegalovirus infection, and
hepatic artery thrombosis.44 These can be treated effec-
Rejection tively with balloon dilation and indwelling stent placement,
Acute cellular rejection of the transplanted liver is a risk for usually placed by an interventional radiologist. Endoscopic
all transplant recipients, regardless of indication. Several attempts at dilation and stenting may be attempted but
centers have identified an increased incidence of acute cel- generally require the use of longer enteroscopes to traverse
lular rejection in patients undergoing transplantation for the Roux limb and access the biliary tract. If unsuccessful,
PSC. In one series an increased incidence of acute rejec- reconstructive biliary surgery may be necessary.
tion was seen when compared with patients undergoing Recurrence of PSC in the transplanted liver continues
transplantation for other diseases (68.7% versus 59.3%).37 as a topic of debate for a number of reasons. The absence
Coexistent IBD may also increase the risk for rejection.37 of other contributing factors must be ruled out before
Chronic/ductopenic rejection can also occur in PSC recurrence is considered. For example, the biliary
patients undergoing transplantation for PSC. The largest system of the liver allograft receives its blood supply solely
series showed an incidence of 8%, with a significant from the hepatic artery. Thus any compromise in hepatic
decrease in patient and allograft survival.37 A similar arterial blood flow, such as profound hypotension, hepatic
decrease in patient and allograft survival was seen in artery thrombosis, or hepatic artery stenosis, may lead to
another series in which 13% of patients developed ischemic bile duct injury. Cholangiographically, the
chronic/ductopenic rejection.41 The year of the trans- appearance of ischemic bile duct injury is no different
plant likely influences the risk, because patients undergo- from the classic appearance of PSC (Fig. 14-1). Severe
ing transplantation earlier (before 2000) in one series had preservation injury and an ABO-incompatible donor liver
a lower rate of chronic/ductopenic rejection the later the can also lead to biliary strictures. Chronic/ductopenic
transplant was performed, likely caused by the develop- rejection, with its characteristic arteriopathy, could also
ment of additional immunosuppressive agents.42 lead to bile duct ischemia, although one study did not
demonstrate bile duct stricturing in patients with PSC
Inflammatory Bowel Disease Following with ductopenic rejection. Chronic/ductopenic rejection
occurred earlier than what was defined as recurrent PSC
Transplantation (mean of 5 months versus 25 months) and was associated
The course of IBD following a liver transplant is variable. with a significant decrease in both patient and allograft
Many patients have improvement in symptoms or may be survival.37 Thus, although fibro-obliterative bile duct
maintained on lower doses of antiinflammatory agents, changes may be seen in both chronic/ductopenic rejection
which are thought to be related to the immunosuppres- and recurrent PSC, an early appearance of these changes
sive agents required to prevent rejection. However, some may be more consistent with ductopenic rejection.
patients actually have worsening of their disease or the PSC recurrence is estimated to occur in 20% to 25%
new onset of IBD after transplantation. In a recent retro- of deceased donor recipients, anywhere from 5 to 10
spective analysis at King’s College Hospital, 110 patients years post transplant.45 In a recent analysis of 230 trans-
were identified who underwent transplantation for PSC plant recipients with a median follow-up of approximately
 14 Transplantation for Sclerosing Cholangitis 171

FIGURE 14-2 n Liver biopsy specimen demonstrating periductal

fibrosis in a patient with recurrent primary sclerosing cholangitis
post liver transplantation.

FIGURE 14-1 n Percutaneous cholangiogram demonstrating bili-

ary strictures in a patient with recurrent primary sclerosing chol- A number of controversies remain regarding the natu-
angitis post liver transplantation. ral history of recurrent PSC. Reported risk factors fol-
lowing liver transplantation include active and
corticosteroid-dependent IBD, male sex, the presence of
6 years, the recurrence rate was 23.5%, with the mean CCA, and a history of acute cellular rejection.47,48 The
time to developing recurrent disease at 4 years.46 The impact of recurrent PSC on graft survival is not fully
diagnosis of recurrent disease can be extremely difficult. characterized, with conflicting study reports of either no
The Mayo Clinic group looked at their experience with effect48 or diminished graft survival.49
patients undergoing transplantation for PSC and Ideally the identification of recurrent disease in its ear-
attempted to define disease recurrence in the absence of liest stages could lead to medical therapy that theoreti-
compromised hepatic arterial blood flow, established cally could slow disease progression or halt progression
chronic/ductopenic rejection, ABO incompatibility altogether. Unfortunately, the lack of an identifiable
between the donor and the recipient, and an anastomotic medical therapy for this disease, at any stage, makes it
stricture without other biliary strictures.37 Their proposal impossible to make definitive recommendations. Poten-
included patients with an established diagnosis of PSC at tial medical interventions include additional immunosup-
least 90 days following the transplant with either of the pressive agents, bile acid therapy, or both. Controlled
following: trials will have to be performed before definitive recom-
1. A cholangiogram marked by nonanastomotic biliary mendations can be made regarding preemptive medical
strictures of the intrahepatic or extrahepatic biliary therapy immediately following the transplant or at the
tree time histological changes are identified.
2. Liver biopsy results showing fibrous cholangitis
or fibro-obliterative lesions with or without duc-
topenia, biliary fibrosis, or biliary cirrhosis (Fig. SUMMARY
14-2)
Cholangiographic evidence was seen at a mean of 421 Since the second edition of this book was published, a
days (range 92 to 1275 days) following a transplant in greater understanding of PSC and its associated compli-
18.3% of patients. Histological evidence was seen at a cations has been achieved. Despite this understanding, no
mean of 1380 days following the transplant (range 420 to directed medical therapy exists for treatment to slow its
3240 days) in 9.2% of the patients. Cholangiographic progression. As such, patients with disease progression
and histological changes were seen in 7.5% of the study are subject to the development of end-stage liver disease,
group. No obvious precipitating factors could be identi- as well as CCA. Liver transplantation remains the only
fied, that is, patients with recurrent disease had no evi- viable treatment for advanced disease. Both patient and
dence of more frequent episodes of prolonged cold allograft survival are excellent. In the future, molecular
ischemia time, different preservation solutions, cyto- and imaging advances are expected to develop and refine
megalovirus infections, or positive lymphocytotoxic both the diagnosis and treatment of biliary neoplasia.
crossmatches. However, IBD was seen more frequently Greater experience with transplantation for CCA will
in the patients with recurrent disease. No difference in allow for enhanced selection protocols to identify those
patient or allograft survival was seen at 5 years in those who will benefit most. Further insights into risk factors
with recurrent disease versus those without based on this for and the development of recurrent PSC in the allograft
definition. will be gained, as will its effect on survival.
172 PART II Patient Evaluation: Adult

12. Wolfhagen FHJ, Sternieris E, Hop WCJ, et al. Oral naltrexone

Pearls and Pitfalls treatment for cholestatic pruritus: a double-blind, placebo-­
controlled study. Gastroenterology. 1997;113:1264-1269.
• Diagnosis of primary sclerosing cholangitis (PSC) 13. Schworer H, Hartman H, Ramadori G. Relief of cholestatic pruri-
should prompt investigation for concurrent inflamma- tus by a novel class of drugs: 5-Hydroxytryptamine type 3 (5-HT3)
tory bowel disease (IBD) (if not previously established), receptor antagonists. Effectiveness of ondansetron. Pain. 1995;61:
as well as assessment of bone mineral density. 33-37.
• Patients with PSC are at an increased risk for the devel- 14. Cohen LB, Ambinder EP, Wolke AM, et al. Role of plasmaphere-
opment of cholangiocarcinoma, which may precede the sis in primary biliary cirrhosis. Gut. 1985;26:291-294.
15. Angulo P, Therneau TM, Jorgensen RA, et al. Bone disease in
development of parenchymal fibrosis. Decompensation
patients with primary sclerosing cholangitis: Prevalence, severity,
in a previously stable patient or the development of a and prediction of severity. J Hepatol. 1998;29:729-735.
dominant stricture should prompt immediate investiga- 16. Campbell MS, Lichtenstein GR, Rhim AD, et al. Severity of liver
tion with serum CA 19-9, magnetic resonance imaging, disease does not predict osteopenia or low bone mineral density in
and cholangiography. primary sclerosing cholangitis. Liver Int. 2005;25:311-316.
• Liver transplantation for PSC is a well-established treat- 17. Porayko MK, Wiesner RH, Hay JE, et al. Bone disease in liver
ment modality when cirrhosis and consequent manifesta- transplant recipients: Incidence, timing, and risk factors. Trans-
tions of end-stage liver disease develop. Disease-specific plant Proc. 1991;23:1462-1465.
indications include recurrent episodes of cholangitis, in- 18. Aadland E, Schrumpf E, Fausa O, et al. Primary sclerosing cholan-
gitis: a long-term follow-up study. Scand J Gastroenterol.1987;
tractable pruritus, and cholangiocarcinoma, in carefully
22:655-664.
selected patients. 19. Schrumpf E, Elgjo K, Fausa O, et al. Sclerosing cholangitis in
• The preferred biliary anastomosis in patients with PSC ulcerative colitis. Scand J Gastroenterol. 1980;15:689-697.
is a Roux-en-Y choledochojejunostomy. 20. Verdonk RC, Dijkstra G, Haagsma EB, et al. Inflammatory bowel
• Recurrence of PSC may occur in up to 25% of trans- disease after liver transplantation: risk factors for recurrence. Am J
plant recipients; however, an exhaustive review of fac- Transplant. 2006;6:1422-1429.
tors that may contribute to nonanastomotic stricturing 21. Said K, Glaumann H, Bergquist A. Gallbladder disease in patients
should be conducted before establishing a diagnosis of with primary sclerosing cholangitis. J Hepatol. 2008;48:
recurrent disease. Decreased arterial blood supply or 598-605.
22. Lewis JT, Talwalkar JA, Rosen CB, et al. Prevalence and risk fac-
blood pressure are the most common causes of post-
tors for gallbladder neoplasia in patients with primary sclerosing
transplant biliary strictures. cholangitis: evidence for a metaplasia-­ dysplasia-carcinoma
• Patients with IBD and PSC are at an increased risk for sequence. Am J Surg Pathol. 2007;31:907-913.
colonic neoplasia, which persists after liver transplan- 23. Rosen CB, Nagorney OM, Wiesner RH, et al. Cholangiocarci-
tation, mandating continued endoscopic surveillance noma complicating primary sclerosing cholangitis. Ann Surg.
   postoperatively. 1991;213:21-25.
24. Claessen MM, Vleggaar FP, Tytgat KM, et al. High lifetime risk of
cancer in primary sclerosing cholangitis. J Hepatol. 2009;50:
158-164.
25. Chalasani N, Baluyut A, Ismail A, et al. Cholangiocarcinoma in
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5. Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo ing cholangitis. Dig Dis Sci. 2005;50:1734-1740.
Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study 30. Charatcharoenwitthaya P, Enders FB, Halling KC, Lindor KD.
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Petz JL, et al. Randomized, double-blind controlled trial of high- Hepatology. 2008;48:1106-1117.
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[Abstract]. Hepatology. 2008;48:378A. ary brush cytology in cholangiocarcinoma in primary sclerosing
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nant strictures in patients with primary sclerosing cholangitis. Am 32. Moreno Luna LE, Kipp B, Halling KC, et al. Advanced cytologic
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8. Lindberg B, Arnelo U, Bergquist A, et al. Diagnosis of biliary stric- tures. Gastroenterology. 2006;131:1064-1072.
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36. Kashyap R, Safadjou S, Chen R, et al. Living donor and deceased 43. Joshi D, Bjarnason I, Belgaumkar A, et al. The impact of inflamma-
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and sclerosing cholangitis: Clinical characteristics and effect on time course. Liver Transpl. 2008;14:181-185.
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1124-1125. risk factors for the recurrence of primary sclerosing cholangitis in
39. Narumi S, Roberts JP, Emond JC, et al. Liver transplantation for liver allografts. Liver Transpl. 2009;15:330-340.
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40. Murad SD, Kim R, Therneau T, et al. Predictors of pre-transplant primary sclerosing cholangitis after liver transplantation. Liver
dropout and post-transplant recurrence in patients with perihilar Transpl. 2008;14:245-251.
cholangiocarcinomaHepatology. 201210.1002/hep.25629:Jan 30. 48. Cholongitas E, Shusang V, Papatheodoridis GV, et al. Risk factors
41. Jeyarajah TR, Netto GJ, Lee SP, et al. Recurrent PSC after ortho- for recurrence of primary sclerosing cholangitis after liver trans-
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 CHAPTER 15

Transplantation for
Autoimmune Hepatitis
Kareem Sassi • Jose M. Nieto • Sammy Saab

CHAPTER OUTLINE

HISTORICAL PERSPECTIVE Adjunctive Medical Treatment

Other Pharmacotherapies
EPIDEMIOLOGY
ROLE OF LIVER TRANSPLANTATION
PATHOPHYSIOLOGY
IMMUNOSUPPRESSION AFTER LIVER
CLINICAL MANIFESTATIONS
TRANSPLANTATION
Clinical Symptoms
Physical Findings ACUTE AND CHRONIC ALLOGRAFT REJECTION
Associated Extrahepatic Disorders RECURRENT AUTOIMMUNE HEPATITIS AFTER
Laboratory Findings TRANSPLANT
Histological Features Risk Factors for Recurrence
Diagnostic Criteria Pathogenesis
IMMUNOSEROLOGICAL SUBCLASSIFICATIONS DE NOVO AUTOIMMUNE HEPATITIS AFTER LIVER
MEDICAL TREATMENT TRANSPLANTATION (GRAFT DYSFUNCTION
MIMICKING AUTOIMMUNE HEPATITIS)
First-Line Medical Regimen
Pathogenesis
Special Considerations in Treatment

Autoimmune hepatitis (AIH) is a chronic necroinflamma- described in the early 1940s,13,14 but idiopathic autoim-
tory liver disease of unknown etiology characterized by mune hepatitis was not recognized until 1950 when
the presence of various circulating autoantibodies, hyper- Waldenström15 described the constellation of cirrhosis,
gammaglobulinemia, and interface hepatitis of predomi- plasma cell infiltration of the liver, and hypergamma-
nant lymphoplasmacytic necroinflammatory infiltration globulinemia in young women. In 1955 the lupus ery-
on histological examination.1,2 AIH reflects a complex thematous cell phenomomena16 and the presence of
interaction between triggering factors, autoantigens, antinuclear antibodies (ANA) led Mackay et al17 to
genetic predispositions, and immunoregulatory networks.3 introduce the term lupoid hepatitis. In the 1960s sub-
There is a higher prevalence among females,4 an immu- groups of patients were distinguished by specific immu-
nogenetic connection with the human leukocyte antigen noserological findings, and Page et al18 demonstrated
(HLA) A1-B8-DR3 or DR4 haplotype,5 and an association that treatment with 6-mercaptopurine (6-MP) improved
with extrahepatic conditions.6 AIH tends to respond well clinical symptoms and decreased the level of hypergam-
to immunosuppressive therapy.7 Patients who do not maglobulinemia. Whittingham et al19 distinguished
achieve remission are at risk for developing liver cirrhosis.8 between chronic active hepatitis and systemic lupus
Liver transplantation is the treatment of choice in patients erythematosus and introduced the term autoimmune
with decompensated AIH,9 but acute allograft rejection hepatitis. In 1973 Rizzetto et al20 described an autoanti-
and recurrence of primary disease is common.10,11 body reacting with the microsomal fraction of hepatocytes
Although de novo autoimmune hepatitis after transplant and renal tubular epithelium in patients with chronic
can occur in both pediatric and adult populations, it is active hepatitis. In 1987 the first formal proposal to sub-
more common among children.12 classify AIH was introduced. The same year, Manns
et al21 described anti–soluble liver antigen/liver pancreas
(anti-SLA/LP), which occurred in about 30% of patients
HISTORICAL PERSPECTIVE who presented with seronegative conventional autoanti-
bodies, and type 3 classification for AIH was suggested.
Hyperproteinemia and idiopathic recurrent jaundice However, Ballot et al22 later showed that the clinical and
with unresolving hepatic inflammation were first biological features of anti-SLA/LP seropositive patients

174
 15 Transplantation for Autoimmune Hepatitis 175

were similar to those of AIH type 1 and therefore did not process against the liver in a genetically predisposed
warrant being distinguished as a separate subgroup. individual. Multiple triggering factors have been impli-
cated, such as viruses, drugs, and toxins.40 Proposed
viral triggers include measles virus; hepatitis A, B, and
EPIDEMIOLOGY C; and the Epstein-Barr virus.41-46 Drugs that have
been associated with AIH include diclofenac, methyl-
Early epidemiological studies from 1970 to 1995 in dopa, oxyphenisatin, nitrofurantoin, and minocycline.46
western European populations showed a mean annual The actual mechanisms by which these environmental
incidence of AIH ranging from 1.9 to 16.9 cases per agents can initiate autoimmunity and trigger AIH are
100,000 persons.23-27 However, the incidence may have unknown.
been overestimated because the condition was included During immunological development, individuals are
within the spectrum of chronic active hepatitis. In protected against self-reactive T and B cells by nega-
Europe AIH accounts for 2.6% of the transplantations28 tive clonal selection and apoptosis of these cells. Many
and in the United States, 5.9%.29 Type 2 AIH is most studies support the idea of epitope mimicry in which a
prevalent in southern Europe. Females are affected more susceptible individual is presented with an environ-
than males (3.6:1), and all ages and ethnic groups are mental agent that exhibits antigens that share homolo-
susceptible. gies with host antigens. These shared homologies
The mortality of untreated AIH is high. Up to 40% result in a cross-reaction and loss of self-tolerance
of untreated patients with decompensated liver disease leading to an immune response generated against the
die within 6 months.30 Cirrhosis develops in about 40% host tissue. There can potentially be a long lag time
of diagnosed untreated patients.31 Of patients with cir- between exposure to the trigger and onset of disease,
rhosis, 54% develop esophageal varices within 2 years, and the environmental agent may or may not be pres-
and 20% die of variceal hemorrhage.32 For patients ent when the autoimmune disease becomes clinically
with sustained serum aminotransferase levels of more apparent.47
than tenfold normal or more than fivefold normal in There appears to be a clear association between HLA
conjunction with serum γ-globulin concentrations of at and AIH. The frequency of HLA markers varies between
least twofold elevation, mortality without treatment is ethnic groups. HLA-DR3 and DR4 are the major risk
90% at 10 years.30 The risk for developing cirrhosis is factors for type 1 AIH in white European and North
associated with histological findings. In patients with American populations. HLA-DR3 is more commonly
periportal hepatitis, cirrhosis develops in 17% within 5 found in the early-onset, severe form of disease (often
years, bridging necrosis or multiacinar necrosis pro- occurring in girls and young women), whereas HLA-
gresses to cirrhosis in 82% within 5 years, and mortality DR4 is more common in whites with late-onset disease
is 45%.33,34 Cirrhosis develops within 15 years in 49% and is associated with a higher incidence of extrahepatic
of patients with moderate laboratory findings or serum manifestations and a better response to corticosteroids.
aminotransferase levels less than tenfold normal or less More advanced molecular analysis reveals that there
than fivefold normal in conjunction with serum appears to be a common susceptibility determinant in the
γ-globulin concentrations less than twofold elevation, HLA-class II binding groove important to antigen recog-
and death from fulminant hepatic failure occurs in nition that is carried by the DRB1*0301, DRB3*0101,
10%.35 Hepatocellular carcinoma is relatively uncom- and the DRB1*0401 alleles in whites. Furthermore, a
mon in patients with cirrhosis, occurring in approxi- thorough analysis of the amino acid sequences encoded
mately 4% of those with type 1 AIH, with a 10-year by these susceptibility alleles revealed a particular motif
probability of developing this neoplasm at 2.9% and of Leu-Leu-Glu-Gln-Lys-Arg at positions 67 to 72 of the
the risk for hepatocellular carcinoma increasing in DR polypeptide, which is encoded by DRB1*0301,
those who have AIH cirrhosis.36 With immunosuppres- DRB3*0101, and DRB1*0401, with the critical amino
sion treatment, 65% of patients achieve clinical, bio- acid in this motif likely being the Lys residue at position
chemical, and histological remission within 18 months; 71.48 However, how these alleles confer susceptibility to
80% do so within 3 years. The 20-year survival is 80% AIH is still not well understood.
of treated patients in contrast to 10-year survival of Both cellular and humoral immunity are involved in
10% in untreated patients.37 Although immunosup- the autoimmune destruction of hepatocytes. It is mediated
pression remains the mainstay of therapy for AIH, 9% by CD4+ helper T cells that recognize self-antigen.49,50
deteriorate on traditional regimens, 13% develop treat- Cytokines such as interferon-γ, tumor necrosis factor-α,
ment-related side effects that warrant premature dis- and interleukin-2 (IL-2) in the environment will lead to
continuation of medication, 13% have an incomplete the differentiation of different effector cells. CD8+ cytotoxic
response, and of those who experience remission and T cells are involved in both cell-mediated and humoral
discontinue therapy, 74% to 85% relapse within 3 autoimmunity in AIH. Antibody-dependent cytotoxic
years.38,39 activity mainly involves antibodies against the asialoglyco-
protein receptor (ASGPR), a hepatocyte membrane pro-
tein.51,52 Natural killer cells are present in the normal liver
PATHOPHYSIOLOGY and may be involved with liver destruction, possibly
through the expression of the Fas ligand and the binding
The most accepted hypothesis for the cause of AIH of its Fc receptor with an antigen-antibody complex on
­suggests an environmental agent triggers an autoimmune the hepatocyte.
176 PART II Patient Evaluation: Adult

CLINICAL MANIFESTATIONS AIH; therefore cholangiography is indicated to exclude

primary sclerosing cholangitis (PSC). The presence of
Clinical Symptoms concurrent extrahepatic immunological disorders in the
patient or family member supports the diagnosis.
Autoimmune hepatitis is typically an insidious disease of
young females, although there is a subset of patients who
can present with acute fulminant hepatitis.53 Women
Laboratory Findings
constitute approximately 70% of all cases, and as many as The major biochemical abnormalities include elevated
50% of patients are less than 30 years old. Onset usually serum aminotransferase activity and bilirubin concentra-
occurs between the third and fifth decade, but patient tions with normal or only moderately elevated serum
ages range from 9 months to 77 years. An acute presentation alkaline phosphatase with hypergammaglobulinemia.
that mimics acute viral hepatitis clinically and biochemi- When serum aminotransferase levels are greater than
cally occurs in approximately 30% of patients.54 A rare 1000 International Units/L, viral, drug-induced, and
fulminant presentation with severe encephalopathy has ischemic hepatitis should be considered, although these
been described, particularly among the anti–liver-kidney levels can be seen in AIH. It is now recognized that
microsomal (LKM)-1 group.55 Postmenopausal women aminotransferase and bilirubin levels vary widely among
constitute a subgroup that derives less net benefit from individuals and fluctuate or normalize at times; therefore
corticosteroid therapy and has a greater frequency of a threefold elevation is no longer considered diagnostic of
associated complications.56 AIH.63 Hypergammaglobulinemia is characteristically
Many patients with AIH may be asymptomatic for long caused by a disproportionate increase in the immuno-
periods of time. In most cases the clinical presentation does globulin G fraction, which may be elevated even if total
not differ from that of other forms of chronic hepatitis.57 globulin concentrations are normal.
Fatigability is the most common symptom at presentation, Autoantibodies are the serological hallmark of AIH;
occurring in 85% of patients; whereas 77% of patients also therefore ANA, smooth muscle antibodies (SMA), and
describe features of jaundice (scleral icterus, change in anti-LKM levels should be determined in all patients with
color of urine and stool). Mild right upper quadrant pain clinical, laboratory, and/or histological suspicion of AIH.
(48%), pruritus (36%), anorexia (30%), polymyalgias When these autoantibodies are undetectable and AIH is
(30%), diarrhea (28%), and constant pyrexia (18%) are still considered, then assessing for SLA/LP antigen may
frequent complaints (58%). Menstrual abnormalities be helpful. ANA are present alone (13%) or with SMA
(89%) include delayed menarche, irregular menstrual (54%) in 67% of patients with AIH.64 They represent the
cycles, and amenorrhea. In later stages the consequences of most common autoantibody in AIH and occur in high
portal hypertension dominate, including ascites, bleeding titers usually exceeding 1:160. ANA is nonspecific and can
esophageal varices, and encephalopathy.58 be found in primary biliary cirrhosis (PBC), PSC, chronic
viral hepatitis, drug-induced hepatitis, and alcohol liver
Physical Findings disease. SMA are directed against actin and nonactin
components and are present in 87% of patients with AIH,
Physical findings reflect the duration and severity of liver either alone (33%) or in conjunction with ANA (54%).64
disease. Hepatomegaly (78%) and jaundice (69%) are SMA autoantibodies are also nonspecific and occur in
common physical findings at the time of diagnosis. Sple- titers lower than 1:80 in other liver diseases, rheumato-
nomegaly can be present in 56% and 32% of patients logical disorders, and infectious diseases. SMA have been
with and without portal hypertension, respectively. Asci- found to be associated with HLA-DR3 in actin-positive
tes (20%) and hepatic encephalopathy (14%) are recog- patients and with HLA-DR4 with non–actin-positive
nized less frequently, but when they occur they are highly patients.65
suggestive of underlying cirrhosis.59 Esophageal varices Anti-LKM typically occurs in the absence of SMA and
(8%) are not common initial findings.60 Rare cutaneous ANA.66,67 Up to 78% of those found to have anti LKM-1
manifestations include acne, facial rounding, hirsutism, antibodies concurrently test positive for hepatitis C virus
hyperpigmented striae, xanthelasmas, and spider nevi. (HCV) with or without viremia.68 Antibodies to LKM-1
occur in only 4% of adults with AIH in the United
Associated Extrahepatic Disorders States.66 They are usually described in pediatric patients
in Europe, and 20% of patients with anti-LKM-1 in
A specific feature of AIH is the association of extrahepatic France and Germany are adults.67 Anti-LKM-2 is directed
autoimmune-mediated syndromes, including autoimmune against cytochrome P-450 (CYP) 2C9. Anti-LKM-3 has
thyroiditis, rheumatoid arthritis, and diabetes mellitus.56 been identified in 6% to 10% of patients with chronic
One study showed that concurrent immunological diseases hepatitis D virus infection.69
are more common with AIH (38%) than with viral hepatitis Anti-SLA/LP are highly specific markers of AIH and
(22%).61 Other disorders include Sjögren’s syndrome, are present as the only marker in 10% to 30% of
polymyositis, IgA deficiency, idiopathic thrombocytopenia, patients.70 In about 75% of cases, SLA/LP are present
urticaria, vitiligo, CREST syndrome, Addison’s disease, simultaneously with other autoantibodies and appear in
lichen planus, and nail dystrophy. Inflammatory bowel 12% of cases with SMA- and/or ANA-positive patients.
disease is also common, and screening for antiendomysial ASGPR is observed in 88% of all patients with AIH.71
antibodies is advisable to exclude celiac sprue.62 Associated However, it can also be found in chronic hepatitis B, C,
ulcerative colitis raises suspicions about the diagnosis of PBC, and alcoholic hepatitis. Its presence correlates with
 15 Transplantation for Autoimmune Hepatitis 177

histological activity, its disappearance connotes response Diagnostic Criteria

to treatment, and its persistence signifies relapse after
corticosteroid treatment. Anti–liver-cytosol autoantibodies The trigger or cause of AIH is unknown, and no pathog-
type 1 (anti-LC1) are present in 32% of type 2 AIH, and nomonic features have been identified. Therefore diag-
their presence may correlate with disease activity. Peri- nosis requires the presence of a combination of clinical,
nuclear antineutrophil cytoplasmic antibodies (pANCA) histological, and laboratory abnormalities together with
occur in 92% of type 1 AIH, but their role is not clear, the exclusion of other possible causes of liver disease
and routine determination is not recommended. (Table 15-1). Because AIH shares common features with
hereditary (Wilson’s disease, genetic hemochromatosis,
and α1-antitrypsin deficiency), infectious, and drug-induced
Histological Features liver injury, it is appropriate to consider and work up
There are no pathognomonic histological features of these entities when evaluating a patient.63
AIH. Interface (periportal or paraseptal) hepatitis with a A set of diagnostic criteria was proposed by an interna-
predominantly lymphoplasmacytic necroinflammatory tional panel in 1993, and its validity has been confirmed
infiltrate is the most common histological finding in AIH. by six major studies evaluating a total of 983 patients.72
Piecemeal or periportal hepatitis is characterized by dis- These criteria were later updated in 1999, and subse-
ruption of the limiting hepatocyte plate, where the interface quently revised guidelines were issued by the American
between the parenchyma and portal tracts is the site of Association for the Study of Liver Diseases (AASLD) in
active inflammation and hepatocellular necrosis. 2010.73 In addition, a scoring system has been proposed
Plasma cell infiltration is abundant at the interface and to assess the certainty of the diagnosis (Table 15-2).63
through the acinus, but 34% of patients with AIH have Subsequently a less complicated system using simplified
few or no plasma cells. Rosettes are small clusters of criteria was proposed in 2008 by Hennes et al74; however,
hepatocytes surrounded by inflammatory cells that are this has not been widely accepted as the standard scoring
prominent in the periportal regions. Necrosis of pyknotic system by the AASLD. The diagnostic criteria include
(apoptotic) cells and ballooning degeneration of hepato- gender, serum γ-globulin levels, autoantibodies, alcohol
cytes are present in 39% of patients, and scattered multi- use, medications, viral markers, histological features,
nucleated hepatocytes are nonspecific findings of AIH. HLA, and immunosuppression treatment response.
Other nonspecific findings of AIH include steatosis, These different variables help rule out other possible
lymphoid aggregates, copper deposits, siderosis, and bile causes of chronic active hepatitis. The score is based on
ductile proliferation. pretreatment features; therefore it can be adjusted by the
Cirrhosis in patients with AIH is described as active or response to treatment. By taking into account each com-
inactive depending on whether periportal (piecemeal) ponent of the syndrome, discrepant features and biases
necrosis is present or not. These various patterns of associated with isolated inconsistencies can be avoided.72
necrosis represent fluctuations in the degree and extent of The sensitivity of the scoring system for AIH ranges from
disease activity. 97% to 100%,75-77 and its specificity for excluding AIH in

TABLE 15-1 Diagnostic Criteria for Autoimmune Hepatitis

Diagnostic Criteria
Requisites Definite Probable
No genetic liver disease Normal α1-antitrypsin phenotype Partial α1-antitrypsin deficiency
Normal serum ceruloplasmin, iron, and ferritin Nonspecific serum copper, ceruloplasmin, iron,
levels or ferritin abnormalities
No active viral infection No markers of current infection with hepatitis No markers of current infection with hepatitis
A, B, and C viruses A, B, and C viruses
No toxic or alcohol injury Daily alcohol < 25 g/day and no recent use of Daily alcohol < 50 g/day and no recent use of
hepatotoxic drugs hepatotoxic drugs
Laboratory features Predominant serum aminotransferase Predominant serum aminotransferase
abnormality abnormality
Globulin, γ-globulin or immunoglobulin G Hypergammaglobulinemia of any degree
level ≥ 1.5 times normal
Autoantibodies ANA, SMA, or anti-LKM-1 ≥ 1:80 in adults and ANA, SMA, or anti-LKM-1 ≥ 1:40 in adults or
≥ 1:20 in children; no AMA other autoantibodies*
Interface hepatitis Interface hepatitis
Histological findings No biliary lesions, granulomas, or prominent No biliary lesions, granulomas, or prominent
changes suggestive of another disease changes suggestive of another disease

Based on recommendations from Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune Hepatitis Group report: review of criteria
for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31:929-938.
*Includes perinuclear antineutrophil cytoplasmic antibodies and the not generally available antibodies to soluble liver antigen/liver pancreas,
actin, liver cytosol type 1, and asialoglycoprotein receptor.
AMA, Antimitochondrial antibodies; ANA, antinuclear antibodies; LKM, liver-kidney microsomal antibody; SMA, smooth muscle antibodies.
178 PART II Patient Evaluation: Adult

patients with chronic hepatitis C ranges from 66% to not have different etiologies or responses to corticosteroid
92%.78-79 therapy. Transplantation outcomes are similar between
In most cases the scoring system is not needed for the different subclassifications (Table 15-3).
diagnosis of AIH when the clinical, laboratory, and histo- Type 1 is the most common subclass of the AIH
logical features of the syndrome are well defined. The worldwide, representing 80% of cases. It is mostly
importance of the scoring system is in its assessment of associated with non–organ-specific ANA and/or SMA;
variant or atypical syndromes that resemble the classical however, other autoantibodies, including antiactin,
diagnosis.80 A limitation of the scoring system has been atypical pANCA, and antimitochondrial, can be found
its ability to exclude cholestatic syndromes, such as cho- as well (see Table 15-3). It affects all age groups, with
lestatic overlap syndromes, PSC, and PBC that present a bimodal age distribution between 10 to 20 years and
with autoimmune features. Excluding biliary disease has 45 to 75 years and a female prevalence of 78%. It is
shown a better performance in the scoring system, and associated with HLA-DR3 (DRB1*0301) and DR4
cholangiography is recommended for all patients with (DRB1*0401) in white northern European and North
definite or probable AIH scores that do not respond to American patients. White patients with type 1 AIH and
standard steroid therapy.81 DR3 are younger and have a higher treatment failure
rate, relapse after corticosteroid withdrawal, and
require liver transplantation. Patients with DR4 are
IMMUNOSEROLOGICAL older, frequently have concurrent autoimmune diseases
SUBCLASSIFICATIONS (48%), and have a better corticosteroid response.82
The clinical course is often unremarkable, and acute
Currently there are two types of AIH subclassifications onset is very rare. About 25% have cirrhosis at the time
based on immunoserological markers. The subclasses do of diagnosis.

TABLE 15-2 Diagnostic Scoring System for Atypical Autoimmune Hepatitis in Adults
Category Factor Score Category Factor Score
Sex Female +2 Concurrent immune Any nonhepatic disease +2
disease of an immune nature
Alk Phos: AST (or ALT) ratio >3 −2 Other autoantibodies* Anti-SLA/LP, actin, LC1, +2
pANCA
<1.5 +2
γ-globulin or IgG >2.0 +3 Histological features Interface hepatitis +3
(times above upper limit of 1.5-2.0 +2 Plasma cells +1
normal)
1.0-1.5 +1 Rosettes +1
<1.0 0 None of above −5
Biliary changes† −3
Atypical features‡ −3
ANA, SMA, or anti-LKM-1 titers >1:80 +3 HLA DR3 or DR4 +1
1:80 +2
1:40 +1
<1:40 0
AMA Positive −4 Treatment response Remission alone +2
Remission with relapse +3
Viral markers of active infection Positive −3
Negative +3
Hepatotoxic drugs Yes −4 Pretreatment score >15
No +1 Definite diagnosis 10-15
Probable diagnosis
Alcohol <25 g/day +2 Posttreatment score >17
>60 g/day −2 Definite diagnosis 12-17
Probable diagnosis

Based on recommendations from Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune Hepatitis Group report: review of criteria
for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31:929-938.
*Unconventional or generally unavailable antibodies associated with liver disease include perinuclear antineutrophil cytoplasmic antibodies (pANCA)
and antibodies to actin, soluble liver antigen/liver pancreas (anti-SLA/LP), asialoglycoprotein receptor (ASGPR), and liver cytosol type 1 (LC1).
†Includes destructive cholangitis, nondestructive cholangitis, or ductopenia.

‡Includes steatosis, iron overload consistent with genetic hemochromatosis, alcohol-induced hepatitis, viral features (ground-glass hepatocytes),
or inclusions (cytomegalovirus, herpes simplex).
Alk phos, Serum alkaline phosphatase level; ALT, serum alanine aminotransferase level; AMA, antimitochondrial antibodies; ANA, antinuclear
antibodies; AST, serum aspartate aminotransferase level; HLA, human leukocyte antigen; IgG, serum immunoglobulin G level; LKM,
liver-kidney microsomal antibody; SMA, smooth muscle antibodies.
 15 Transplantation for Autoimmune Hepatitis 179

A subclass of type 1 AIH is associated with anti-SLA/LP, is characterized by ectodermal disorders, chronic muco-
a UGA-suppressor tRNA-associated protein. The age cutaneous candidiasis, immune-mediated destruction of
range of patients is between 30 and 50 years, and 90% of endocrine tissues (parathyroids, adrenals, ovaries), auto-
patients are women. Patients respond well to corticosteroid antibody production to (CYP) 1A2, and AIH (10% to
treatment.83 Anti-SLA/LP can also be seen in type 2 AIH. 18%). It is caused by a mutation in the AIRE gene.84
Type 2 AIH is a rare disorder that affects 20% of AIH Patients with AIH and APECED have no sex predomi-
patients in Europe but only 4% in the United States, and nance and have particularly aggressive liver disease that
it is characterized by anti-LKM-1 and anti–liver cytosol does not respond well to immunosuppressive therapy.
type 1 (anti-LC1). Serum immunoglobulin levels are A second type of LKM autoantibodies, anti-LKM-2, is
moderately elevated with a reduction in immunoglobulin directed against P-450 (CYP) 2C9 and is induced in
A, and susceptibility may relate to DRB1*0701. pANCA ticrynafen-associated hepatitis. A third group of LKM
is common in type 1 but is not detected in type 2 AIH. autoantibodies, anti-LKM-3 occurs in 6% to 10% of
The anti-LKM-1 autoantibodies inhibit P-450 (CYP) patients with chronic hepatitis D virus infection.
2D6 activity and may occur with chronic HCV infection.
Female predominance is 89%. Extrahepatic autoimmune
syndromes are less common than AIH type 1. The age
range is from 2 to 14 years, but type 2 is also reported in
MEDICAL TREATMENT
adults in Europe. Type 2 carries a higher risk for progres- First-Line Medical Regimen
sion to cirrhosis and fulminant hepatitis at presentation.
It has been proposed to subdivide type 2 into 2a (HCV- The fundamental goals of medical treatment are induc-
negative young women with severe liver disease and high tion of remission and maintenance of remission. Multiple
titers of anti-LKM-1) and 2b (HCV-positive, predomi- randomized, controlled trials have demonstrated clinical,
nantly older males, with low anti-LKM-1 titers). biochemical, and histological improvement of severe
A distinct form of LKM-positive has been recognized AIH, as well as survival, with corticosteroids or in con-
in association with autoimmune polyglandular syndrome junction with azathioprine (AZA) treatment.30,32,82
characterized by autoimmune polyendocrinopathy-­ Although corticosteroids improve histological parameters
candidiasis-ectodermal dystrophy (APECED). APECED and survival, there is no evidence that it hinders disease
progression to cirrhosis.38 All immunoserological sub-
types of AIH have been shown to respond to standard
medical treatment. Treatment success depends on the
TABLE 15-3 T
 ype of Autoimmune Hepatitis and appropriate selection of patients, treatment to complete
Associated Autoantibodies end points, and effective management of suboptimal
Type Autoantibodies
treatment outcomes, such as incomplete response, drug
toxicity, and treatment failures.
1 Antinuclear The absolute indications for therapy as proposed by a
Anti–smooth muscle
Anti–soluble liver antigen/liver pancreas (anti-SLA/LP) 2010 consensus statement by the AASLD (Table 15-4)
Anti-actin include aminotransferase levels greater than tenfold normal,
Atypical perinuclear antineutrophil cytoplasmic or aminotransferase levels greater than fivefold normal
antibodies (pANCA) and γ-globulin levels greater than twofold normal, histo-
Antimitochondrial antibodies (AMA)
logical evidence of bridging necrosis or multilobular
2 Anti-LKM (liver-kidney microsomal)-1
Anti-liver cystol-1 (anti-LC1)
necrosis, or incapacitating symptoms.73 In patients with
Anti-SLA/LP asymptomatic or mild AIH, the indication for corticoste-
roid therapy is currently uncertain because no prospective,

TABLE 15-4 Indications for Immunosuppressive Treatment

Absolute Relative None
Serum AST ≥ to tenfold ULN Symptoms (fatigue, arthralgia, jaundice) Asymptomatic with normal serum AST
and γ-globulin levels
Serum AST ≥ to fivefold ULN and Serum AST and/or Inactive cirrhosis or mild portal
γ-globulin level ≥ twofold ULN γ-globulin less than absolute criteria inflammation
Bridging necrosis or multilobular Interface hepatitis Severe cytopenia or complete deficiency
necrosis on histologic examination TPMT activity precludes azathioprine
use
Incapacitating symptoms Osteopenia, emotional instability, HTN, Vertebral compression, psychosis, brittle
DM, or cytopenia DM, uncontrolled HTN, known
intolerances to prednisone or
azathioprine

Recommendations from Manns MP, Czaja AJ, Gorham JD, et al. Diagnosis and management of autoimmune hepatitis. Hepatology.
2010;51:2193-2213.
AST, Serum aspartate aminotransferase; DM, diabetes mellitus; HTN, hypertension; TPMT, thiopurine methyltransferase; ULN, upper limits
of normal.
180 PART II Patient Evaluation: Adult

randomized, controlled treatment trials have been per- TPMT enzyme activity may identify individuals at
formed on this group.85 Therefore indications for corti- increased risk for medication toxicity before the initia-
costeroid treatment in patients with mild AIH must be tion of AZA or 6-MP therapy.87
individualized according to the clinical symptoms and The goal of treatment is aminotransferase normaliza-
disease progression, and potential drug-related risks and tion and histological resolution, as well as the clinical
benefits must be weighed against each other. Patients remission of symptoms. Liver biopsy assessment before
with inactive cirrhosis, complication of portal hyperten- termination of treatment is suggested but not essential if
sion without hepatocellular inflammation, or mild interface clinical and laboratory criteria for remission are satisfied.
hepatitis in the absence of symptoms are generally not Liver biopsy can accurately identify histological remis-
candidates for drug therapy because the risks of drug sion and avoids premature drug withdrawal, which has a
therapy may outweigh the benefits. higher incidence of relapse. After remission a normal
The standard initial treatment of AIH is prednisone liver biopsy result has a relapse rate of 20%, compared to
monotherapy or combination therapy with lower-dose portal hepatitis, which has a 50% frequency of relapse at
prednisone and AZA (Table 15-5). Both treatment 6 months. A sustained response without relapse occurs in
strategies are equally effective. Either prednisolone or only 17% of treated patients.
prednisone can be used, and both are effective. Combi- Relapse is the recurrence of disease activity after
nation treatment is generally preferred because of the remission and drug withdrawal, and it occurs in
decreased adverse-effect profile (10% versus 44% in approximately 80% of patients who initially achieve
monotherapy). Determining which strategy to use remission.73 It is characterized by both clinical symp-
involves consideration of the individual patient; combi- toms (fatigue, arthralgias) and a biochemical increase
nation therapy is more appropriate for older adults, in the serum aminotransferase to more than threefold
patients with osteoporosis, and patients with a metabolic normal and/or increase in serum γ-globulin to more
syndrome (postmenopausal, diabetes, hypertension, than 2 g/dL. These biochemical changes are associated
obesity, acne) and/ or psychiatric instability. Monother- with interface hepatitis, and retreatment with standard
apy with corticosteroids is preferred in patients with medical therapy is indicated. Patients that relapse have
hematological abnormalities (cytopenia), thiopurine a higher rate of esophageal varices, progression to cir-
methyltransferase (TPMT) deficiency, malignancy, and rhosis, and death from hepatic failure than patients
pregnancy, and in young fertile patients. A brief treat- with sustained remission.88
ment trial can be used as a diagnostic tool. Patients Two treatment strategies for patients that have
receiving corticosteroids should undergo routine eye relapsed more than two times have been established. One
examinations for cataracts and glaucoma, and those strategy is to use prednisone and titrate the dose accord-
receiving AZA should be monitored for leukopenia and ing to symptoms and biochemical remission. Another
thrombocytopenia (see Table 15-5). It may be prudent strategy is AZA maintenance after remission has been
to monitor AZA metabolites (thioguanine [6-TG]) in achieved. The long-term use of these two strategies has
patients treated with AZA, because there is a narrow not been compared head to head, but both strategies
therapeutic window for this medication. Some individu- have shown inactive or minimal histological disease in
als have genetic polymorphisms of TPMT, an enzyme 94% of follow-up liver biopsies. Twelve percent of
that participates in AZA and 6-MP metabolism. Low or patients treated with these schedules were able to be per-
absent TPMT activity is associated with increased rate manently withdrawn from medications after 70 months
of adverse effects of AZA and 6-MP.86 Thus determining of follow-up.88

TABLE 15-5 Treatment Regimens for Adults

Monotherapy Combination
Prednisone Only (mg/day) Prednisone (mg/day) Azathioprine (mg/day)
Week 1 60 30 50
Week 2 40 20 50
Week 3 30 15 50
Week 4 30 15 50
Maintenance until end point 20 and below 10 50
Reasons for preference Cytopenia Postmenopausal state
Thiopurine methyltransferase Osteoporosis
deficiency
Brittle diabetes
Obesity
Pregnancy Acne
Malignancy Emotional lability
Short course (≤6 mo) Hypertension

Recommendations from Manns MP, Czaja AJ, Gorham JD, et al. Diagnosis and management of autoimmune hepatitis. Hepatology.
2010;51:2193-2213.
 15 Transplantation for Autoimmune Hepatitis 181

Treatment failure is characterized by sustained dis- trimester and post partum. Therefore patients who are
ease activity and can lead to the development or pro- pregnant or who become pregnant should be treated
gression to cirrhosis with portal hypertension and its appropriately for their AIH with either monotherapy
complications leading to death or liver transplantation. or combination therapy through their entire preg-
Treatment failures are treated with high-dose predni- nancy.89 Lastly, those who have coexistent HCV infec-
sone (60 mg) or combination treatment with predni- tions should be treated for their AIH before receiving
sone (30 mg) and AZA (150 mg). Doses are reduced treatment for HCV because interferon therapy may
after each month of clinical and biochemical improve- exacerbate AIH.
ment until conventional maintenance levels of medica-
tions are reached. Seventy-five percent of patients
treated with high doses obtain clinical and laboratory
Adjunctive Medical Treatment
remission, but only 20% achieve histological resolu- Adjunctive medical treatment should be implemented in
tion.72 Treatment is therefore indefinite. Patients who patients who are on chronic corticosteroid treatment or
fail this regimen are at risk for liver failure and drug are at high risk for developing steroid-induced complica-
toxicity, and they commonly become candidates for tions. Adjunctive therapies may prevent or minimize the
liver transplantation and investigational protocols. side effects associated with AIH and its treatments. Reg-
Alternative treatment strategies include cyclosporine, ular exercise (e.g., walking, biking, swimming) and
6-MP, methotrexate, tacrolimus, and mycophenolate weight control should be emphasized because of the high
mofetil.72 incidence of osteoporosis. Postmenopausal women
Incomplete responders achieve moderate clinical, lab- should consider hormonal replacement therapy, and
oratory, and histological improvement that is insufficient symptomatic osteoporosis or progressive osteopenia
to satisfy remission criteria within 3 years. Treatment should be treated with bisphosphonates such as alendro-
extended beyond 3 years is associated with a 7% per year nate (70 mg/wk).90 Antihypertensive medications, diabe-
probability of remission and an increasing risk for drug- tes treatments, gastric acid suppression, and
related toxicity.72 Benefit-risk analysis calculations sug- antidepressants should be administered if corticosteroid
gest that standard therapy should be terminated in these complications arise. Patients should also be monitored
patients after 3 years, and long-term low-dose prednisone for bone disease by annual bone mineral densitometry,
or every-other-day regimen and/or AZA should be and standard yearly health maintenance should also be
started indefinitely. emphasized.
Drug toxicity is the development of severe, drug-
related complications, which may require premature drug
withdrawal or dose reduction. Corticosteroid-related
Other Pharmacotherapies
intolerances are the most common causes of drug discon- Immunosuppression with corticosteroids and azathio-
tinuation. Cytopenia, nausea, emotional liability, hyper- prine have been proven to be effective in the majority of
tension, cosmetic changes, and diabetes are dose-related patients with AIH, but 10% to 20% of treated patients
complications. The corticosteroids should be reduced to do not respond or cannot tolerate doses required for
the lowest dose possible to attenuate symptoms, and AZA optimal inhibition of hepatocellular inflammation and
may be coadministered. Appropriate therapy of the com- fibrogenesis. Alternative immunosuppressive agents
plication must be included, which may include antihyper- have been suggested, but currently there is limited
tensive medication, diabetic regimens, bone maintenance experience with their use.91-96 Cyclosporine has been
schedules, gastric acid suppression, and/or antidepres- used successfully and well tolerated as a primary treat-
sants. If severe reactions occur, the offending drug must ment in pediatric and adult patients. Cyclosporine
be discontinued. inhibits clonal expansion of activated CD4 T helper
cells, blocks the release on IL-2, impairs activation and
expansion of cytotoxic T cells, and decreases antibody
Special Considerations in Treatment production. Tacrolimus (FK-506) inhibits expression
There are several circumstances that may influence the of the IL-2 receptor and prevents expansion of cyto-
decision when and how to treat AIH. These circum- toxic T cells, and results in biochemical improvement
stances include populations at high risk for corticoste- in the majority of treated patients.91 Another option is
roid side effects, those who are pregnant, and those mycophenolate mofetil, which inhibits inosine mono-
who have concurrent HCV infection. High risk for cor- phosphate dehydrogenase, and thus results in the deple-
ticosteroid side effects include brittle diabetes, emo- tion of guanine nucleotides and inhibition of DNA
tional instability, psychosis, osteoporosis, and synthesis.92
uncontrolled hypertension. Corticosteroid therapy is Oral budesonide, a synthetic corticosteroid, may
not necessarily contraindicated in these populations; also successfully induce remission in patines with auto-
however, special precautions and monitoring should be immune hepatitis.93,94 Budesonide undergoes a high
employed, and AZA as part of the initial treatment for degree of first-pass metabolism, reducing its systemic
AIH may be more heavily considered. Cessation of bioavailability, and has a 15-fold greater affinity for the
therapy in pregnant woman has been associated with cotricosteroid receptor than prednisolone, making it a
relapse of disease, and it has been shown that both desirable agent in treating AIH as it has a lower sys-
prednisone and AZA are safe for the fetus. Pregnant temic side effect profile. A recent study by Manns et al.
women are at highest risk for relapse during their third showed that budesonide induced remission more
182 PART II Patient Evaluation: Adult

effectively than prednisone in a controlled trial of and the majority of recipients require long-term ste-
patients with AIH.95 One limitation of budesonide is roids.103,104 Immunosuppressive treatment must be
that it should not be used in patients who are already titrated not only to allograft function but also to its
cirrhotic, as its high degree of first-pass metabolism adverse effects.
renders it an inappropriate agent in such patient
populations.
Because AZA is a prodrug that is metabolized to 6-MP, ACUTE AND CHRONIC ALLOGRAFT
some data have suggested that 6-MP can be used in lieu REJECTION
of the traditional AZA regimen. One such study by Pratt
et al. illustrated the biochemical and clinical response to Patients grafted for AIH are at greater risk for both
6-MP in patients who could not tolerate or failed to acute and chronic rejection.29,105 There is no evidence
respond to ASA.96 that acute rejection is associated with an ominous impact
on graft survival, and there is some evidence suggesting
that it may actually promote tolerance. Acute rejection
ROLE OF LIVER TRANSPLANTATION occurs in about 56% to 83% of patients and is steroid
resistant in 23% to 59%. Patients are also at higher risk
Liver transplantation should be considered in all patients for having multiple acute rejections. Molmenti et al106
who develop decompensated liver disease from autoim- reported an incidence of acute allograft rejection of
mune hepatitis. In fact, transplant is favored over admin- 75% in the first 3 months and 80% in the first year in
istration of corticosteroids as initial treatment in those patients with a diagnosis of AIH before orthotopic liver
who present with fulminant hepatitis and liver failure, transplantation (OLT) compared to 57% and 60%,
because up to 20% of patients progress despite cortico- respectively, in patients without AIH. Having multiple
steroid use and develop potentially life-threatening com- episodes of acute cellular rejection is associated with
plications from the immunosuppression and are at higher AIH recurrence after transplant.106 Sasaki et al107
risk for sepsis.97 Liver transplantation has been associ- reported on a patient with AIH who developed acceler-
ated with a 5-year patient and graft survival ranging from ated rejection during antirejection therapy with OKT3.
83% to 92% and 10-year survival of about 75%.39,98-100 The immunosuppressive regimen should address this
Recurrent disease after transplantation occurs in about concern for acute allograft rejection, and any reduction
12% to 36%, but it is usually mild and manageable.101 in immunosuppression should be performed cautiously,
HLA DR3 or DR4 is found in 100% of patients with particularly in the first several months following liver
recurrent disease compared to 40% of those without transplantation.
recurrence; however, recurrent disease is unrelated to Chronic rejection after liver transplantation is a cause
the HLA status of the donor.101 De novo AIH occurs in of allograft dysfunction, leading to graft failure and
0.7% to 1.4% of adults and 2.3% to 5.2% of children retransplantation. Milkiewicz et al105 reported that
after transplant.102 patients with AIH have an incidence of 15.6% chronic
A multivariate analysis to look for prognostic factors rejection compared to 2% in alcoholic liver disease
that were associated with a more rapid progression of patients. The authors identified the following risk fac-
AIH before transplantation demonstrated that patients tors: young age of transplantation and moderate to
who are age 60 and greater, male sex, with type 2 AIH, severe acute rejection on liver biopsy, which have a
HLA-A1-B8 DR3, and concurrent extrahepatic autoim- higher rate of progression to chronic rejection.105
mune diseases are more likely to progress to liver failure. Patients transplanted for AIH are more prone to devel-
These patients when transplanted are not at a greater risk oping chronic rejection, and therefore they may require
for decompensation.86 The histological and biochemical more intensive immunosuppression after liver
indicators associated with a higher mortality from liver transplantation.
failure are multilobular necrosis and progressive
hyperbilirubinemia.
RECURRENT AUTOIMMUNE HEPATITIS
AFTER TRANSPLANT
IMMUNOSUPPRESSION AFTER LIVER
TRANSPLANTATION Recurrent autoimmune hepatitis after liver transplanta-
tion is characterized by the combination of clinical
AIH patients require more aggressive immunosuppres- symptoms, biochemical changes, autoantibodies, histo-
sion because of the higher incidence of acute rejection, logical features (portal and/or lobular hepatitis with
chronic rejection, and disease recurrence in the allograft. lymphoplasmatic infiltration, plasma cells, piecemeal
The optimal regimen is not established, but most cen- necrosis, bridging fibrosis), steroid dependence, and
ters use a calcineurin inhibitor together with AZA or exclusion of other causes of allograft dysfunction.108
mycophenolate and corticosteroids. It seems sensible to Recurrence of AIH after liver transplant was initially
maintainminimum effective immunosuppression, but reported by Neuberger et al109 in 1984; they reported a
these patients must be carefully monitored with both case of a 26-year-old HLA-B8-DR3–positive woman
serological studies (serum autoantibodies and immuno- with AIH who received an HLA-B8-DR3–negative
globulins) and histological examination. Withdrawal of graft. Recurrent AIH has been reported in several stud-
immunosuppression is rarely possible in these patients, ies with an incidence ranging from 0% to 80%, but in
 15 Transplantation for Autoimmune Hepatitis 183

the majority of large studies ranging from 20% to treated with either increasing immunosuppressants or
30%110-116 (Table 15-6). corticosteroid depending on the disease severity. The dif-
In many cases recurrent AIH is related to suboptimal ference is in the duration of treatment. Recurrent autoim-
immunosuppression, and both biochemical and histolog- mune hepatitis requires a slower taper and potentially
ical features rapidly resolve once adequate immunosup- continual use of additional immunosuppressants.
pression is restored. However, in other cases recurrent
AIH is more aggressive with progression to cirrhosis and
graft failure leading to retransplantation. Recurrence in
Risk Factors for Recurrence
pediatric populations has been reported to be more Recurrence of AIH was found to be more commonly asso-
aggressive, leading to retransplantation more often. ciated with HLA-DR3– or HLA-DR4–positive recipients
Recurrence tends to occur more aggressively in retrans- regardless of donor status, but these findings have not
planted patients. been universally confirmed.10,11,101 There was no increased
Currently there are no established diagnostic criteria for risk depending on the immunosuppression used, such as
recurrent AIH. Its diagnosis is based on the constellation of tacrolimus or cyclosporine.106 A number of studies have
symptoms, autoantibodies, steroid dependence, increased suggested that recurrent AIH is associated with a reduc-
serum transaminase levels, and hypergammaglobulinemia. tion in immunosuppressive medication dosage. However,
The histological diagnosis of recurrent AIH is based on corticosteroids have been successfully withdrawn in many
evidence of portal and/or lobular hepatitis in the presence patients after transplantation.118 In a review of 89 cases
of lymphatic, plasmacytic, or lymphoplasmacytic infil- only 5% with AIH type 2 developed recurrent disease
trates, acidophilic bodies in the liver, and the absence of compared with 34% of AIH type 1.108 The presence of
other histological changes, including those of viral hepatitis, severe necroinflammatory activity in the native hepatec-
drug toxicity, alcoholic hepatitis, and acute or chronic tomy specimen at the time of transplantation was found to
rejection.63,108 be a strong predictor of recurrent AIH.117 There is no
It is important to differentiate acute cellular rejection evidence to support that liver allograft rejection is a risk
from AIH recurrence. The majority of acute rejection epi- factor for the development of recurrent AIH.
sodes occur during the first month after transplantation, Acute cellular rejection has also been found to be
whereas most cases of recurrent AIH are diagnosed more associated with AIH recurrence. Ayata et al117 first
than 12 months after transplantation. Recurrent AIH can described a high incidence of acute cellular rejection (10
be distinguished from acute cellular rejection by the pres- of 12 patients) in patients with recurrent AIH. Recently
ence of periportal and lobular hepatocellular necrosis, lack Molmenti et al106 demonstrated a greater incidence of
of portal or centrilobular venulitis, lack of immunoblasts acute cellular rejection during the first year after OLT in
in the inflammatory infiltrate, and cholestasis. Both recur- patients with recurrent AIH; however, graft failure was
rent autoimmune hepatitis and acute rejection can be not increased.

TABLE 15-6 Recurrent Autoimmune Hepatitis After Liver Transplantation

Onset After LT Response to
Author Patients Recurrent AIH (months) Treatment Risk Factors Identified
González-Koch et al101 41 7 (17%) 52 Yes Recipient HLA-DR 3/4
Prados et al98 27 9 (33%) 30 Yes 5/9 LKM-1 negative pre-LT
Ratziu et al12 15 3 (20%)
Milkiewicz et al28 47 13 (28%) 3 regrafts
Bahar et al99 40 13 (32%)
Reich et al100 32 6 (19%) 3 regrafts
Ayata et al117 12 5 (42%)
Duclos-Vallee et al114 17 7 (41%)
Birbaum et al110 6 5 (83%) 11.4 3 regrafts
Campsen et al115 66 23 (35%)
Vogel et al116 28 5 (18%)
Narumi et al11 40 5 (12%) 17.5 Yes 4/5 Recipient HLA-DR3
Sanchez-Urdazpal et al39 24 0 (0%)
Ahmed et al9 33 20 (61%) 24 Yes
Wright et al10 43 11 (26%) 18 Recipient HLA-DR3
Gotz et al112 24 12 (50%) Yes
Yusoff et al113 12 2 (17%)
Molmenti et al106 55 11 (20%) 3 Yes ACR episodes

Note: Only studies/reports with N greater than or equal to 5 used in this table.
ACR, Acute cellular rejection; AIH, autoimmune hepatitis; HLA, human leukocyte antigen; LKM, liver-kidney microsomal antibody;
LT, Liver transplantation.
184 PART II Patient Evaluation: Adult

Pathogenesis grafted for AIH, but their features were reminiscent of clas-
sic AIH, including high levels of immunoglobulin G, serum
One hypothesis of recurrent AIH involves the existence autoantibodies (1 ANA, 2 ANA/SMA, 3 atypical LKM, 1
of memory T cells in the recipient that can be reactivated gastric parietal cell antibody), and histological findings of
by antigens expressed by the donor liver that are processed interface hepatitis, perivenular cell necrosis, bridging fibro-
and presented by the antigen-presenting cells (APCs) of sis, and collapse. The presence of autoantibodies is associ-
the recipient.52 The speed of replacement of APCs of the ated with an unfavorable post-LT clinical course that
donor allograft with APCs of the recipient and/or the includes chronic hepatitis, graft dysfunction, chronic rejec-
number of recipient APCs outside the liver in lymph tion, and death.122,125 Interestingly, the reported cases did
nodes and spleen may in part determine the onset and/or not respond to high-dose steroids and an increased dose of
severity of AIH recurrence. calcineurin inhibitors but only to standard treatment for
Another hypothesis is direct activation of the recipient AIH, which led to excellent graft and patient survival.101
T-cell receptors by the major histocompatability complex Relapse tends to occur after decreasing or withdrawing ste-
(MHC) molecules expressed by the APCs of the allo- roid maintenance therapy.122 De novo AIH has subse-
graph.52 Therefore the existence of other autoimmune quently been reported and identified in adults. Because this
promoters that impair self-tolerance has been postulated. is an exceedingly rare outcome, there are no definitive inci-
Autoimmune promoters, such as polymorphisms of the dence rates reportable as of now. One such report identified
genes producing cytokines, may facilitate direct cytotox- AIH in seven adult patients after LT, and two patterns of
icity and regulate immunocyte activation.119 disease were identified. One was characterized by low trans-
Another hypothesis is molecular mimicry between aminase levels and ANA or SMA positivity at low titers, and
unidentified hepatotropic viruses infecting the allograft the other by high transaminase levels and high-titer LKM-
and self-antigens cannot be excluded as a basis for recur- 1.126 All patients were treated with immunosuppression, but
rence, and there is a possibility of undiscovered viruses unlike the pediatric group, two patients developed graft
that could trigger immunoreactivity.120 failure. There are also two reported cases of three patients
In summary, patients who continue to have evidence transplanted for primary biliary cirrhosis who developed
of recurrent autoimmune hepatitis may benefit from concurrent de novo AIH and recurrent PBC and responded
increasing the dose of existing immunosuppression or very well to corticosteroids.129,130
restarting corticosteroids without AZA. In patients that Some risk factors for developing de novo AIH pro-
have progressive disease, tacrolimus may offer an advan- posed by Salcedo et al131 include receiving a graft from a
tage over cyclosporine-based immunosuppression.121 male donor, original liver disease being non–alcohol
related, and having autoantibodies besides glutathione
S-transferase T1 (GSTT1).
The following items have proposed in the evaluation
DE NOVO AUTOIMMUNE HEPATITIS of de novo AIH: (1) allograft dysfunction not associated
AFTER LIVER TRANSPLANTATION with other known causes of graft dysfunction, such as
vascular or biliary disease, rejection, or viral hepatitis; (2)
(GRAFT DYSFUNCTION MIMICKING presence of autoantibodies; (3) histological evidence of
AUTOIMMUNE HEPATITIS) portal and periportal hepatitis with or without centrilobu-
lar necrosis, and lymphoplasmacytic portal tract infiltrate
De novo autoimmune hepatitis is a posttransplantation with a variable degree of plasma cells; (4) response to
clinical syndrome that rarely occurs unpredictably in standard therapy.122
patients transplanted for nonautoimmune liver disease122-125
(Table 15-7). This syndrome was originally reported in 7
out of 180 pediatric liver allografts that developed graft dys-
Pathogenesis
function at a median period of 24 months after liver trans- The pathogenesis and development of de novo autoimmu-
plantation (LT).102 None of the patients were originally nity after LT in patients transplanted for nonautoimmune

TABLE 15-7 De Novo Autoimmune Hepatitis After Liver Transplantation

Author Patients De Novo AIH Group Response to Treatment
Heneghan et al126 1000 7 (0.7%) Adults 2 lost grafts
Andries et al124 471 11 (2.3%) Children Yes 7/11
Gupta et al127 115 6 (5.2%) Children 2 lost grafts
Kerkar et al102 180 7 (3.9%) Children Yes
Hernandez et al125 155 5 (3.2%) Children Yes 3/5
Spada et al123 116 5 (4.3%) Children Yes
Salcedo et al122 350 12 (3.4%) Children Yes
Venrick et al128 788 41 (5.2%) Children Yes

Note: Only studies/reports with N greater than or equal to 5 used in this table.
AIH, Autoimmune hepatitis; LT, liver transplantation.
 15 Transplantation for Autoimmune Hepatitis 185

conditions remain unclear. In addition to release of auto- Pearls and Pitfalls—Cont’d

antigens from damaged tissues, a possible mechanism is
molecular mimicry, in which exposures to viruses with • Those who develop de novo AIH need long-term
autoantigens leads to cross-reactive immunity.47 Viral immunosuppression that should not be discontinued
infections may also lead to autoimmunity through other prematurely.
mechanisms, including polyclonal stimulation, enhance- • Patients that present with AIH in fulminant liver fail-
ment and induction of membrane expression of MHC ure should proceed directly to OLT, because they can
class I and II antigens, and interference with immunoregu- develop life-threatening complications (i.e., sepsis)
latory cells and/or with idiotype anti-idiotype network.132 with corticosteroid administration.
• Do not treat de novo AIH with high-dose steroids be-
Another possible mechanism suggested by animal experi- cause it does not typically respond well to high-dose
ments is that calcineurin inhibitors predispose to autoim-    steroids, but rather to standard AIH treatment.
munity and autoimmune disease, possibly by interfering
with the maturation of T lymphocytes or with the function
of regulatory T cells, with consequent emergence and acti-
vation of autoaggressive T-cell clones.133 Tacrolimus REFERENCES
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 CHAPTER 16

Transplantation for Primary

Hepatic Malignancy
Nicholas Onaca • Marvin J. Stone • James M. Fulmer • Göran B.G. Klintmalm

CHAPTER OUTLINE

DIAGNOSTIC MEDICAL IMAGING EVALUATION OF Technical Considerations

SOLID HEPATIC MASSES Improvement in Results After Liver
Transplantation
HEPATOCELLULAR CARCINOMA
Tumor Recurrence After Transplantation
Epidemiology
Adjuvant Treatment
Clinical Presentation and Diagnosis
Immunosuppression
Staging
Liver Transplantation in Patients
Prognostic Factors and Risk Factors for Poor With Hepatocellular Carcinoma and
Tumor Biological Properties No Cirrhosis
Organ Allocation
Ablation Therapies and Liver Transplantation CHOLANGIOCARCINOMA
Neoadjuvant Chemotherapy EPITHELIOID HEMANGIOENDOTHELIOMA
Pretransplant Treatment and Follow-up METASTATIC HEPATIC TUMORS
Orthotopic Liver Transplantation

Fifty years have passed since the first liver transplanta- the waiting list for progression of tumor. Whether neo-
tion was performed by Thomas E. Starzl. Orthotopic adjuvant treatments have an effect on overall posttrans-
liver transplantation (OLT) has become the recom- plant survival is unclear.16
mended treatment in patients with hepatocellular carci- Since the previous edition of this textbook, pretrans-
noma (HCC) and cirrhosis,1-4 as well as for other plant and posttransplant management of hepatic tumors
selected tumors. This was not always straightforward; has shifted significantly. Some issues remain unresolved,
the first cases, performed starting in 1967, resulted in and some new controversies arose. This chapter aims to
early recurrence of tumor in the first months after trans- review the role of OLT in the treatment of primary liver
plantation, with early mortality in most cases.4-9 This malignancies and the current scope and use of neoadju-
led the health authorities in the United States to recog- vant and adjuvant therapies.
nize HCC as a contraindication for liver transplantation
in 1989.10 Further research showed that tumor burden
in the native liver correlates with tumor recurrence and
mortality after transplantation. The Milan group showed
DIAGNOSTIC MEDICAL IMAGING
in 1996 that transplantation of patients with a small EVALUATION OF SOLID HEPATIC
tumor burden results in posttransplant survival similar MASSES
to that of noncancer patients.11,12 Their results were
quickly replicated by other centers,13,14 leading to the With more imaging being performed, it is more likely to
uniform acceptance of the Milan tumor inclusion crite- diagnose solid hepatic masses. Evaluation of solid liver
ria as a benchmark for patient selection in the United lesions has evolved to include various imaging technolo-
States (http://www.unos.org) and elsewhere.15 By that gies, and a multimodality approach is typically used to
time the liver transplant waiting list had increased in address them.17-20 With progress being made in image
size, and waiting time for transplant became close to a accuracy, the same characteristics of the liver lesions need
year, resulting in patient dropout (and subsequent death) to be addressed—their precise location within the liver
due to progression of tumor. This led to a broader adop- parenchyma, the spatial relationship of the lesions to the
tion of neoadjuvant therapy as a bridge to transplanta- vascular and biliary structures, the number of lesions,
tion, which has been shown to decrease dropout from their margins, their internal structure, and possible

189
190 PART II Patient Evaluation: Adult

invasion beyond the liver or distant lesions, related or occasionally mimic malignant processes, and therefore
unrelated. they need careful assessment for typical benign features
The location of a liver lesion can be determined based (Fig. 16-6).
on the known surgical planes and the anatomical land- A complete evaluation of liver tumors requires
marks within the liver. Location is best determined by characterization of the nontumor liver tissue, a search
contrast-enhanced computed tomography (CT) scan or for additional tumor nodules, and extrahepatic spread
magnetic resonance imaging (MRI) (Fig. 16-1). Defining with abdominal adenopathy and metastases (lung,
the location of a liver lesion is important for treatment bone). Positive emission tomography (PET) scanning
planning, whether through surgery (anatomical or non- is helpful in differentiating metastases from benign
anatomical resection) or ablation therapy. processes.
The benign or malignant nature of liver lesions can The evaluation of hepatic masses requires a multidisci-
be determined by imaging, and therefore pathological plinary approach—because characterization of liver
confirmation is not mandatory. Despite some variabil- masses dictates both the therapeutic approach and the
ity, certain tumor features, if present, can lead to strong follow-up imaging modality and frequency.
suspicion of malignancy, such as a solid, round lesion
with enhancement denoting rich arterial supply. Mar-
gins of malignant lesions are usually irregular from
compression of adjacent tissue, thus resulting in local-
ized edema and somewhat feathery or indistinct contour
(Fig. 16-2). When abutting the liver capsule, they can
cause retraction and thus liver contour deformity. Vas-
cular invasion by tumors is found as intrinsic occlusion
of portal vein branches more often than by extrinsic
compression.
Primary biliary malignancy (cholangiocarcinoma
[CCA]) localized centrally in the liver can be very diffi-
cult to diagnose based on imaging. These tumors are
frequently similar in imaging characteristics to the sur-
rounding hepatic tissue: isoechoic on sonography,
isodense on CT, isointense on MRI scanning (Figs. 16-3
and 16-4). Hilar adenopathy can raise suspicion,
although it can be present in underlying primary scle-
rosing cholangitis (PSC). Peripheral CCAs have a more
typical appearance, with brisk arterial contrast enhance-
ment on CT and high signal intensity on T2-weighted
MRI scans.
Some of the liver tumors identified on imaging have
clear-cut features of benign processes, such as cavernous FIGURE 16-2 n Contrast-enhanced computed tomography dem-
hemangiomas, focal nodular hyperplasia, hepatic cysts, onstrates typical enhancement pattern in a patient with multifo-
and focal fatty infiltration (Fig. 16-5). They can cal hepatocellular carcinoma (arrows).

A B
FIGURE 16-1 n Magnetic resonance evaluation with T1-weighted, contrast-enhanced, fat-suppressed axial image (A) and T1-weighted
coronal image (B) accurately depict the size and precise location of central hepatocellular carcinoma (arrows).
 16 Transplantation for Primary Hepatic Malignancy 191

The case-fatality ratio is 0.8, and the median survival is

HEPATOCELLULAR CARCINOMA less than 6 months in most cases.
In the United States, HCC is more prevalent in
Epidemiology Asians and American Indians, followed by African Amer-
The majority of the malignant lesions of the liver in the icans, and whites.26 HCC is three times more frequent
United States are metastatic in origin. HCC accounts for in men compared to women. Patients with established
80% to 90% of the primary malignancies, whereas CCA cirrhosis have an annual HCC incidence of 3% to 10%
constitutes most of the rest.21,22 Some of the tumors depending on the underlying liver disease. Chronic
exhibit mixed features of HCC and CCA.23 Most patients inflammation in the liver leads to necrosis followed by
with HCC in the Western Hemisphere (70% to 90%) increased regeneration, which can lead to a higher rate
have some degree of cirrhosis.21 In Asia and West Africa, of cell mutation and hence carcinogenesis.27 The hepa-
HCC occurs frequently in normal liver tissue. The inci- titis B virus can also act directly with disruption of the
dence rate in these areas is 30 cases per 100,000 popula- hepatocyte DNA followed by faulty repair. HCC can
tion.21 HCC is the fifth most common malignancy also occur via the pathway of adenomatous hyperplasia,
worldwide, with more than a million new cases a year. It which can lead to malignant transformation. These
ranks as the third most fatal tumor worldwide.21 The changes are associated with marked alteration of the
incidence of HCC more than doubled in the United apoptosis-to-mitosis ratio.
States in the last decades21,24: it rose from 1.6 cases per In Asia the incidence of HCC correlates with that of
100,000 population in 1975 to 4.9 per 100,000 in 2005.25 hepatitis B, whereas the most frequent cause of HCC in
the West is hepatitis C (HCV). The risk of HCC seems
to be maximal 30 years after infection with HCV. There
is an increase in the incidence of HCC parallel to the
rise of HCV, which is expected to peak in 2025.28,29 In
Western countries, the United States in particular, the
obesity epidemic leads to an increase in the incidence of
nonalcoholic steatohepatitis, which if uncontrolled, will
be the leading cause of cirrhosis and HCC. Hemochro-
matosis, although relatively rare in the population, car-
ries a 45% risk of HCC.30 Genetic abnormalities, such
as chromosome aberrations or gene mutations, have
been described with HCC,31,32 but a unifying genetic/
molecular mechanism was not characterized. Other risk
factors for HCC include aflatoxin, azo dyes, aromatic
amines, N-nitroso compounds, chlorinated hydrocar-
bons, hydrosol compounds, pesticides, radiation,
thorotrast, smoking, porphyria, Budd-Chiari syndrome,
oral contraceptives, anabolic steroids, and α1-antitripsin
FIGURE 16-3 n Magnetic resonance cholangiopancreatography
deficiency.21,22 HCC is less common in patients with
demonstrates malignant long-segment narrowing of the common autoimmune hepatitis, Wilson's disease, and alcohol-
bile duct (arrows) in a patient with central cholangiocarcinoma. induced cirrhosis.33

A B
FIGURE 16-4 n Computed tomography demonstrates vague soft tissue density in the hepatic hilum surrounding the common bile duct
(A; arrows) and omental caking (B; arrows) in a patient with cholangiocarcinoma presenting with peritoneal carcinomatosis.
192 PART II Patient Evaluation: Adult

A B

C
FIGURE 16-5 n Contrast-enhanced magnetic resonance evaluation demonstrates typical enhancement pattern of cavernous hemangi-
oma. Lobulated contour and peripheral, nodular, or cloudlike enhancement (A; arrows) associated with progressive centripetal filling
of the lesion (B and C; arrows) confirm cavernous hemangioma.

A B
FIGURE 16-6 n Contrast-enhanced magnetic resonance imaging demonstrates a typical appearance of focal nodular hyperplasia. This
lesion is nearly isointense to hepatic parenchyma, often demonstrates central nidus (A; arrow), and shows arterial-phase contrast
enhancement (B; arrow).
 16 Transplantation for Primary Hepatic Malignancy 193

Although PET scans may predict microvascular inva-

Clinical Presentation and Diagnosis sion,56 they are rarely used in practice.
In patients with known chronic hepatitis, most cases of At times it is difficult to differentiate benign nodules in
HCC are found by screening imaging. Unfortunately, the cirrhotic liver from HCC, or focal nodular hyperpla-
HCC tumors become symptomatic when already in an sia can mimic malignancy. In this situation a tumor biopsy
advanced stage. Some patients may present with diffuse is warranted. Tumor biopsy had excellent sensitivity and
or localized abdominal pain, sometimes radiating to the specificity, except for small nodules55; 2% to 11% of
right shoulder, postprandial fullness, or jaundice. Others specimens are inadequate. Routine biopsy of lesions sus-
present with a palpable mass or deterioration of liver picious for HCC has been discouraged. Because HCC is
function. Sudden abdominal enlargement is an ominous a well-vascularized tumor, there is a higher risk of bleed-
sign, as it can be related to portal vein thrombosis or ing than with liver biopsy.57 There is also a 1% to 5.1%
tumor bleeding. Patients typically display symptoms of risk of parietal tumor seeding, which results in metastasis,
chronic liver disease, with splenomegaly, ascites, and with a median occurrence of 17 months,55 and most
jaundice. Some patients have paraneoplastic syndromes, metastases are hard to treat.58-63 Currently the diagnosis
with polycythemia, polymyositis, deep vein thrombosis, of HCC can be made using two different imaging modal-
hypoglycemia, and chronic diarrhea. ities or one imaging modality and elevated AFP level.64
Serum α-fetoprotein (AFP) level is a useful marker Diagnosing HCC without a biopsy comes at the expense
when elevated, especially if above 400 ng/mL,34 and 70% of false-positive results (e.g., no tumor in the pathological
of patients have elevated AFP level. Des-gamma-carboxy examination of the explant).65,66
prothrombin level is similarly useful when elevated35,36; When performed, a tumor biopsy can diagnose poorly
however, it has not gained widespread use. Further diag- differentiated tumors or vascular invasion, in which case a
nosis is made with imaging.37 Ultrasonography is mostly liver transplant is contraindicated. However, tumors, espe-
a screening tool for the diagnosis of HCC.38 Contrast- cially large ones, are heterogenous, and at times tumor dif-
enhanced sonograms (with liquid microspheres) increase ferentiation can be overestimated, and vascular invasion is
the sensitivity for HCC39-41; the procedure is not avail- missed. Certain tumors require differentiation from CCA
able in most countries. A more complete assessment of or metastatic tumors, typically with additional staining for
tumor size, characteristics, and tumor burden is made AFP, carcinoembryonic antigen, CD10, and CD15.60
with multiphasic contrast CT scanning or MRI scan.37,42 Imaging for extrahepatic staging of HCC include
Most tumors have the characteristic arterial blush. In CT scan of chest, abdomen, and pelvis, and bone scan
this situation the suspicion of HCC is very strong. CT or (Fig. 16-7).
MRI provides complete imaging of the liver. Both
CT19,38,43-49 and MRI scans19,45-47,50-54 have good sensi- Staging
tivity and specificity. In a systematic review of studies
where imaging was compared with pathological charac- Multiple staging systems were adopted for HCC, whether
teristics of explants, the sensitivity of imaging increased strictly oncological or prognostic or combined. The
from 60.5% for sonograms, to 67.5% for CT, and 80.6% TNM system, based on tumor size and number (T),
for MRI, whereas the specificity decreased from 96.9% lymph node involvement (N), and the presence or absence
(sonogram), to 92.5% (CT), and 84.8% (MRI).55 of metastasis (M) has undergone a few revisions; the most

A B
FIGURE 16-7 n Contrast-enhanced computed tomography (CT) demonstrates peripheral hepatocellular carcinoma (HCC) in a patient
with cirrhosis (A; arrow). The skeletal windows (B) reveal multifocal osseous metastases (arrows).
194 PART II Patient Evaluation: Adult

TABLE 16-1 T
 NM Staging for Hepatocellular TABLE 16-3 C
 ancer of the Liver Italian Program
Carcinoma (CLIP) Scoring System for
Hepatocellular Cancer
T1 Solitary tumor without vascular
invasion Variable Score
T2 Solitary tumor with vascular
invasion or multiple tumors none Child-Turcotte-Pugh class
more than 5 cm A 0
T3 Multiple tumors more than 5 cm or B 1
tumor involving a major branch of C 2
the portal or hepatic vein(s)
T4 Tumor(s) with direct invasion of Tumor Morphological Characteristics
adjacent organs other than the Uninodular and extension ≤ 50% 0
gallbladder or with perforation of Multinodular and extension ≤ 50% 1
visceral peritoneum Massive or extension > 50% 2
N0 Indicates no nodal involvement
N1 Indicates regional nodal involvement α-Fetoprotein
<400 ng/mL 0
M0 Indicates no distant metastasis
≥400 ng/mL 1
M1 Indicates metastasis presence
beyond the liver Portal Vein Thrombosis
Stage Grouping No 0
Stage I T1 + N0 + M0 Yes 1
Stage II T2 + N0 + M0
Stage IIIA T3 + N0 + M0
Stage IIIB T4 + N0 + M0
portal vein thrombosis, and AFP levels, with severity
Stage IIIC TX + N1 + M0
ranging from 0 to 6 (Table 16-3).69-71
Stage IVB TX + NX + M1
Although considered a staging system, the Barcelona
NX, Any N; TX, any T. Clinic Liver Cancer (BCLC) classification is a treatment
algorithm and not a pure staging tool. It combines the
Okuda staging with the CTP score, number and size of
TABLE 16-2 O
 kuda Staging System for nodules, portal vein thrombosis, and functional status to
Hepatocellular Carcinoma recommend treatment modalities (Fig. 16-8).
Criteria Positive Negative
Prognostic Factors and Risk Factors for
Tumor size* >50% <50%
Poor Tumor Biological Properties
Ascites Clinically detectable Clinically absent
Albumin level <3 mg/dL >3 mg/dL Because most of the HCC tumors arise in the setting of
Bilirubin level >3 mg/dL <3 mg/dL chronic liver disease with or without cirrhosis, the prog-
Stage
nosis of HCC is dictated not only by the tumor biological
I No positive properties and progression, but also by the severity and
II One or two positives evolution of the underlying liver disease. Adverse tumor
III Three or four positives factors have been studied extensively. Adverse tumor fac-
tors include tumor size, number of nodules, poor tumor
*As percentage of liver volume. differentiation, vascular invasion, nodal or extrahepatic
involvement, and portal vein thrombosis.72-75 Portal vein
thrombosis due to HCC is a contraindication and needs
recent version is shown in Table 16-1. Liver transplanta- to be differentiated from bland portal vein thrombi. Poor
tion mostly benefits patients with stage I or II tumors, tumor differentiation and vascular invasion are strong
although some transplants are performed for some stage determinants of poor oncological outcome.13,76-78 Unfor-
IIIA patients using expanded tumor inclusion criteria. tunately, vascular invasion cannot be diagnosed with the
The TNM system has limitations,14 because the data current imaging or laboratory tests available.56 Patho-
used in decision making are based on imaging and not logical data are seldom available before transplant, and a
actual histological results, and imaging can underestimate tumor biopsy sample can miss vascular invasion. Vascular
tumor burden in stage II patients by 27% to 33%. The invasion is the strongest predictor of poor outcome, and
severity of the background liver disease, an important it correlates with tumor size and number of nodules.77
part of prognosis, is not part of TNM. TNM staging Tumors greater than 5 cm in diameter, a larger number
does not correlate with posttransplant survival.67 of nodules,77 and high AFP level are associated with
To better evaluate prognosis, several groups have pro- poorer differentiation and a higher likelihood of vascular
posed staging systems that include both pathological and invasion.73,77,79 AFP values greater than 400 ng/mL and
functional criteria. The Okuda staging system (Table 1000 ng/mL are associated with poor outcome in group
16-2) combines tumor size with serum bilirubin level, comparison, but not for every patient. High levels of des-
albumin level, and ascites.68 The Cancer of the Liver Ital- gamma-carboxy prothrombin (protein induced by vita-
ian Program (CLIP) score combines tumor morphologi- min K antagonist II [PIVKA-II]) are associated with
cal characteristics, Child-Turcotte-Pugh (CTP) score, worse posttransplant outcomes.36,80,81 Fast tumor
 16 Transplantation for Primary Hepatic Malignancy 195

HCC

Stage 0 Stage A-C Stage D

PST 0, CTP A, Okuda 1 Okuda 1-2, PST 0-2, CTP A-B Okuda 3, PST >2, CTP C

Very early stage (0) Early stage (A) Intermediate stage (B) Advanced stage (C) Terminal
Single <2 cm Single or 3 nodules <3 cm, PS 0 Multinodular, PS 0 Portal invasion N1, M1, PS 1–2 stage (D)
Carcinoma in situ

Single 3 nodules ≤3 cm

Portal pressure/bilirubin
Increased Associated diseases Portal invasion, N1, M1

Normal No Yes No Yes

Liver transplantation New

Resection PEI/RF Chemoembolization
(CLT/LDLT) agents

Curative treatments (30%) Randomized controlled trials (50%) Symptomatic treatment

5-yr survival: 50-70% 3-yr survival: 20-40% (20%)
1-yr survival: 10-20%
FIGURE 16-8 n The Barcelona Clinic Liver Cancer staging classification and treatment plan. CLT, cadaveric liver transplantation;
CTP, Child-Turcotte-Pugh; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; PEI, percutaneous ethanol injection;
PS,; PST, performance status test; RF, radiofrequency ablation.

progression typically denotes poor tumor biological to that of patients within Milan criteria, whereas patients
properties and is associated with high recurrence rate and exceeding both Milan and UCSF criteria have signifi-
mortality after transplantation. cantly worse outcome. Using data from the International
Registry of Hepatic Tumors in Liver Transplantation,
Organ Allocation our group showed results identical to the Milan criteria
in patients with single tumors up to 6 cm, or up to three
The ideal deceased donor liver allocation scheme should tumors up to 5 cm in diameter (Dallas criteria), and poor
result in minimum patient dropout from the waiting list outcomes in patients exceeding these criteria.84 This was
for progression of HCC, should minimize tumor recur- observed by another group in a smaller series.85 Based on
rence after OLT, and should not put other patients at these data, UNOS Region 4 has introduced expanded
disadvantage in terms of pretransplant and posttransplant tumor inclusion criteria, based on the Dallas criteria,
survival. Current tumor inclusion criteria for liver trans- except that with multiple tumors the maximum sum of
plantation for HCC are based on a combination of tumor diameters can be up to 9 cm. The implementation of the
size and tumor nodules. Mazzaferro et al11 showed in Region 4 criteria allowed transplantation of 15% more
1996 that patients who had a single tumor of 5 cm diam- patients with no penalty in outcome.86 If expanded tumor
eter or up to three tumors up to 3 cm in size had the same inclusion criteria are used, pretransplant ablation therapy
survival after liver transplantation as patients trans- is recommended to obtain good posttransplant
planted without HCC. Although never validated in a outcomes.87
controlled study, these criteria, known as the Milan crite- Other expanded criteria were proposed. Mazzaferro
ria, were extensively validated by other groups and et al, studying a large number of HCC patients exceeding
became both the tumor inclusion criteria in most West- the Milan criteria, described the concept of
ern countries for allocation of deceased donor organs and “Metroticket”—where the farther away we stray with
the benchmark that all subsequent criteria are compared tumor inclusion criteria, the higher price we pay in tumor
to. However, many centers have eventually transplanted recurrence rate and mortality—suggesting the up-to-
patients exceeding the Milan criteria with good out- seven tumors criteria.88,89 The Asian groups are advocat-
comes, and therefore many believe that the Milan criteria ing transplantation in patients with higher tumor burden,
might be too restrictive. Yao et al designed the Univer- such as the 7-7 criteria from Tokyo (7 tumors up to 7
sity of California, San Francisco (UCSF) criteria, where cm). Whether wide expansion of criteria can be applied to
inclusion applies to single tumors up to 6.5 cm or up to patients in the Western hemisphere is a matter of debate.
three tumors, where the sum of diameters does not Whereas in Asian countries most transplants are per-
exceed 8 cm. The criteria were designed retrospectively formed using living donor liver transplantation (LDLT),
and validated prospectively by UCSF and others.82,83 any expansion of criteria for deceased donor allocation
Posttransplant survival and tumor recurrence of patients can result in diversion of organs from other patients on
exceeding Milan but within UCSF criteria were similar the liver transplant waiting list.
196 PART II Patient Evaluation: Adult

Patients with HCC are prioritized on the waiting list progression of tumors while waiting for a transplant. Pro-
in many countries in an effort to avoid progression of gression of tumor can make the patient ineligible for
tumors beyond the inclusion criteria, which in turn transplant, leading to delisting and death. Another con-
results in dropout from the waiting list and death from troversial aim is tumor downstaging—where patients
cancer. Despite the fact that the UNOS allocation sys- exceeding the acceptable tumor burden are brought into
tem gave some priority to HCC patients in the United the eligibility criteria by ablation treatments.106 The con-
States, dropout rates from HCC tumor progression were troversy arises from the fact that a higher tumor burden
as high as 25% at 1 year and 43% in 2 years' waiting time is associated with a higher probability of adverse tumor
by 2001.90 The current deceased donor liver allocation is biological properties, which in turn is associated with
based on the Model for End-Stage Liver Disease higher recurrence rate of HCC and poor survival after
(MELD) score.91,92 Most patients with HCC do not have transplantation.77 Therefore advocates for downstaging
a high bilirubin level/creatinine level/ international nor- recommend waiting time after the ablation procedure,
malized ratio and thus have a low MELD score. There- coined ablate and wait strategy.107 The degree of response
fore HCC patients require allocation of a higher score to after ablation correlates with posttransplant survival.108,109
facilitate their access to transplantation.92 At its intro- Rapid progression of tumor after ablation indicates poor
duction in 2002, HCC patients received high MELD tumor biological characteristics and is associated with
scores and had too high a priority on the waiting list, poor prognosis following transplant108,109; in this situa-
which resulted in waiting times to transplant of less than tion, liver transplantation should not be performed.
a month, which was felt to disadvantage the other The choice of ablation method depends on the ana-
patients waiting on the list.66,93-95 This resulted in a six- tomical location of the tumors and the number of nod-
fold increase in the number of patients with HCC trans- ules, the proximity to vascular structures, the patency of
planted. This raised the concern non-HCC patients on the portal vein, hepatic veins, and their branches, and
the waiting list could be disadvantaged or harmed by the institutional preference. Chemotherapy infusion and bland
allocation.96 The allocation since then was revised twice; hepatic arterial embolization are not effective and were
the current allocation of exception points applies to largely abandoned in favor of transarterial chemoemboli-
patients with tumors more than 2 cm in diameter (T2). zation (TACE)110 with or without chemotherapy drug–
Patients exceeding tumor inclusion criteria are not allo- eluting beads. TACE with drug-eluting beads leads to
cated exception points. Patient survival after transplant superior tumor response.111 Radiofrequency ablation is
for HCC has improved.97,98 an effective ablation therapy for tumors not located close
The relatively long waiting times to transplantation to large vessels, resulting in complete or partial ablation.
for patients with HCC and the severe shortage or lack of It slows down tumor progression while the patient is on
deceased donor livers led to the introduction of the waiting list.112-116 Beta radioactive beads, cryother-
LDLT.99-101 As the MELD score–based system was apy, and CyberKnife ablation are performed for specific
introduced and waiting time for HCC patients has indications. Ethanol or acetic acid injection of tumors is
decreased, LDLT for HCC has declined in the United effective and is used in some institutions.117,118
States. With the newer limitations of priority and higher There are no large studies comparing the various abla-
MELD scores at transplantation there may be a renewal tion methods. Although ablative procedures can slow
of interest in living donation. It is unclear whether down tumor progression while the patient is on the trans-
LDLT achieves similar results, especially outside the plant waiting list, there is no solid evidence that pretrans-
Milan criteria.89,102-104 A higher tumor recurrence rate plant ablation improves patient survival and cancer-free
was reported with LDLT,104 possibly from shorter survival after transplantation.119-122 Ablative procedures
waiting time. However, in countries where deceased seem to be more effective in T2 and T3 lesions. The
donation is rare, LDLT is a very good alternative.100,105 tumor recurrence rate with T1 lesions is low, and there-
fore ablation therapy is not recommended with T1
Ablation Therapies and Liver tumors if OLT is contemplated. Ablative procedures
seem to be more effective if the waiting time to transplant
Transplantation is longer than 6 months.123
The majority of patients with HCC are diagnosed with Liver resection has been performed before OLT.
either advanced disease or cirrhosis. Resection of the However, this was done mainly in CTP class A cirrhotic
tumors is a potentially curative procedure. However, the patients and OLT followed as “rescue” treatment for
5-year survival after hepatic resection is only 30%. This tumor recurrence or for metachronous tumors.124 Most
is due to multiple reasons. The underlying liver disease studies show that “rescue” OLT carries a poor posttrans-
can generate multiple synchronous or metachronous plant prognosis,125 although it can be performed with
HCC lesions, can progress to liver failure, or both. good survival rates with proper (i.e., longer) waiting
Resection is often not feasible, because 80% to 90% of time.126,127
the patients in the Western Hemisphere have cirrhosis
and the liver dysfunction precludes resection. Liver
transplantation, when used in selected patients, has a
Neoadjuvant Chemotherapy
5-year survival of 75% to 80%. Neoadjuvant chemotherapy has gained renewed interest.
Neoadjuvant treatments include chemotherapy and The initial experience showed modest advantage from
ablative therapy. The mainstay is currently ablation ther- neoadjuvant treatment. Sorafenib, a vascular endothelial
apy. The aim of neoadjuvant treatment is to prevent the growth factor (VEGF) inhibitor, was introduced in the
 16 Transplantation for Primary Hepatic Malignancy 197

treatment of HCC and is associated with prolonged sur- and caval sparing (piggyback technique). Originally,
vival in patients with advanced HCC. The median sur- caval interposition was recommended as the sole
vival advantage reported is only 3 months, which does not approach for liver transplantation for HCC. However,
look promising in the general population. However, 3 tumor recurrence rates are similar with the piggyback
months' survival benefit can be a huge advantage on the technique. If the HCC is in the caudate lobe, however,
waiting list for transplantation.128 resection of the native cava should in theory offer better
tumor control.
Pretransplant Treatment and Follow-up Some of the recipients who underwent transarterial
treatments, such as TACE, are more prone to dissection
Regardless of the use of neoadjuvant treatment or not, of the hepatic artery and branches. This needs to be care-
HCC patients on the waiting list for liver transplantation fully assessed before or during hepatic artery anastomo-
require periodic imaging by CT scanning or MRI every 3 sis, because some patients will require an aortohepatic
months to ensure tumor stability.129 Progression of tumor arterial conduit.
can require additional ablative procedures or, sadly,
removal from the waiting list. As mentioned earlier, rapid Improvement in Results After Liver
progression of tumors is associated with poor biological
properties and poor outcome after transplant.
Transplantation
Results with liver transplantation have improved over
time. A review of the UNOS database showed a steady
Orthotopic Liver Transplantation improvement in patient and graft survival, with patient
Untreated HCC has a median survival of 6 months from survival improving from 25% in patients transplanted
diagnosis, and most patients present with advanced- between 1987 and 1991, to 47% between 1992 and 1995,
stage tumors. OLT, when feasible, offers the most radi- and 61% between 1996 and 2001, compared to 75% for
cal approach to eradication of the liver tumor burden. patients transplanted for benign disease.
Although this sounds too radical, unfortunately, leaving The International Registry of Hepatic Tumors in
the native liver remnant behind leads to possible devel- Liver Transplantation, based in Dallas, Texas, gathered
opment of metachronous lesions from destruction and data from 1491 patients from 57 centers worldwide who
regeneration. However, all attempts should be made to underwent liver transplantation and had HCC in their
ensure that there is no extrahepatic spread, whether ade- liver explants. Similar to the results of the UNOS data-
nopathy or metastases. Frequent imaging, as described base report, patient survival has improved significantly
earlier, lessens the possibility of understaging before over time, with a 5-year patient survival of 25.3% for
surgery. transplants performed in 1983-1990, 44% for the years
The surgery for liver transplantation starts with an 1991-1996, and 67.8% for 1997-2004 (see Fig. 16-9).
abdominal exploration. Patients should be informed The HCC tumor recurrence dropped significantly from
ahead of time that in case of an unexpected adenopathy 59% at 5 years for patients transplanted in 1983-1990
or metastatic disease at exploration, the transplant will to 15% for patients transplanted in 1997-2004.98 The
be cancelled. In many cases, especially in patients with 5-year tumor recurrence rate dropped to 8.4% for
viral hepatitis B or C and PSC, there are enlarged peri- 2002-2007 in the Baylor experience130 (see Fig. 16-9).
hepatic lymph nodes, which require biopsy and frozen The improvement in results can be attributed to a more
section. Other suspicious unexpected lesions should be conservative approach in patient selection with regard
biopsied as well. Portal vein thrombosis is especially to overall tumor burden. The most significant improve-
challenging, because at times a thrombus considered ment in results occurred after 1997, following the
bland might be metastatic HCC. Most thrombi at the implementation of the Milan criteria. There are multi-
portal vein bifurcation and in the portal vein branches ple possible reasons for the results. Both the tumor size
in a patient with HCC usually contain tumor and thus and the number of tumors decreased over time.98
are a contraindication to liver transplantation. Unfortu- Patients have lower levels of AFP than in the past. The
nately, by the time the thrombus can be sampled for tumors had better differentiation in the more recent
pathological examination, other structures vital to the eras.98 Interestingly, vascular invasion, which is a known
liver, such as the native hepatic artery, are already dis- poor prognostic outcome parameter, remained
connected. The decision then is whether to abort the unchanged.98,130
transplant (which leads to the patient's demise in hours Transplantation of patients with tumors within Milan
or days) or to proceed—knowing there is a high likeli- criteria is associated with excellent results, with 4-year
hood of tumor recurrence in a number of months and patient survival of 75% in the original report from 1996.11
patient survival of less than 1 year. Because deceased This has been later cross-validated by numerous reports,
donor livers are scarce, the ethical question is whether including when comparing results for patients within the
to allocate a donor liver to a patient with low chance of Milan criteria and expanded criteria.
survival. The Milan inclusion criteria remain for now the
benchmark against which other tumor criteria are judged.
Using expanded tumor inclusion criteria was associated
Technical Considerations with similar results, including with UCSF criteria, Dallas
There are two main technical options for liver transplanta- criteria, and further expanded criteria from South Korean
tion with regard to the recipient cava—caval interposition and Japanese groups.
198 PART II Patient Evaluation: Adult

HCC Recurrence-free survival (%) 100 100

HCC Tumor recurrence rate (%)

90 90
80
80
70
70 60
60 50
P < .0001
50 40
30 P < .0001
40
20
30 10
20 0
0 12 24 36 48 60 0 12 24 36 48 60
A Months after transplant B Months after transplant
1987-1992 1992-1997 1997-2002 2002-2007 1987-1992 1992-1997 1997-2002 2002-2007
FIGURE 16-9 n Improvement of results with transplantation for hepatocellular carcinoma (HCC) over time. A, HCC recurrence-free sur-
vival across eras. B, Tumor recurrence rate across eras.

Tumor Recurrence After Transplantation tumor recurrence or improve survival. Studies performed
Tumor recurrence and metastasis after transplant are of early in the course included patients with high tumor
concern, because most are associated with poor patient burden, who would not have been transplanted today.151
survival.76 Tumor recurrence rates have decreased from Within Milan criteria, adjuvant therapy does not provide
40% to 56% in the 1980s to 8% to 10% in recent statistical oncological advantage. Chemotherapy has
data.76,131,132 Posttransplant tumors occur in the liver renewed attention in high-risk patients (with poorly dif-
allograft, as local recurrences in the diaphragm or sur- ferentiated tumors or vascular invasion in their explants).
rounding tissue, adrenal glands, lungs, bone, brain, and A protocol using Licartin resulted in lower HCC recur-
abdominal lymph nodes.133,134 Recurrent HCC tends to rence.152 Sorafenib shows promise for lowering HCC
be disseminated and is rarely amenable to ablative ther- recurrence in high-risk patients.153
apy. Most tumors occur within the first 2 years after
transplantation. However, in more recent years, more of
posttransplant HCC occurs after 2 years.130,135,136 There-
Immunosuppression
fore a 2-year follow-up is not appropriate in all cases. Calcineurin inhibitors are the mainstay immunosuppres-
The prognosis of tumor recurrence is dismal, because sion agents after liver transplantation. Cyclosporine
HCC after transplantation can rarely be cured with che- increases tumor recurrence rate in animal models.154
motherapy, ablation, or surgery. Late recurrences seem Tumor doubling time is shorter in patients treated with
to have a better prognosis than early ones (<2 years after cyclosporine than in the native liver.155 Higher cyclospo-
transplant)135,136 and so do recurrences without bone rine doses/level are associated with higher HCC recur-
metastases.136 Surgical resection of isolated lesions in the rence rates.132,156 Tacrolimus augments hepatoma cell
liver or lung can result in median survival of 5 years if proliferation in experimental animal models.157 The use of
they are late occurrences and the tumors are well differ- antithymocyte globulin or, in the past, OKT3, is associ-
entiated.134,136,137 Ablative therapies with TACE can ated with higher tumor recurrence rates.158 The exposure
result in improved survival, with a high rate of tumor to steroids does not seem to correlate with recurrence.132
recurrence after treatment.76,138,139 Sorafenib can slow Modifications of the immunosuppression regimen may
down progression or induce remission in recurrent HCC, result in improved outcomes after transplant. Mammalian
with fairly low adverse effects.140-142 target of rapamycin (mTOR) inhibitors, such as sirolimus
There are no follow-up guidelines for detecting and everolimus, inhibit VEGF, which is important in the
HCC recurrence after transplantation; some centers development of HCC tumors. Sirolimus-based immuno-
advocate close follow-up imaging and AFP to detect suppression is associated with better patient and recur-
recurrence.76 rence-free survival compared to standard, tacrolimus-based
immunosuppression.159-162 It has also been advocated in
Adjuvant Treatment patients with recurrent HCC.138

Adjuvant treatment was attempted starting at transplan-

tation in the anhepatic phase of the transplant. Agents Liver Transplantation in Patients With
used include doxorubicin monotherapy16,143-146 or in
combination with fluorouracil and cisplatin147; gem-
Hepatocellular Carcinoma and No Cirrhosis
citabine and cisplatin148; mitoxantrone149; or epirubi- HCC in non–cirrhotic liver patients occurs mainly in
cin.150 Adjuvant treatment has not been shown to decrease younger individuals. Most patients present with advanced
 16 Transplantation for Primary Hepatic Malignancy 199

tumors. Resection is the mainstay of treatment, when fea- offers a 3-year survival of 74% for stage I, 48% for stage
sible. Liver transplantation is performed mainly when the II, 18% for stage IIIA, and 7% for stage IIIB.
tumors are not amenable to resection due to their ana- Surgery is the only curative treatment for CCA. How-
tomical location. However, liver resection in this setting ever, only a third of the patients have resectable tumors.164
is associated with high tumor recurrence rate, and “res- Initial results with liver transplantation were poor, due
cue” liver transplantation was performed in this setting to early recurrence of CCA (pulmonary, bone, intrahe-
with good results.163 patic), including with incidental tumors.7 The 1-year sur-
vival was 36%, and the 5-year survival was 5% to 15%,
not different from patients who underwent palliative
CHOLANGIOCARCINOMA treatments.166-168 Therefore known CCA is still consid-
ered a contraindication to liver transplantation, unless
CCAs are tumors arising in the biliary duct epithelium. transplantation is performed as part of a multimodal
There are two types: peripheral, arising from intrahe- approach.169,170 Indeed, multimodality therapies have
patic bile ducts, and extrahepatic, arising at the conflu- resulted in better outcomes.171,172
ence of the hepatic ducts in the hilum. Hilar CCAs, also The Mayo protocol is designed for patients with
known as Klatskin tumors, are 60% of all extrahepatic biopsy-proven CCA, or malignant-appearing strictures
CCAs. The histological characteristics of CCA can be by ERCP with positive brushings for cytology and/or
hard to differentiate from metastatic adenocarcino- FISH or with CA 19-9 greater than 100 units/mL, or a
mas.60 At times there is a histological mix of CCA and malignant-appearing stricture and tumor on imaging.
HCC.23 Some are mucin producing. Most are well Exclusion criteria include intrahepatic CCA, extrahepatic
differentiated. disease, history of biopsy, attempt at resection, and
CCA is mostly associated with PSC and inflammatory PTC.173
bowel disease. Other causes include history of exposure The Mayo protocol starts with external beam radio-
to thorotrast contrast agent, choledochal cysts, biliary therapy combined with chemotherapy (5-flurouracil) for
adenomas, and parasitoses such as clonorchiasis. 4 weeks, followed by brachytherapy via probes intro-
Most CCAs are asymptomatic until late in the course, duced by ERCP, followed by oral capecitabine. Explor-
when they present with jaundice, pruritus, dark urine, atory laparotomy is performed at least 2 weeks after
and weight loss. Pain occurs late in the course. Most brachytherapy and as close as possible before transplanta-
CCAs are multicentric at the time of diagnosis. tion, with sampling of the perihilar lymph nodes to
Local invasion occurs along the hilar structures, which exclude metastasis. One fifth of the patients have tumor
results in compression of vascular structures, but vascular spread at exploration. Transplantation is difficult due to
invasion is rare. Metastases are rare in early disease, but radiation changes in the hilum of the liver, and radiation
frequent by the time most are diagnosed—40% with hilar injury to the vascular structures can develop later, after
CCA and 80% with intrahepatic CCA. Most metastases transplant.
are lymphatic, peritoneal, followed by lung and bone (see Results with the Mayo protocol are superior to those
Fig. 16-7). with other modalities and similar to transplantation for
Patients with known PSC who develop CCA can nonmalignant disease, if the protocol is strictly fol-
develop abrupt deterioration in the liver function, with lowed, with 5-year survival of 72% to 82%174; these
deep jaundice and a cholangitis type of picture. The diag- results are superior to surgical resection treatment.175
nosis of CCA is difficult in this situation. Levels of tumor CCA recurrence rates are higher in patients with ele-
markers, such as CA 19-9, can be elevated but do not vated CA 19-9 level above 500 international units/mL,
serve as confirmation of diagnosis, especially in patients portal vein encasement, and residual tumor at the time
with active cholangitis. Biliary imaging by endoscopic of transplant.174
retrograde cholangiopancreatography (ERCP) or mag-
netic resonance cholangiopancreatography (MRCP)
shows biliary strictures, which are hard to differentiate EPITHELIOID HEMANGIOENDOTHELIOMA
from the strictures commonly seen with PSC. Brushings
for cytologic examination or fluorescence in situ hybrid- Epithelioid hemangioendothelioma is a rare hepatic
ization (FISH) polysomy can confirm the diagnosis of tumor arising from the endothelium.176-179 Risk factors
PSC. Sensitivity of cytologic examination results is 20% are not well defined, although there is some association
to 60%, and specificity varies between 61% and 100%.164 reported with use of contraceptives. Most present in an
Of note, percutaneous transhepatic cholangiography otherwise normal liver and tend to be asymptomatic. As a
(PTC) is contraindicated, because it can result in seeding result, most tumors are large at diagnosis. Cross-sectional
of tumor in the tube tract in the body wall, which results imaging shows typically single tumors with homogenous
in incurable metastases. Pathological confirmation is not contrast enhancement and possible capsular retraction.
always necessary.165 Tumor microscopy shows clusters of atypical cells with a
Staging for CCA was designed to assess outcome with high nuclear-cytoplasmic ratio in a sclerotic stroma,179
resection. Stage I tumors are solitary with no vascular and immunohistochemical staining can be positive for
invasion, stage II refers to solitary tumors with vascular factor VIII, CD31, or CD34.179
invasion, stage IIIA tumors are multiple (with or without Tumor size does not correlate with aggressive bio-
vascular invasion), stage IIIB tumors have adenopathy, logical characteristics. Also, extrahepatic lesions, which
and stage IV have distant metastases. Resection for CCA can occur in the ribs, lung, pleura, diaphragm, and
200 PART II Patient Evaluation: Adult

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Adjuvant treatment is questionable. p. iii1-iii8.
11. Mazzaferro V, et al. Liver transplantation for the treatment of
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102. Todo S, Furukawa H. Living donor liver transplantation for adult 126. Belghiti J, et al. Resection prior to liver transplantation for hepa-
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 16 Transplantation for Primary Hepatic Malignancy 203

130. Onaca N, Klintmalm GB. Liver transplantation for hepatocellular 153. Saab S, et al. Sorafenib as adjuvant therapy for high-risk hepato-
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131. Zimmerman MA, et al. Recurrence of hepatocellular carcinoma 154. Freise CE, et al. Effect of systemic cyclosporine on tumor recur-
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after liver transplantation for hepatocellular carcinoma: key role 1991;68(10):2095-2100.
of immunosuppression. Liver Transpl. 2005;11(5):497-503. 156. Vivarelli M, et al. Low recurrence rate of hepatocellular carci-
133. Franca AV, Martinelli A, Silva Jr OC. Brain metastasis of hepato- noma after liver transplantation: better patient selection or lower
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troenterol. 2004;41(3):199-201. 157. Schlitt HJ, et al. Immunosuppression and hepatocellular carci-
134. Viola C, et al. Solitary pulmonary metastasis arising thirteen years noma. Liver Transpl. 2011;17(suppl 2):S159-S161.
after liver transplantation for HBV-related hepatocellular carci- 158. Decaens T, et al. Role of immunosuppression and tumor differen-
noma. World J Gastroenterol. 2006;12(30):4911-4913. tiation in predicting recurrence after liver transplantation for
135. Chok KS, et al. Late recurrence of hepatocellular carcinoma after hepatocellular carcinoma: A multicenter study of 412 patients.
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136. Roayaie S, et al. Recurrence of hepatocellular carcinoma after 159. Zimmerman MA, et al. Sirolimus-based immunosuppression fol-
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2004;10(4):534-540. Transpl. 2008;14(5):633-638.
137. Kornberg A, et al. Long-term survival after recurrent hepatocel- 160. Chinnakotla S, et al. Impact of sirolimus on the recurrence of
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138. Zhou B, et al. Chemoembolization with lobaplatin mixed with 161. Kneteman NM, et al. Sirolimus-based immunosuppression for
iodized oil for unresectable recurrent hepatocellular carcinoma liver transplantation in the presence of extended criteria for hepa-
after orthotopic liver transplantation. J Vasc Interv Radiol. 2010; tocellular carcinoma. Liver Transpl. 2004;10(10):1301-1311.
21(3):333-338. 162. Zhou J, et al. Conversion to sirolimus immunosuppression in liver
139. Ko HK, et al. Tumor response to transcatheter arterial chemo- transplantation recipients with hepatocellular carcinoma: Report
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141. Kim R, et al. Safety and feasibility of using sorafenib in recurrent 164. Khan SA, et al. Guidelines for the diagnosis and treatment of
hepatocellular carcinoma after orthotopic liver transplantation. cholangiocarcinoma: an update. Gut. 2012;61(12):1657-1669.
Oncology. 2010;79(1-2):62-66. 165. Rosen CB, et al. Neoadjuvant therapy and liver transplantation
142. Yeganeh M, Finn RS, Saab S. Apparent remission of a solitary for hilar cholangiocarcinoma: is pretreatment pathological confir-
metastatic pulmonary lesion in a liver transplant recipient treated mation of diagnosis necessary?. J Am Coll Surg. 2012;215(1):
with sorafenib. Am J Transplant. 2009;9(12):2851-2854. 31-38. discussion 38-40.
143. Olthoff KM, et al. Adjuvant chemotherapy improves survival after 166. Goldstein RM, et al. Is liver transplantation indicated for cholan-
liver transplantation for hepatocellular carcinoma. Ann Surg. giocarcinoma?. Am J Surg. 1993;166(6):768-771. discussion
1995;221(6):734-741. discussion 731-43. 771-2.
144. Roayaie S, et al. Long-term results with multimodal adjuvant 167. Shimoda M, et al. Liver transplantation for cholangiocellular car-
therapy and liver transplantation for the treatment of hepatocel- cinoma: analysis of a single-center experience and review of the
lular carcinomas larger than 5 centimeters. Ann.Surg. literature. Liver Transpl. 2001;7(12):1023-1033.
2002;235(4):533-539. 168. Robles R, et al. Liver transplantation for hilar cholangiocarci-
145. Soderdahl G, et al. A prospective, randomized, multi-centre trial noma: Spanish experience. Transplant Proc. 2003;35(5):
of systemic adjuvant chemotherapy versus no additional treat- 1821-1822.
ment in liver transplantation for hepatocellular carcinoma. 169. Sudan D, et al. Radiochemotherapy and transplantation allow
Transpl Int. 2006;19(4):288-294. long-term survival for nonresectable hilar cholangiocarcinoma.
146. Pokorny H, et al. Does additional doxorubicin chemotherapy Am J Transplant. 2002;2(8):774-779.
improve outcome in patients with hepatocellular carcinoma 170. Senzer NN, et al. Adjuvant radiochemotherapy following ortho-
treated by liver transplantation? Am J Transplant. 2005;5(4 Pt 1): topic liver transplantation for bile duct cancer. Transplantation.
788-794. 1990;50(6):1045-1047.
147. Zhang ZH, et al. [Adjuvant chemotherapy after orthotopic liver 171. Hassoun Z, Gores GJ, Rosen CB. Preliminary experience with
transplantation for advanced hepatocellular carcinoma]. Zhonghua liver transplantation in selected patients with unresectable hilar
Zhong Liu Za Zhi. 2005;27(1):45-47. cholangiocarcinoma. Surg Oncol Clin N Am. 2002;11(4):
148. Hsieh CB, et al. Preliminary experience with gemcitabine 909-921.
and cisplatin adjuvant chemotherapy after liver transplantation 172. Darwish Murad S, et al. Efficacy of neoadjuvant chemoradiation,
for hepatocellular carcinoma. Eur J Surg Oncol. 2008;34(8): followed by liver transplantation, for perihilar cholangiocarci-
906-910. noma at 12 US centers. Gastroenterology. 2012;143(1):88-98. e3;
149. Cherqui D, et al. Multimodal adjuvant treatment and liver trans- quiz e14.
plantation for advanced hepatocellular carcinoma. A pilot study. 173. De Vreede I, et al. Prolonged disease-free survival after ortho-
Cancer. 1994;73(11):2721-2726. topic liver transplantation plus adjuvant chemoirradiation for
150. Li N, et al. Adjuvant adenovirus-mediated delivery of herpes sim- cholangiocarcinoma. Liver Transpl. 2000;6(3):309-316.
plex virus thymidine kinase administration improves outcome of 174. Darwish Murad S, et al. Predictors of pretransplant dropout and
liver transplantation in patients with advanced hepatocellular car- posttransplant recurrence in patients with perihilar cholangiocar-
cinoma. Clin Cancer Res. 2007;13(19):5847-5854. cinoma. Hepatology. 2012;56(3):972-981.
151. Duvoux C, et al. What is the role of adjuvant therapy after liver 175. Rea DJ, et al. Liver transplantation with neoadjuvant chemoradia-
transplantation for hepatocellular carcinoma? Liver Transpl. tion is more effective than resection for hilar cholangiocarcinoma.
2011;17(suppl 2):S147-S158. Ann Surg. 2005;242(3):451-458. discussion 458-61.
152. Xu J, et al. A randomized controlled trial of Licartin for prevent- 176. Ishak KG, et al. Epithelioid hemangioendothelioma of the liver: a
ing hepatoma recurrence after liver transplantation. Hepatology. clinicopathologic and follow-up study of 32 cases. Hum Pathol.
2007;45(2):269-276. 1984;15(9):839-852.
204 PART II Patient Evaluation: Adult

177. Marino IR, et al. Treatment of hepatic epithelioid hemangioendo- 181. Koffron A, Fryer JP, Abecassis M. Indications and results of liver
thelioma with liver transplantation. Cancer. 1988;62(10):2079-2084. transplantation for primary and metastatic liver cancer. Cancer
178. Demetris AJ, et al. Hepatic epithelioid hemangioendothelioma: Treat Res. 2001;109:77-99.
biological questions based on pattern of recurrence in an allograft 182. Pichlmayr R, et al. Appraisal of transplantation for malignant
and tumor immunophenotype. Am J Surg Pathol. 1997;21(3): tumours of the liver with special reference to early stage hepato-
263-270. cellular carcinoma. Eur J Surg Oncol. 1998;24(1):60-67.
179. Makhlouf HR, Ishak KG, Goodman ZD. Epithelioid hemangio- 183. Lehnert T. Liver transplantation for metastatic neuroendocrine
endothelioma of the liver: a clinicopathologic study of 137 cases. carcinoma: an analysis of 103 patients. Transplantation. 1998;66(10):
Cancer. 1999;85(3):562-582. 1307-1312.
180. Kayler LK, et al. Epithelioid hemangioendothelioma of the liver
disseminated to the peritoneum treated with liver transplantation
and interferon alpha-2B. Transplantation. 2002;74(1):128-130.
 CHAPTER 17

Transplantation for
Cholangiocarcinoma
Johnny C. Hong • Ronald W. Busuttil

CHAPTER OUTLINE

BACKGROUND Mayo Clinic Protocol for Hilar

Cholangiocarcinoma
RISK FACTORS
Complications of Neoadjuvant Radiation
CLINICAL PRESENTATION Therapy
PREOPERATIVE WORKUP AND DIAGNOSIS Liver Transplantation for Intrahepatic
Cholangiocarcinoma
SURGICAL TREATMENT FOR HILAR Liver Transplantation for Locally Advanced
CHOLANGIOCARCINOMA AND INTRAHEPATIC Hilar and Intrahepatic Cholangiocarcinoma:
CHOLANGIOCARCINOMA The UCLA Treatment Protocol
Resection MIXED HEPATOCELLULAR CARCINOMA AND
Liver Transplantation for Early-Stage Hilar INTRAHEPATIC CHOLANGIOCARCINOMA
Cholangiocarcinoma
SUMMARY

BACKGROUND For patients with unresectable HCCA or ICCA, ortho-

topic liver transplantation (OLT) presents a viable option
Cholangiocarcinoma (CCA), first described by Durand- and has been reported to provide survival benefits.5,6 This
Fardel in 1840, is a malignant neoplasm arising from epi- chapter focuses on the role of OLT in combination with
thelial cells of the extrahepatic and intrahepatic bile ducts, neoadjuvant therapies and reviews patient selection crite-
excluding the papilla of Vater and the gallbladder.1 CCA ria predictive of survival outcomes and post-OLT out-
is the second most common primary hepatobiliary malig- comes for patients with unresectable HCCA and ICCA.
nancy in the United States. The incidence of CCA is
increasing, and its prognosis remains grim without surgi-
cal treatment.2,3 Early diagnosis has been a constant chal- RISK FACTORS
lenge because there is no effective screening test, and
most patients with unresectable disease die within 6 to 12 The cause of CCA is associated with chronic biliary
months of diagnosis. inflammation. Malignant transformation of the cholan-
Anatomically, CCA is classified into the proximal type, giocyte occurs in the background of chronic inflamma-
also known as hilar (HCCA), perihilar, or Klatskin tumors, tion and cholestasis. This environment induces the
which accounts for 60% to 70% of cases; distal type for production of cytokines and reactive oxygen species that
20% to 30%; and intrahepatic (ICCA) or peripheral for cause permanent DNA damage.7 Established risk factors
the remaining 5% to 10% (Fig. 17-1). The three different for ICCA include primary sclerosing cholangitis (PSC),
types of CCA have distinct pathophysiological character- liver fluke infestations, hepatolithiasis, Thorotrast expo-
istics, differ in epidemiological features and clinical pre- sure, choledochal cysts, biliary-enteric anastomosis, Car-
sentations, and vary in surgical treatments. The primary oli’s disease, and hepatitis.7,8 Patients with PSC have a
modality of treatment for HCCA is radical bile duct definite risk for developing CCA, approximately 1.5%
resection with partial hepatectomy; for ICCA, partial per year after diagnosis of cholestatic liver disease.9
hepatectomy; and for the distal type of CCA, pancreati- Because only a minority of patients with CCA present
coduodenectomy. Survival outcomes after resection for with known risk factors, early diagnosis remains a chal-
distal CCA are superior than for perihilar tumors.4 lenging task.10

205
206 PART II Patient Evaluation: Adult

CLINICAL PRESENTATION soft tissue mass along the ductal system or may not be
visible. Although tumor may not be apparent in some
The typical age of presentation for CCA is the seventh cases, radiological findings of ipsilateral hepatic atrophy
decade of life, although with predisposing risk factors strongly suggest the presence of portal venous inflow
CCA can develop up to 2 decades earlier.11-13 The clinical compromise from tumor encasement and/or long-­
presentation depends on the anatomical location of the standing bile duct obstruction. As such, preoperative
tumor and is often nonspecific. HCCA and distal CCA high–resolution contrast-enhanced imaging modalities
often present with jaundice, pruritus, and cholangitis, are imperative to adequately assess the tumor extent and
whereas ICCA frequently presents as incidentally discov- vascular involvement for operative planning. The diag-
ered large tumors in the absence of jaundice or other con- nostic accuracy of computed tomography (CT) has been
stitutional symptoms.14,15 In advanced ICCA, symptoms reported to be significantly higher for ICCA than for
may include abdominal pain, weight loss, malaise, and extrahepatic CCA (79% to 97% versus 56% to 84%).22,23
cachexia.16 Although CT and magnetic resonance imaging (MRI) are
comparable in diagnostic accuracy for ICCA, MRI in
conjunction with magnetic resonance cholangiopancrea-
PREOPERATIVE WORKUP AND tography (MRCP) provides a superior anatomical visual-
DIAGNOSIS ization of the bile ducts and the relationship of the tumor
to the vascular structures.24 Integrated positron emission
There is no effective screening for CCA. The laboratory tomography (PET) and CT imaging has an emerging
test results often indicate obstructive cholestasis with role in preoperative staging of CCA.22 Although PET/
elevated levels of bilirubin and alkaline phosphatase. Lev- CT scanning has a similar diagnostic accuracy for pri-
els of all three serum tumor markers—CA 19-9, CEA, mary tumors compared to conventional CT, it has a sig-
and CA-125—may be elevated; however, only CA 19-9 is nificantly better sensitivity (58% to 100%) for detecting
sensitive and specific, 79% and 98% respectively, at a cut- distal metastases.22,25
off value of 129 units/mL. CA 19-9 has less sensitivity in Endoscopic retrograde cholangiopancreatography
patients with PSC, 53% at a cutoff of greater than and percutaneous transhepatic cholangiography allow
100 units/L and would be undetectable in patients lack- therapeutic interventions, as well as collection of tissue
ing the blood type Lewis antigen (10%), who do not pro- samples for pathological and cytological analysis. Pre-
duce CA 19-9.17-19 An elevated α-fetoprotein level in operative diagnostic accuracy from tissue or brushing
conjunction with CA 19-9 suggests a mixed hepatocellular-­ remains a challenge because of the desmoplastic charac-
cholangiocarcinoma.20 Another diagnostic limitation of teristic of CCA that frequently results in acellular sam-
using CA 19-9 is that elevation of the marker is often seen ples. Advanced cytological technique for detection of
in advanced stages of CCA where radical excisions are not aneuploidy using digital image analysis and fluorescence
possible.21 Although CA 19-9 does not serve as a sole in situ hybridization (FISH) analysis of the brushing has
diagnostic test for CCA, this tumor marker can support a improved the diagnostic accuracy.26 The sensitivity of
diagnosis or be used to assess response to treatment and digital image analysis for CCA is 39% compared to
progression of disease in patients who demonstrated ele- 18% for conventional cytological techniques.27,28 FISH
vated CA 19-9 level before treatment.12 analysis in PSC patients has a sensitivity and specificity
The preoperative workup for HCCA and ICCA aims of 47% and 100%, respectively, for the detection of
to exclude extrahepatic tumor spread from CCA, another CCA.25
primary malignancy with metastatic disease to the liver,
and to evaluate feasibility of complete extirpation of the
tumor, including all microscopically detectable tumor
(R0 resection). With regard to diagnostic imaging SURGICAL TREATMENT FOR HILAR
studies, HCCA and ICCA may present as an irregular CHOLANGIOCARCINOMA AND
INTRAHEPATIC CHOLANGIOCARCINOMA
Intrahepatic (5-10%) Resection
Surgical R0 resection is the definitive first-line therapy
for HCCA and ICCA, offers the only possibility of long-
Hilar (60-70%) term survival in patients with CCA, and should be con-
sidered in all patients with resectable tumor who are
appropriate surgical candidates. The addition of preop-
erative portal vein occlusion of the ipsilateral (tumor)
Distal (20-30%) hemiliver and biliary drainage of the contralateral side
(future liver remnant) has allowed an aggressive and safe
FIGURE 17-1 n Distribution frequency of intrahepatic and extra- resection of intrahepatic and hilar CCA.29 Although ear-
hepatic cholangiocarcinoma. (From Hong JC, Jones CM, Duffy JP, lier studies on long-term survival outcomes with radical
et al. Comparative analysis of resection and liver transplantation for
intrahepatic and hilar cholangiocarcinoma: a 24-year experience in a
resection of early-stage hilar tumors report a 5-year sur-
single center. Arch Surg. 2011;146(6):683-689, Fig. 1, with permis- vival rate of up to 34%,30 outcomes for CCA with aggres-
sion of the American Medical Association.) sive features, including multifocality and large tumor size
 17 Transplantation for Cholangiocarcinoma 207

greater than 2 cm, remain poor because of the limitations principal limiting factor for resectability.12,37-42 Under
of resection as treatment modality in achieving clear mar- these circumstances of a locally advanced HCCA or
gins.31-34 For ICCA the 5-year survival rates with nega- ICCA in the absence of distant metastasis, a total hepa-
tive surgical margins approach 31%; conversely, there are tectomy with regional lymphadenectomy followed by
no survivors with residual disease.32,35 The median time OLT offers a viable treatment option because OLT
for recurrence ranges from 9 to 20 months, with the most addresses all relevant resection margins and treats the
common site being the liver remnant, occurring in 38% underlying liver disease (Fig. 17-2).
to 70% of cases, followed by metastasis to the regional
lymph nodes, lung, and bone.31,36 Unfortunately, many Liver Transplantation for Early-Stage Hilar
of the HCCA and ICCA tumors are deemed unresectable
because of tumor extension to hepatic parenchyma and/
Cholangiocarcinoma
or major vessels (hepatic artery and portal vein) of both Historical experience with OLT for CCA was disap-
right and left hemilivers, and/or metastasis to regional pointing because of the universal recurrence of the dis-
lymph nodes. In cases with localized disease, insufficient ease and subsequent mortality (Table 17-1)* and has led
hepatic functional reserve (due to the presence of many centers to consider CCA as a contraindication for
advanced liver disease) despite interventions to optimize OLT until the introduction of a multidisciplinary
the hypertrophy of the future liver remnant is the approach of neoadjuvant chemoradiation therapy fol-
lowed by OLT.53 The early reports from Thomas Jef-
100
ferson University and the Mayo Clinic indicated the
P = .10 utility of radiation and chemotherapy in palliative therapy
80 of CCA.54,55 Patients with unresectable CCA who
received at least 55 Gy of radiation treatment demon-
Survival (%)

60 strated a 2-year survival of 48% compared to 0% for

OLT those without radiation treatment.54 Furthermore, 14%
40 of the patients who received radiation therapy survived
for 5 years or more. The University of Nebraska pio-
20 Resection neered the use of neoadjuvant radiation therapy prior to
0 OLT.46 Their protocol used only intrabiliary brachy-
0 12 24 36 48 60 therapy delivered through iridium Ir 192 wires, to a total
Survival Time in Months dose of 60 Gy followed by daily intravenous 5-flurouracil
FIGURE 17-2 n Kaplan-Meier disease recurrence–free survival in until the time of transplantation. Patients with extrahe-
locally advanced intrahepatic cholangiocarcinoma by operative patic malignancy discovered during exploratory laparot-
treatment. Treatments included orthotopic liver transplant (OLT) omy were ineligible for liver transplantation. Tumor-free
and radical resection. (From Hong JC, Jones CM, Duffy JP, et al. survival of 45% was observed with a median follow-up of
Comparative analysis of resection and liver transplantation for intra-
hepatic and hilar cholangiocarcinoma: a 24-year experience in a sin-
7.5 years after OLT.46
gle center. Arch Surg. 2011;146(6):683-689, Fig. 3A, with permission
of the American Medical Association.) *References 6, 13, 37, 47, 48.

TABLE 17-1 Collected Series of Liver Transplantation for Cholangiocarcinoma

Patient Survival (%)
2 3
Author Period n Adjunctive Therapy Recurrence Rate (%) yr yr 5 yr
Steiber et al43 1980-1988 10 Adjuvant 60 30 --- ---
Goldstein et al44 1984-1992 17 Adjuvant 78 21 --- ---
Meyer et al37 1968-1997 207 Adjuvant 51 48 --- 23
Shimoda et al45 1984-2000 25 Adjuvant 41 --- 35 ---
Sudan et al46 1987-2000 11 Neoadjuvant 18 --- --- 30
Robles et al47 1988-2001 59 Adjuvant 46 --- --- 42 (Intrahepatic)
30 (Hilar)
Ghali et al48 1996-2003 10 None 80 --- 30 ---
Heimbach et al49 1993-2006 65 Neoadjuvant 17 --- --- 76
Becker et al50 1987-2005 280 — --- --- --- 38
Morris-Stiff et al51 1981-2004 13 — --- --- --- 46
Hong et al52 1985-2009 38 41 52 38 32
None 40 27 20 20
Neoadjuvant + 28 88 75 47
Adjuvant
Adjuvant 50 58 33 33
Darwish Murad et al5 1993-2019 287 Neoadjuvant 20 78 --- 65
208 PART II Patient Evaluation: Adult

operation remain eligible for transplantation. The first

Mayo Clinic Protocol for Hilar
Cholangiocarcinoma published result of this protocol showed a patient survival
rate of 100% among the transplanted patients with a
With the apparent benefits of chemotherapy and radia- median follow-up of 44 months and only one case of
tion therapy before OLT, the group from the Mayo tumor recurrence. However, among the 19 patients
Clinic developed a protocol with the intent of treating a enrolled who received neoadjuvant therapy, only 12
highly select group of patients with hilar CCA with a patients remained eligible for OLT; one died from biliary
stringent regimen of preoperative staging and neoadju- sepsis, and six patients (33%) had tumor progression that
vant treatment followed by OLT.53 The inclusion criteria precluded transplantation. Since the application of the
for patients with CCA involve a strict selection of patients Mayo Clinic protocol, the survival analysis of patients
with early-stage CCA either deemed locally unresectable with CCA has yielded 1- and 5-year patient survival rates
or arising in the setting of underlying PSC (Table 17-2). of 91% and 76%, respectively, and 5-year recurrence-free
Patients with hilar CCA were included only if there was survival of 60%.49 Predictors for tumor recurrence
no mass lesion below the level of the cystic duct. The include older patients, CA19-9 levels above 100 units/mL
upper limit of tumor size was 3 cm when the mass was on the day of transplantation, prior cholecystectomy,
visible on cross-sectional imaging studies, and there must mass on cross-sectional imaging, tumor grade, and resid-
be no evidence of intrahepatic or extrahepatic metastases ual tumor larger than 2 cm, as well perineural invasion in
by any imaging studies. The protocol specifically excluded explant. A multicenter study showed a 2- and 5-year post-
patients with intrahepatic (peripheral) CCA or gallblad- OLT recurrence-free survival of 78% and 65%, respec-
der cancer. Surgical intervention and percutaneous biopsy tively.5 The patient dropout rate was 11.5% at 3.5 months
were avoided to minimize peritoneal seeding. Candidates of therapy. Under the current Model for End-Stage Liver
must have no active infections or medical conditions that Disease (MELD) organ allocation system in the United
preclude neoadjuvant therapy or liver transplantation. States, patients with unresectable early-stage hilar CCA
Since 2002 an endoscopic ultrasound-guided regional within the Mayo Clinic criteria receiving neoadjuvant
lymph node aspiration has been routinely done in all therapy are granted a MELD exception score, equivalent
patients before beginning neoadjuvant therapy.56 The to 3-month waiting list mortality risk of 10%, to priori-
identification of lymph node metastases obviated the tize patients for transplantation.
need for staging exploratory laparotomy and disqualified
the patients from subsequent liver transplantation.
Complications of Neoadjuvant Radiation
In the Mayo Clinic protocol, patients receive external
Therapy
beam radiotherapy to a target dose of 45 Gy followed by
transcatheter radiation (20 to 30 Gy) with iridium Ir 192 The survival benefits with this protocol were associated
wires. These wires are placed by endoscopic retrograde with significant morbidity. Cholangitis, intrahepatic
cholangiography or percutaneous transhepatic cholangi- abscess, and sepsis were frequent infectious complica-
ography. Systemic 5-flurouracil is given during radiation tions related to indwelling stent alone, neoadjuvant
treatment followed by oral capecitabine (Xeloda) after radiation–induced tumor necrosis, or in conjunction
radiation therapy until the day of transplantation. Before with other treatment-related neutropenia.53 Severe
transplantation all patients undergo a scheduled staging inflammatory changes and dense fibrosis in the porta
laparotomy, including biopsy of at least one lymph node hepatis attributable to radiation therapy may lead to
along the proper hepatic artery and another along the difficulty in identifying and isolating the portal struc-
common bile duct, as well as any lymph nodes or nodules tures during transplantation. The greatest concern,
suspicious for tumor. Only patients with negative staging however, is the risk for long-term vascular complica-
tions after transplantation. The overall late vascular
complication rate after transplantation was 41% in the
Mayo Clinic series; 21% of the patients developed
TABLE 17-2 C
 omparison of Inclusion Criteria hepatic arterial complications, whereas 20% experi-
for Mayo Clinic and UCLA enced portal venous complications.57 These vascular
Treatment Protocol of events have been attributed to the late effects of vascu-
Cholangiocarcinoma lar tissue injury from radiation therapy leading to fibro-
sis and chronic ischemic injury. To avoid using the
Variables Mayo Clinic UCLA
irradiated native hepatic artery, an infrarenal interposi-
Hilar CCA Yes Yes tion arterial graft was routinely used to reconstruct
Hilar CCA size <3 cm ≤3.5 cm arterial inflow to all deceased donor grafts, whereas the
Intrahepatic CCA No Yes native hepatic artery was used in live donor grafts. The
Intrahepatic CCA size — ≤8 cm native portal vein was used in deceased donor trans-
Metastasis to hepatic Absent Present or plants, whereas an interposition graft was constructed
parenchyma absent using a blood-group–compatible third-party iliac vein
Metastasis to regional Absent Present or between the donor right portal vein and the recipient
lymph node absent
portal vein in live-donor liver transplantation. In this
Metastasis to distant organ Absent Absent
analysis, hepatic arterial complications were more prev-
CCA, Cholangiocarcinoma; UCLA, University of California Los alent in recipients of live donor partial grafts who
Angeles. received neoadjuvant chemoradiation therapy for CCA
 17 Transplantation for Cholangiocarcinoma 209

than in recipients transplanted with live donor grafts has resulted in excellent long-term recurrence free-sur-
for other indications. For patients who received vival outcomes,62 proponents for expansion of OLT cri-
deceased donor whole-organ grafts reconstructed with teria for CCA argue that patient inclusion guidelines
interposition infrarenal aortic conduit, the rates of restricted to hilar tumors based only on size may exclude
hepatic arterial complication were similar to those of patients with locally advanced hilar CCA, stage IIA, IIB,
recipients transplanted for other indications who did and III, (American Joint Committee on Cancer, 6th Edi-
not receive neoadjuvant chemoradiation therapy. In tion) from a potentially curative procedure despite the
contrast, late portal vein stenosis was more prevalent in absence of metastatic disease. Hong et al52 have recently
both deceased donor whole graft and live donor partial reported that survival benefits can also be achieved in
graft with CCA when compared with controls. Most patients with locally advanced CCA (>3 cm in size; tumor
vascular complications were managed with a percutane- extension to hepatic parenchyma, branches of the portal
ous endovascular approach, and these complications vein, or hepatic artery; and presence of perineural and
were reported not to have adversely affected patient and lymphovascular invasion) using a modified neoadjuvant
graft survival. and adjuvant protocol. The 5-year disease recurrence-
free survival was 47% in patients who received OLT in
Liver Transplantation for Intrahepatic combination with neoadjuvant and adjuvant therapies
compared to 0% in the resection group.
Cholangiocarcinoma To facilitate decision making in selection of patients
Similar to HCCA, the initial enthusiasm for OLT for with unresectable intrahepatic and hilar CCA, including
ICCA in the early 1990s was short lived because of the those with locally advanced disease in the absence of dis-
universal poor results. The University of Pittsburgh tant metastasis, the UCLA group developed a risk stratifi-
reported a 2-year survival of 30% with a 60% disease cation system to predict post-OLT tumor recurrence
recurrence, and data from the Cincinnati Transplant based on preoperative clinical information to identify
Tumor Registry demonstrated 84% tumor recurrence at patients who would benefit from OLT.6 In the analysis the
2 years.37,43 Other centers reported similar outcomes and independent predictors that portend diminished survival
high rates of disease recurrence even for stage I and II included five tumor histological features (Table 17-3):
incidentally found ICCA on explant pathological exami- multifocality (hazard ratio [HR] = 9.6), perineural invasion
nation.44,48,50,58 However, it is noteworthy that the stud- (HR = 8.3), infiltrative tumor growth pattern (HR = 5.3),
ies on outcomes after OLT for CCA included a mixture lymphovascular invasion (HR = 2.1), and hilar type (HR =
of patients with known ICCA, incidentally discovered 1.8) versus ICCA. Other risk factors included no neoadju-
ICCA, and hilar CCA. Furthermore, the vast majority of vant therapy (HR = 4), history of PSC (HR = 2.5). Each
patients did not receive neoadjuvant therapy before OLT. predictor was assigned a risk score point (RS) proportional
Robles et al38 reported on 23 patients who underwent to the log hazard ratio for graft failure. These points are
OLT for ICCA. Ten patients had incidentally discovered then added together to place the patient in one of three
ICCA, whereas the remainder had known ICCA. None risk categories, with 5-year graft failure-free survival rates
of the patients underwent neoadjuvant therapy. The of 78% for the low risk (RS = 0 to 3), 19 % for intermedi-
5-year survival rate was 42%. In another study, 10 patients ate (RS = 4 to 7), and 0% for the high-risk (RS = 8-to 15)
with known ICCA underwent OLT without neoadjuvant groups. Figure 17-3 shows that patient survival rates were
therapy and showed a 5-year survival rate of only 33%.59 excellent and acceptable for the low and intermediate.6
Although most studies showed that OLT for ICCA was The absence of neoadjuvant therapy before OLT was
associated with inferior survival compared to hilar CCA, strongly predictive of posttransplant disease recurrence.
a report from the University of California Los Angeles
(UCLA) demonstrated that incidentally discovered ICCA
on explant pathological examination after OLT had simi- TABLE 17-3 Independent Predictor of Disease
lar survival to patients without ICCA (5-year 83% sur- Recurrence and Assigned Risk
vival); however, patients with known CCA before OLT Score Points
demonstrated poor outcomes.60 At present, OLT for
ICCA remains controversial, and patients with unresect- Variables Risk Score Points
able ICCA on the liver waiting list do not receive addi- Multifocality 4
tional MELD exception points under the MELD organ Perineural invasion 4
allocation system.61 Infiltrative tumor growth pattern 3
No neoadjuvant therapy 3
History of primary sclerosing 2
cholangitis
Liver Transplantation for Locally Hilar CCA 1
Advanced Hilar and Intrahepatic Lymphovascular invasion 1
Cholangiocarcinoma: The UCLA
CCA, Cholangiocarcinoma.
Treatment Protocol Modified from Hong JC, Petrowsky H, Kaldas FM et al. Predictive
index for tumor recurrence after liver transplantation for locally
Although the application of strict Mayo Clinic patient advanced intrahepatic and hilar cholangiocarcinoma. J Am Coll
selection criteria, regimen of preoperative staging, and Surg. 2011;212:514-521,with permission of the American
neoadjuvant chemoradiation treatment followed by OLT Medical Association.
210 PART II Patient Evaluation: Adult

100
% Disease Recurrence–Free Survival
Unresectable intrahepatic or hilar CCA
90
Low risk
80 Biopsy for predictive variables
70
60 Neoadjuvant therapy
50
P < .001 Operative staging and risk stratification
40 Intermediate risk
30 Low and intermediate risk High risk
20
10 High risk OLT Biopsy to evaluate response to
0 neoadjuvant therapy
0 12 24 36 48 60 Adjuvant chemotherapy
Posttransplant Months based on tumor biology No response
FIGURE 17-3 n Disease recurrence–free survival in locally
advanced intrahepatic and hilar cholangiocarcinoma by predic- No OLT
tive index categories. (From Hong JC, Petrowsky H, Kaldas FM, et al. FIGURE 17-4 n Flow diagram of the University of California Los
Predictive index for tumor recurrence after liver transplantation for Angeles treatment protocol for orthotopic liver transplantation
locally advanced intrahepatic and hilar cholangiocarcinoma. J Am Coll (OLT) candidates with intrahepatic cholangiocarcinoma. CCA,
Surg. 2011;212(4):514-521, Fig. 1, with permission of Elsevier Inc.) Cholangiocarcinoma. (From Hong JC, Petrowsky H, Kaldas FM, et al.
Predictive index for tumor recurrence after liver transplantation for
locally advanced intrahepatic and hilar cholangiocarcinoma. J Am Coll
The inclusion criteria for the UCLA treatment proto- Surg. 2011;212(4):514-521, Fig. 2, with permission of Elsevier Inc.)
col for unresectable intrahepatic and hilar CCA (see Table
17-2) include tumor size less than or equal to 8 cm for
intrahepatic and less than or equal to 3.5 cm for hilar Although the 5-year tumor recurrence -free survival is
CCA in patients, disease confined within the confines of less than 50% in the intermediate risk group, only 27% of
the operative field for total hepatectomy and regional the patients in that cohort received neoadjuvant therapy.
lymphadenectomy for OLT, and absence of distant The utility of neoadjuvant therapy for tumor downstag-
metastasis. Figure 17-4 shows the treatment algorithm. A ing in the patients with intermediate risk is currently
tumor biopsy is performed before neoadjuvant therapy. being evaluated in a prospective study. For high-risk
Our neoadjuvant treatment protocol uses locoregional patients, another biopsy of the tumor is performed after
treatment followed by chemotherapy for locally advanced completion of neoadjuvant therapy to evaluate response
intrahepatic and hilar CCA. Intrahepatic CCA less than to treatment. Although OLT may still be considered for
or equal to 6 cm or hilar tumors are treated with stereo- patients who exhibit disease downstaging, definitive sur-
tactic body radiation therapy (SBRT) for a total dose of 40 gical therapy is not recommended in the absence of a
Gy, fractionated into five treatment sessions over 7 to 12 favorable tumor response to neoadjuvant treatments.
days.63,64 Although the response to external beam radia- Adjuvant chemotherapy is given based upon tumor
tion therapy for CCA has been poor, reduction in tumor biological characteristics determined in pretreatment
burden could be achieved with SBRT.63,65 A phase I study biopsy and in explanted specimen. Although the survival
of SBRT in patients with unresectable CCA provided a benefit with adjuvant chemotherapy after resection is
median survival of 15 months.63 The short locoregional unproven, post-OLT adjuvant chemotherapy may have a
treatment course allows the administration of full, uncom- role in reducing the risk for tumor recurrence by control-
promised doses of chemotherapy as early as 10 to 14 days ling potential occult disease in the face of impaired
from the last radiation session. For intrahepatic tumors immune surveillance of the patient from immunosup-
larger than 6 cm, transarterial chemoembolization is given pressive therapy. Furthermore, we use a sirolimus-based
instead of SBRT.66 Transarterial chemoembolization maintenance immunosuppression regimen in our treat-
demonstrated local disease control of up to 76%.66,67 ment protocol because of its antiproliferative and antian-
Neoadjuvant chemotherapy includes a 5-fluorouracil- giogenic properties.70-72
or capecitabine-based regimen until the time of trans-
plantation. Other agents include oxaliplatin, leucovorin,
and gemcitabine.68,69 Surveillance of tumor progression MIXED HEPATOCELLULAR CARCINOMA
includes imaging with CT or MRI of the chest and abdo-
men, as well as determination of serum tumor marker AND INTRAHEPATIC
carbohydrate antigen (CA) 19-9 levels regularly every 3 CHOLANGIOCARCINOMA
months. PET scan is used selectively in patients with sus-
picion of metastasis on routine imaging. Progression of Mixed hepatocellular-cholangiocarcinoma (HCC-CCA)
disease beyond the confines of the operative field of total is a rare tumor with histological characteristics of both
hepatectomy and regional lymphadenectomy for OLT, HCC and ICCA. The incidence has been reported in
identified during neoadjuvant treatment or in pre-OLT the range of 1.4% to 6.5%.73 Mixed HCC-ICCA was
surgical staging laparotomy, precludes transplantation. identified and classified into three types in 1949: type A
The UCLA treatment guidelines recommend OLT for separate nodules, type B for contiguous masses, and
for patients in the low- and intermediate-risk category. type C for individual masses.74 The 3- and 5-year
 17 Transplantation for Cholangiocarcinoma 211

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 17 Transplantation for Cholangiocarcinoma 213

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 CHAPTER 18

Transplantation for
Metastases
Ferdinand Mühlbacher • Susanne Rasoul Rockenschaub

CHAPTER OUTLINE

TRANSPLANT INDICATIONS FOR SECONDARY DOES IMMUNOSUPPRESSION STIMULATE

MALIGNANCIES IN THE PAST TUMOR GROWTH?
Purely Surgical Approach to Colorectal Liver DONOR SHORTAGE AND LIVER
Metastases
TRANSPLANTATION FOR MALIGNANT
Liver Transplantation Combined With DISEASE—USE OF LIVING DONOR ORGANS
Myelotoxic Chemotherapy and Autologous
Bone Marrow Transplantation for Breast ALTERNATIVE METHODS OF TREATING LIVER
Cancer Metastases METASTASES
Multimodal Therapeutic Approach for
SUMMARY
Colorectal Liver Metastases
Liver Transplantation for Metastases
From Neuroendocrine Tumors

TRANSPLANT INDICATIONS confinement of the tumor to the liver. No adjuvant che-

motherapy was applied. A larger single-center series of
FOR SECONDARY MALIGNANCIES patients with colon carcinoma metastases was reported
IN THE PAST by the group in Vienna, with an actuarial 1-year tumor-
free survival rate of 68%; however, with the larger expe-
Liver transplantation for secondary malignancies has a rience of 19 patients, median survival did not exceed
long history; many programs included this indication in 13.1 months.3 Neither surgery nor chemotherapy was
their pioneer phase in cases where the primary tumor was considered if tumor recurrence was detected. This
successfully removed and metastatic disease was confined group terminated the “surgery only” program after 28
to the liver. Metastases from cancers of the colon, tail of cases, the longest survivor reaching 30 years after sur-
the pancreas, hypernephroma, meningioma, and duode- gery (alive in 2013) (Fig. 18-1). This patient was free of
nal leiomyosarcoma have been reported by Calne.1 The lymphatic micrometastases, as determined by a special
Denver-Cincinnati Registry reported procedures for genetic screening method. The authors proposed free-
liver metastases arising from the colon, carcinoid of the dom of lymphatic involvement as a selection criterion.4
small bowel or bronchial tree, leiomyosarcoma of the
small bowel, breast carcinoma, gastrinomas, glucagono-
mas, meningiomas, neuroblastomas, renal cell carcinoma, Liver Transplantation Combined With
cystosarcoma of the pancreas, hemangiopericytoma, Myelotoxic Chemotherapy and Autologous
seminoma, VIPoma, melanoma, acute myeloid leukemia, Bone Marrow Transplantation for Breast
and unknown primaries.2 For current standards the out-
come was unfavorable; 59% died of tumor recurrence or
Cancer Metastases
suffered surgical complications. A combined approach of debulking by means of liver
transplantation combined with myelotoxic chemother-
Purely Surgical Approach to Colorectal apy and total-body irradiation, followed by autologous
Liver Metastases bone marrow transplantation was reported from Inns-
bruck.4 Five patients were treated according to this
The selection of transplant candidates was based upon protocol, the longest survival time being 5 years. All
histological freedom of central aortic lymph nodes at patients gained several years of good-quality life
primary surgery (N2) and a radiologically assessed extension.5

214
 18 Transplantation for Metastases 215

100 100
90
n = 28
80 80
70

Survival (%)
60
Percent

60
50
40 40
30
20 20
10
0 0
0 1 2 3 4 5 6 7 8 9 1011 1213 14 15
Years 0 1 2 3 4 5
FIGURE 18-1 n Patient survival after orthotopic liver transplanta- Years
Number at risk
tion for colorectal metastases in a purely surgical concept.
21 17 14 9 6 1
FIGURE 18-2 n Overall survival (right; 95% CI) and disease-free
Multimodal Therapeutic Approach for (left) survival in 21 patients who were treated with orthotopic
liver transplantation for nonresectable colorectal metastases in a
Colorectal Liver Metastases multimodal concept. CI, Confidence interval. (From Hagness M,
Foss A, Line PD, et al. Liver transplantation for nonresectable liver
Recently the group in Oslo attempted a revival of liver metastases from colorectal cancer. Ann Surg. 2013;257(5):800-806.)
transplantation for colorectal liver metastases. Based on
substantially improved techniques in liver transplantation
with excellent local 1-year survival rates of greater than Liver Transplantation for Metastases From
90% and an aggressive multimodal approach, including Neuroendocrine Tumors
neoadjuvant, adjuvant chemotherapy, and repeated sur-
gery or other ablative interventions in case of recurrence, Scattered experience with orthotopic liver transplanta-
and adapted immunosuppression with mammalian target tion (OLT) for liver metastases originating from neuro-
of rapamycin (mTOR) inhibitors, enthusiastic 94% endocrine tumors (NETs)1,2,11 and the observation that
2-year survival rates were reported in a pilot series of 16 NETs of the pancreas seem to be a different biological
cases with a high quality of life, for a median observation entity because of their slow progression12 stimulated sev-
time of 23 months.6 From an oncological perspective, the eral programs attempting a more systematic approach.
results are disappointing: 10 of 16 patients suffered recur- Pancreas resection combined with OLT was reported to
rent disease. yield freedom from symptoms for up to 34 months12,13 in
More recently the same group gave an update with three cases.
5-year survival data and an extended cohort of 21 A multimodal protocol was developed at the Mount
patients: the 1-, 3-, and 5-year survival rates are 95%, Sinai Center, with hepatic artery chemoembolization to
68%, and 60%, respectively (Fig. 18-2). These results control symptoms; OLT was carried out in patients with
are only 10% below the current 5-year survival in non- persistent symptoms or evidence of progression. Three
cancer patients.7 Risk factors for high tumor recurrence patients underwent transplantation, with no recurrence
of 67% on a median observation time of 27 months are for 12 to 30 months.14 During the next decade, liver
preoperative tumor load to the liver, time between transplantation was considered an option for unresect-
resection of primary tumor and liver transplantation, able NET metastases; more recently, a consensus paper
and progressive disease despite chemotherapy. Survival estimated the need for liver transplantation for NET
data for liver transplantation are by far superior to metastases as approximately 1%.15 Outcome data were
those for any other treatment modality. Median sur- recently published from the U.S. experience in 184
vival for patients receiving chemotherapy alone was 19 cases16 and from the European Liver Transplant Registry
months, and 5-year survival was 10%; for resectable in 213 cases.17
patients, median survival was 57 months with 5-year Survival data are essentially the same. Two eras are
survival of 65%; and for patients whose tumor was con- compared in each study; survival in the era before the
verted to a resectable one by chemotherapy, median Model for End-Stage Liver Disease (MELD) was 49.2%
survival was 40 months and 5-year survival was 35%.8 and in the post-MELD era was 57.8% in the United
Similar data from a review of resectable patients with States, which essentially compares to 52% before 2000
neoadjuvant chemotherapy are reported to be 15 to 48 and 58% after 2000 in Europe. The U.S. study could not
months median survival and a 5-year survival rate identify a single risk factor in a multivariate regression. In
between 37% and 50%.9 Isolated liver chemotherapeu- the European study, age greater than 45 years emerged as
tic perfusion is no alternative, with a median survival a risk factor, as did concomitant surgery and poor differ-
rate of 23 months.10 entiation of the tumor.18 Single-center studies show a
216 PART II Patient Evaluation: Adult

are considered to protect from tumor growth.24 In a non-

TABLE 18-1 M
 ilan Criteria for Indication for
randomized comparison between liver transplantation
Liver Transplantation in Patients
and liver resection for hepatocellular carcinoma, the sur-
With Hepatic Metastases
vival rates after 1 and 5 years were identical, indicating no
Inclusion Criteria
dramatic effect of immunosuppression on development
1. Histological confirmation of carcinoid tumor (low-grade
of residual tumor disease.25 In addition, a nonrandomized
neuroendocrine tumors) with or without syndrome retrospective analysis of survival data in patients treated
2. Primary tumor drained by the portal system (pancreas for unresectable colorectal liver metastases either with
and intermediate gut: from distal stomach to sigmoid liver transplantation or local transarterial chemotherapy
colon) removed with a curative resection (pretransplant revealed a marked survival benefit in favor of transplanta-
removal of all extrahepatic tumor deposits) through surgi- tion, with no signs of accelerated tumor growth.3 Clinical
cal procedures different and separate from transplantation
data, however, are weak, and the question cannot be
3. Metastatic diffusion to liver parenchyma ≤ 50%
answered definitively.
4. Good response or stable disease for at least 6 months
during the pretransplantation period
5. Age ≤ 55 years
Exclusion Criteria
DONOR SHORTAGE AND LIVER
1. Small cell carcinoma and high-grade neuroendocrine TRANSPLANTATION FOR MALIGNANT
carcinomas (noncarcinoid tumors) DISEASE—USE OF LIVING
2. Other medical or surgical conditions contraindicating
liver transplantation, including previous tumors DONOR ORGANS
3. Nongastrointestinal carcinoids or tumors not drained by
the portal system Organ shortage currently limits liver transplantation.
With a waiting list mortality ranging from 17% to 21%
and a removal rate from the waiting list due to patient
5-year survival rate between 50% and 80% for NET sickness of 3.5%,26 there is no room for substandard
metastases resection, and 37% to 90% for NET metasta- results. With malignant diseases as indications for OLT,
ses liver transplantation.19 there seems to be a consensus that patient survival after
Mazzaferro, who had already defined solid criteria for OLT for malignancies should match the short-term and
hepatocellular carcinoma liver transplantation, proposed midterm results of transplantation for nonmalignant
the Milan criteria for liver transplantation in NET liver indications,27 and even retransplantation has to meet this
metastases, requiring 5 years of disease-free survival as a standard.28 Survival data from the past do not justify
minimum (Table 18-1).19 OLT for colorectal metastases. However, a multimodal
Whether or not NET metastases originating from the approach with aggressive treatment including surgery
small intestine are a different entity remains unclear. Of and ablative interventions shows 5-year survival data
672 patients from a Swedish study, 78 were 65 years or close to registry data for nonmalignant diseases treated
younger, 36 were 55 years or younger, and 33 met the with liver transplantation. However, the recurrence rate
Milan criteria. Patients were treated and observed of more than 67% makes liver transplantation for colorec-
between 1985 and 2012 according to a local standard tal metastases a palliative procedure. Survival rates for
protocol—including radical surgery of the primary
­ OLT at 5 years in registries for NET metastases are
tumor. No patient required liver transplantation. For the around 60%, and in single-center studies even higher,
three groups, the 5-year patient survival rates were 84%, meeting the 70% survival threshold of nonmalignant
92%, and 97%, respectively, figures that have not been transplant indications along with long periods of disease-
observed to date in a single transplant study.20 free survival.
Retrospective data do not adequately report failure of Living donors as a source of liver transplant organs
control of symptoms as an urgent indication for liver may also change the attitude toward transplantation
transplantation. Similarly, tumor grading18 has not been because it obliterates the argument of organ shortage.
considered in the past but will be a strong selection crite-
rion in the future.19
ALTERNATIVE METHODS OF TREATING
LIVER METASTASES
DOES IMMUNOSUPPRESSION
STIMULATE TUMOR GROWTH? There are many alternative methods29 available for deal-
ing with liver metastases after colorectal carcinoma. Liver
There is an increased risk for de novo tumor develop- resection can be combined with cryotherapy,30 radiofre-
ment in transplant patients, both for posttransplantation quency ablation,31 or transarterial catheter embolisa-
lymphoproliferative disorder21 and for solid tumors. This tion,32 and some of these methods can also be applied
risk is between 7% and 8% within 10 years after organ percutaneously.33 Alternative treatment is, of course, also
transplantation in liver and kidney recipients, and almost available for metastases from NETs. These alternatives
30% in heart recipients.22 Of these lesions, 50% are skin have lower procedural mortality than OLT. However,
tumors.23 There is no direct evidence of side effects of alternative methods have their limitations.34 Usually
immunosuppression on tumor growth after liver trans- tumor size, number of lesions, or unresponsiveness to
plantation for malignant liver diseases. mTOR inhibitors treatment suggests reconsidering liver transplantation.
 18 Transplantation for Metastases 217

SUMMARY 12. Eckhauser FE, Cheung PS, Vinik AI, et al. Nonfunctioning malig-
nant neuroendocrine tumors of the pancreas. Surgery.
• OLT for the treatment of metastatic liver disease 1986;100:978-988.
13. Alsina AE, Bartus S, Hull D, et al. Liver transplant for metastatic
has been performed in substantial numbers for only neuroendocrine tumor. J Clin Gastroenterol. 1990;12:533-537.
two different tumor entities: (1) liver metastases 14. Curtiss SI, Mor E, Schwartz ME, et al. A rational approach to the
from NETs originating from the gastrointestinal use of hepatic transplantation in the treatment of metastatic neuro-
tract and the pancreas and (2) liver metastases from endocrine tumors. J Am Coll Surg. 1995;180:184-187.
15. Eriksson B, Kloppel G, Krenning E, et al. Consensus guidelines for
colorectal cancer. the management of patients with digestive neuroendocrine
• OLT for NET metastases shows 5-year survival tumors–well-differentiated jejunal-ileal tumor/carcinoma. Neuro-
rates similar to OLT for nonmalignant diseases, endocrinology. 2008;87:8-19.
with acceptable periods of disease-free survival. 16. Nguyen NT, Harring TR, Goss JA, et al. Neuroendocrine Liver
OLT should be considered only in curative inten- Metastases and Orthotopic Liver Transplantation: The US Expe-
rience. Int J Hepatol. 2011;2011:742890.
tion, taking into account proposed Milan criteria 17. Le Treut YP, Gregoire E, Klempnauer J, et al. Liver transplanta-
and tumor grading. tion for neuroendocrine tumors in Europe-results and trends in
• Controversy still exists whether local treatment patient selection: a 213-case European liver transplant registry
modalities in patients suffering from NET metasta- study. Ann Surg. 2013;257:807-815.
18. Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classi-
ses are as successful in terms of tumor control with- fication of neuroendocrine tumors: a review of nomenclature,
out operative risk. grading, and staging systems. Pancreas. 2010;39:707-712.
• Despite the excellent 5-year survival figures of OLT 19. Mazzaferro V, Pulvirenti A, Coppa J. Neuroendocrine tumors
for colorectal metastases of 60% in one center— metastatic to the liver: how to select patients for liver transplanta-
superior to any other treatment—the procedure has tion? J Hepatol. 2007;47:460-466.
20. Norlen O, Daskalakis K, Oberg K, et al. Indication for liver trans-
to be considered palliative because of the high plantation in young patients with small intestinal NETs is rare?
recurrence rate of more than 67%. It is unclear World J Surg. 2014;38(3):742-747.
whether new selection criteria will be able to iden- 21. Opelz G, Dohler B. Lymphomas after solid organ transplantation:
tify patients with the chance of oncological cure. a collaborative transplant study report. Am J Transplant.
2004;4:222-230.
• Because of organ shortage, OLT for colorectal 22. Margreiter R, Niederwieser D, Frommhold H, et al. Tumor recur-
metastatic disease should be continued only in a rence after liver transplantation followed by high-dose cyclophos-
controlled-study environment. phamide, total body irradiation, and autologous bone marrow
transplantation for treatment of metastatic liver disease. Transplant
REFERENCES Proc. 1987;19:2403-2404.
23. Opelz G, Döhler B. Critical threshold of azathioprine dosage for
1. Calne RY. Liver transplantation: the recent Cambridge-King's
maintenance immunosuppression in kidney graft recipients. Collab-
College Hospital experience. Clin Transpl. 1987:51-54.
orative Transplant Study. Transplantation. 2000;15;69(5):818-821.
2. Penn I. Hepatic transplantation for primary and metastatic cancers
24. Fung J, Kelly D, Kadry Z, et al. Immunosuppression in liver trans-
of the liver. Surgery. 1991;110:726-734. discussion 34-5.
plantation: beyond calcineurin inhibitors. Liver Transpl. 2005;11:
3. Muhlbacher F, Huk I, Steininger R, et al. Is orthotopic liver trans-
267-280.
plantation a feasible treatment for secondary cancer of the liver?
25. Steininger R, Herbst F, Fugger R, et al. Immunosuppression does
Transplant Proc. 1991;23:1567-1568.
not enhance tumor growth after orthotopic liver transplantation
4. Kappel S, Kandioler D, Steininger R, et al. Genetic detection of
for hepatoma. Transplant Proc. 1992;24:2690-2692.
lymph node micrometastases: a selection criterion for liver trans-
26. Eurotransplant. Annual Report. 2011. Accessed at http://www.
plantation in patients with liver metastases after colorectal cancer.
eurotransplant.org.
Transplantation. 2006;81:64-70.
27. Margarit C, Charco R, Hidalgo E, et al. Liver transplantation for
5. Huber C, Niederwieser D, Schonitzer D, et al. Liver transplanta-
malignant diseases: selection and pattern of recurrence. World
tion followed by high-dose cyclophosphamide, total-body irradia-
J Surg. 2002;26:257-263.
tion, and autologous bone marrow transplantation for treatment of
28. Azoulay D, Linhares MM, Huguet E, et al. Decision for retrans-
metastatic breast cancer. A case report. Transplantation. 1984;37:
plantation of the liver: an experience- and cost-based analysis. Ann
311-312.
Surg. 2002;236:713-721. discussion 21.
6. Foss A, Adam R, Dueland S. Liver transplantation for colorectal
29. Fusai G, Davidson BR. Management of colorectal liver metastases.
liver metastases: revisiting the concept. Transpl Int. 2010;23:
Colorectal Dis. 2003;5:2-23.
679-685.
30. Yan DB, Clingan P, Morris DL. Hepatic cryotherapy and regional
7. 2011. (Accessed at http://www.eltr.org).
chemotherapy with or without resection for liver metastases from
8. Kataoka K, Kanazawa A, Iwamoto S, et al. Does “conversion che-
colorectal carcinoma: how many are too many? Cancer. 2003;98:
motherapy” really improve survival in metastatic colorectal cancer
320-330.
patients with liver-limited disease? World J Surg.
31. Moffat FL, Falk RE, Calhoun K, et al. Effect of radiofrequency
2014;38(4):936-946.
hyperthermia and chemotherapy on primary and secondary hepatic
9. Nordlinger B, Van Cutsem E, Rougier P, et al. Does chemother-
malignancies when used with metronidazole. Surgery. 1983;94:
apy prior to liver resection increase the potential for cure in
536-542.
patients with metastatic colorectal cancer? A report from the Euro-
32. Bloomston M, Binitie O, Fraiji E, et al. Transcatheter arterial
pean Colorectal Metastases Treatment Group. Eur J Cancer.
chemoembolization with or without radiofrequency ablation in
2007;43:2037-2045.
the management of patients with advanced hepatic malignancy.
10. Magge D, Choudry HA, Zeh 3rd HJ, et al. Outcome analysis of a
Am Surg. 2002;68:827-831.
decade-long experience of isolated hepatic perfusion for unresectable
33. Livraghi T. Guidelines for treatment of liver cancer. Eur J Ultra-
liver metastases at a single institution. Ann Surg. 2014;259(5):953-9.
sound. 2001;13:167-176.
11. Makowka L, Tzakis AG, Mazzaferro V, et al. Transplantation of
34. Scaife CL, Curley SA. Complication, local recurrence, and survival
the liver for metastatic endocrine tumors of the intestine and pan-
rates after radiofrequency ablation for hepatic malignancies. Surg
creas. Surg Gynecol Obstet. 1989;168:107-111.
Oncol Clin N Am. 2003;12:243-255.
CHAPTER 19

Transplantation for
Hematological Disorders
Deborah J.L. Wong • William D. Tap • Victor J. Marder

CHAPTER OUTLINE

HEREDITARY AMYLOIDOSIS GIANT HEMANGIOMAS

HEMOCHROMATOSIS LIVER TRANSPLANTATION–ACQUIRED
DISORDERS
HEMOPHILIA
Acquired Thrombophilia
THROMBOPHILIA Acquired Bleeding Disorders
MYELOPROLIFERATIVE NEOPLASMS
ERYTHROPOIETIC PROTOPORPHYRIA

Liver transplantation (LT) often affords a last-ditch present with symptoms as early as 30 years of age, and the
treatment option for a disparate group of disorders that disease is often fatal within 10 years.4 About 95% of TTR is
may be managed by the hematologist. In some cases LT synthesized by the liver, the remaining 5% produced in the
cures the patient by correcting the cause of the problem, choroid plexus and retina.5 First used to halt disease pro-
whereas in other cases patients may benefit only tran- gression,6 LT is now applied as a curative modality for
siently because induced organ damage is irreversible. ATTR,7 with an overall 1-year survival rate of 90% and a
Atypically LT may bring a new illness to the patient, as 5-year survival rate of 77%.1
when an affected liver is replaced by one carrying a After LT greater than 95% of plasma TTR is wild-
genetic defect. This chapter reviews LT in patients with type6,8 (Fig. 19-1), and a significant proportion of trans-
hereditary amyloidosis, hemochromatosis, coagulation planted patients have regression of gastrointestinal
disorders, and protoporphyria, most cases of which have symptoms (52%), sensory neuropathy (41%), motor and
a genetic foundation. muscular function (37%), and improved nutritional status
(40%). In a study of 33 FAP patients who underwent LT,
renal failure stabilized, consistent with biopsy evidence
HEREDITARY AMYLOIDOSIS showing no change in renal deposits.9 The data suggest
that replacing the mutated TTR gene (in the transplanted
The most common genetic defect that causes systemic amy- liver) can reverse tissue injury secondary to amyloid
loid deposition derives from the transthyretin (TTR) gene, deposition and that neuronal regeneration may occur.8,10
a mutation of which results in an autosomal dominant dis- However, refractory intraoperative orthostatic hypoten-
ease pattern. TTR, also called prealbumin, is a tetrameric sion and sudden cardiac death resulting from amyloid-
plasma protein that transports thyroxin, triiodothyronine, induced conduction abnormalities may complicate the
and retinal binding protein. More than 80 TTR gene muta- procedure, and only 21% of patients demonstrate
tions have been identified as amyloidogenic (ATTR), the improvement in cardiovascular symptoms.1 Persistent
most common of which is a point mutation at amino acid 30 arrhythmias require close monitoring,11 and reversal of
(V30M) in patients with familial amyloid polyneuropathy myocardial injury is problematic, as evidenced by the
(FAP).1-3 Mutations result in altered TTR solubility, lead- high rate of cardiac death (39%) versus that following LT
ing to deposition of insoluble amyloid fibers in the intracel- for other indications (9%).1 In addition, some patients
lular space1 and causing debilitating neuropathy and experience disease progression after LT, perhaps related
autonomic instability, impaired muscle contractility, restric- to deposited amyloid serving as a nidus for further depo-
tive cardiomyopathy with arrhythmias, renal failure, vitreal sition of even wild-type TTR.
opacity, and severe gastrointestinal complications, includ- Given the 30 years or longer required for patients to
ing dysmotility, malabsorption, and bleeding. Patients may develop symptoms attributable to amyloidosis, several

218
 19 Transplantation for Hematological Disorders 219

HEREDITARY (FAMILIAL) AMYLOIDOSIS

Amyloidogenic Transthyretin
(ATTR) Gene Mutation (V30M)

LT

Hepatocyte synthesis,
deposition of insoluble amyloid

ORGAN DAMAGE
• Neuropathy Potential reversal
• Renal failure of organ damage
• Vitreal opacities Arrhythmia risk,
including peri-
• GI symptoms operative
• Cardiac dysfunction
FIGURE 19-1 n Hereditary (familial) amyloidosis. Amyloidogenic mutations in the transthyretin gene, the most common being T60A
in transthyretin protein, induce hepatic synthesis of insoluble amyloid, which accumulates in various organs, notably the heart,
peripheral nerves, gastrointestinal tract, and kidneys. After liver transplantation (LT), wild-type (normal) instead of the amyloido-
genic transthyretin is synthesized, with the goal of halting further amyloid deposition. Over time, amyloid may be recycled and tissue
damage corrected, but the risk for cardiac arrhythmia remains, especially in the perioperative period. GI, Gastrointestinal; LT, liver
transplantation.

domino liver transplants (DLTs) have been performed in decade, and are less evident in women who are protected
which the explanted liver from the LT recipient with by menstrual blood loss. Feder et al described two mis-
FAP is subsequently transplanted into a non-FAP patient sense mutations (C282Y and H63D) in the HFE gene,20
(Domino Liver Transplant Registry, http://www.fapwtr. which facilitates iron homeostasis via interaction of HFE
org/ram_domino.htm). Amyloid deposits have been protein with the transferrin receptor 121 or by modulation
detected in biopsy autopsy specimens from asymptomatic of hepcidin synthesis.22 S65C is another commonly iden-
DLT recipients of FAP livers.12,13 However, as of 2010, tified mutation in HFE.23 The HFE gene is expressed in
only three cases of neuropathy attributable to amyloido- the liver, but also in the intestines, pancreas, ovary, kid-
sis have been reported in recipients of DLTs at 7 to 9 ney, and placenta.20,21 The homozygous loss of cysteine in
years after transplant.14,15 the C282Y mutation affects 80% to 90% of patients with
LT has been applied to treat other hereditary forms of clinical HH20 and prevents binding of the HFE protein to
amyloidosis in which the liver is the primary source of β2-microglobulin,21,22 resulting in decreased expression of
amyloid, as in the autosomal dominant form caused by hepcidin and increased intestinal iron absorption.24 The
mutation of the fibrinogen A-α chain. Because plasma H63D and S65C mutations convey some propensity for
fibrinogen derives overwhelmingly from hepatic synthe- iron accumulation but do not have the same clinical
sis, LT should be curative, and successful correction by impact as the C282Y mutation.25
LT has been documented in a single case report.16 LT LT has provided insight into the pathogenesis of iron
has not been a viable therapeutic approach for the most accumulation. Inadvertent transplant of a homozygous
common form of acquired systemic amyloidosis, caused C282Y liver and intestine into a wild-type host resulted
by deposition of monoclonal immunoglobulin light- in iron overload,26 and LT of a C282Y heterozygous liver
chain fragments produced by a malignant clone of plasma caused hemochromatosis, the recipient’s HFE genotype
cells in the bone marrow. showing a novel C282Y/R6S compound heterozygous
state.27 Even with transplantation of an affected liver,
most cases do not show iron accumulation that is not
HEMOCHROMATOSIS explainable by concurrent medical illnes.18,26 About 50%
to 75% of homozygous C282Y patients have clinical evi-
Hereditary hemochromatosis (HH) is an autosomal reces- dence of disease,28,29 classified into four stages, namely,
sive disorder linked to chromosome 6,17 with a 10% car- genetic predisposition but no other abnormality, iron
rier rate and overall prevalence of 0.5%,18 notably in overload without symptoms, iron overload with early
northern Europeans.19 A disruption in iron homeostasis symptoms (lethargy, arthralgia), and iron overload with
leads to widespread tissue deposition, with clinical effects organ damage, especially cirrhosis. Before the discovery
of cirrhosis, increased risk for hepatocellular carcinoma of the HFE gene the diagnosis of primary hemochroma-
(HCC), cardiomyopathy, heart disease, arrhythmias, dia- tosis was often based on the Hepatic Iron Index (hepatic
betes mellitus, skin hyperpigmentation, endocrine failure, iron concentration divided by age), a value greater than
and arthropathy. Clinical manifestations are highly vari- 1.9 defining HH. However, a review of more than 450
able, evolve slowly, are rarely present before the second LT patients showed that only 10% of patients with
220 PART II Patient Evaluation: Adult

HEREDITARY SECONDARY
HEMOCHROMATOSIS HEMOCHROMATOSIS

Mutation of the HFE gene (C282Y) Thalassemia, hypertransfusion

LT

Unregulated iron absorption, Iron overload, tissue deposition

accumulation, and tissue deposition

ORGAN DAMAGE
LT LT
Long-term cure • Hepatic cirrhosis Short-term correction

Potential correction, • Cardiomyopathy

but cardiac problems LT • Endocrine dysfunction
may remain (diabetes mellitus)
• Arthropathy
• Skin pigmentation
FIGURE 19-2 n Hereditary and secondary hemochromatosis. In hereditary hemochromatosis (left), mutations in the HFE gene disrupt
iron homeostasis and cause tissue iron accumulation and damage. Hepatic iron deposits can cause panlobular necrosis, cirrhosis
with subsequent increased risk for hepatocellular carcinoma, and overt liver failure, for which liver transplantation (LT) may be a
lifesaving and even curative modality. In secondary hemochromatosis (right), systemic iron overload and organ damage can result
from various acquired processes, for example, hypertransfusion for severe and lifelong anemia. LT can restore hepatic function tem-
porarily, but continued iron accumulation usually follows unless the underlying cause is corrected.

a hepatic iron index of greater than 1.9 were homozygous slightly lower than in patients transplanted for other
for the C282Y mutation.30 Other inherited disorders of indications (86%, 80%, and 74%, respectively).18,43
iron metabolism cause severe iron loading, including However, among 217 patients undergoing LT between
juvenile hemochromatosis resulting from mutations in 1997 and 2006, survival rates were not significantly dif-
hemojuvelin or hepcidin31,32 and mutations in the ferro- ferent than in other LT recipients.45 Younger subjects
poritin33 and transferrin receptor 2 genes.34 may have some degree of protection against subsequent
Acquired (secondary) iron overload also leads to sub- iron deposition,46 but all HH patients are susceptible to
stantial hepatic iron deposition, perhaps as a by-product of bacterial and fungal infection,47,48 perhaps as a result of a
inflammation or viral infection.35 Phlebotomy and chela- deleterious effect of iron on cellular immunity.49 By bio-
tor therapy before significant systemic iron deposition chemical measures, results of LT have been gratifying. A
occurs can prevent clinical sequelae.36 Of 197 homozy- review of 22 HH patients who underwent LT showed
gous C282Y patients, none with a serum ferritin level of that serum markers remained normal for 2.8 years.50
less than 1000 μg/L, normal aspartate aminotransferase Early hepatic biopsy in 41 patients with pretransplant
level, or evidence of hepatomegaly had severe fibrosis,23 hemochromatosis showed no statistical difference in iron
justifying conservative management without liver biopsy. deposition in the new liver from that of a control popula-
In contrast, patients with clinical, radiographic, or bio- tion, and 2 of 3 C282Y homozygous patients had no iron
chemical markers consistent with substantial iron overload accumulation.51 One report52 found no evidence of
who are not homozygous for the C282Y mutation merit a hepatic iron accumulation 11 to 111 months after LT in
diagnostic liver biopsy.23,28 Cardiac iron deposition can four C282Y homozygous transplant recipients.
manifest as a dilated or restrictive cardiomyopathy with As to long-term outcomes after LT, the underlying
increased risk for arrhythmia, heart failure, and myocar- disorder is the principal determinant of success. Patients
dial infarction,37 perhaps related directly to the HFE gene with secondary hemochromatosis have temporary relief
mutation itself.38-40 Increased iron load, regardless of of liver disease, but ultimately, recurrent iron accumula-
cause, may contribute to atherosclerosis,41 and pretrans- tion may follow if the primary disorder is not corrected.
plant iron depletion may improve post-LT survival.42 For the HH patient, the post-LT course depends upon
HH accounts for only 0.5% to 1% of all LT cases.43 whether the hereditary defect affects HFE protein syn-
Decompensated liver disease is the main indication for thesis in the liver or in other organs (Fig. 19-2). Absent
LT, but because HH increases the risk for HCC by up to irreversible cardiac disease, the patient with a mutation
200-fold, this is also considered in decisions for LT.44 affecting hepatic synthesis should have an excellent
For a group of 177 HH patients who underwent cadav- response to LT. The hepatocytes of the allograft would
eric LT in the United States from 1990 to 1996, survival produce a wild-type HFE protein that should correctly
rates were 79%, 72%, and 65% at 1, 3, and 5 years, regulate iron homeostasis, thereby preventing further
 19 Transplantation for Hematological Disorders 221

HEMOPHILIA

Hereditary deficiency of
factor VIII or IX
(hemophilia A or B)

LT
Partial correction of
Hemorrhagic diathesis
bleeding disorder
Clotting factor infusions Exposure to hepatitis C

LT
Short-term correction
Viral hepatitis/cirrhosis
(recurrent hepatitis)
FIGURE 19-3 n Hemophilia. Exposure of hemophiliac patients to blood product concentrates can result in viral hepatitis, cirrhosis, and
liver failure. Liver transplantation (LT) can be a lifesaving modality, but self-recurrence of viral hepatitis is common. Because coagula-
tion factors are produced by hepatocytes and/or endothelial cells, LT will partially correct the bleeding disorder, at least to the degree
that spontaneous hemorrhages do not occur.

abnormal iron accumulation. However, if the primary 23% versus 83% at 3 years.58 Hemophiliac patients are at
defect stems from aberrant HFE proteins made in the risk for recurrent hepatitis, noted in 6 of 20 patients at 9
duodenal mucosa, than LT would only serve to palliate, months after being transplanted for hepatitis C after a
because pathological iron accumulation would not be mean of 9 months.58
controlled and recurrence of hepatic iron deposition and Hemostasis should not be a problem for hemophiliac
hepatic failure would follow. patients undergoing LT, providing that appropriate fac-
tor replacement is administered to achieve blood levels of
100% during surgery and until healing, at approximately
HEMOPHILIA 14 days. Patients with a factor VIII inhibitor require spe-
cial clotting factor management, including use of “bypass”
Hemophilia results from an X-linked deficiency of factor agents (recombinant factor VIIa or prothrombin complex
VIII (hemophilia A) or factor IX (hemophilia B). Hemo- concentrate) and antifibrinolytic agents (ε-aminocaproic
philiacs who received clotting factor concentrates pre- acid or tranexamic acid).61-63
pared from pooled human plasma before the mid 1980s Because all of the vitamin K–dependent clotting fac-
were almost invariably exposed to the hepatitis C virus tors (II, VII, IX, and X) are synthesized in hepatocytes,
and the human immunodeficiency virus (HIV). The transplantation should cure such hereditary deficiencies,
cumulative risk for hepatic decompensation in hemophil- as documented in twin sisters with factor VII deficiency
iacs with hepatitis C is 1.7% in 10 years and 10.8% in and severe bleeding symptoms who underwent LT.64 In a
20 years,53 and 30% of patients with persistent hepatitis patient with factor XI deficiency who was transplanted for
develop cirrhosis.54 Hemophiliac patients with hepatitis HCC and hepatitis C cirrhosis, LT corrected the factor
C are often coinfected with HIV, a combination that XI level within 7 days of transplantation, implicating
increases the risk for substantial hepatic injury.55 hepatocytes as a major site of factor XI synthesis.65 LT
Liver transplantation has two values in the hemophil- has also been used for correction of bleeding in patients
iac patient (Fig. 19-3), serving as a lifesaving treatment with severe von Willebrand’s disease.66,67 Conversely,
for cirrhosis or HCC and as a potentially curative modal- case reports show that factor deficiency may be acquired
ity for hemophiliac bleeding. The first liver transplant in by LT from donors with hereditary deficiency of a spe-
a patient with hemophilia A and end-stage liver disease cific clotting factor (see Liver Transplantation–Acquired
was performed in 1985,56 with allograft function main- Disorders).
taining plasma factor VIII levels in the normal range by
18 hours after surgery; these findings were reproduced in
a patient with hemophilia B in 1987.57 THROMBOPHILIA
Of 26 patients with hemophilia who underwent LT
for liver failure between 1982 and 1996, all had their Homozygous protein C deficiency causes a hypercoagu-
underlying factor deficiency corrected, replacement infu- lable state that presents in the neonatal period with dis-
sions being discontinued at 24 hours after surgery,58 seminated intravascular coagulation, purpura fulminans,
coincident with the onset of de novo factor production. and thromboembolism. Treatment uses anticoagulant
One- and 3-year survival rates were 83% and 68%, drugs plus infusion of blood products containing protein
respectively, similar to data for nonhemophiliac patients C (plasma or protein C concentrate). LT has shown dra-
who underwent LT for hepatitis.59,60 Survival rates for matic and lasting benefit in three cases (Fig. 19-4), as in
patients with HIV were significantly lower than for a 20-month old child who was transplanted after two
patients without HIV, 67% versus 90% at 1 year and attempts to withdraw fresh frozen plasma maintenance
222 PART II Patient Evaluation: Adult

THROMBOPHILIA

Homozygous protein C deficiency Factor V Leiden mutation

LT

Neonatal purpura fulminans Budd-Chiari syndrome

LT LT

Correction of Long-term correction

thrombotic disorder of hepatic disease
FIGURE 19-4 n Thrombophilia. Homozygous protein C deficiency (left) presents peripartum with life-threatening purpura fulminans.
Because protein C is synthesized entirely in the liver, liver transplantation (LT) cures the thrombophilia. Other thrombophilias, such
as factor V Leiden (right), are not usually apparent until adulthood, the Budd-Chiari syndrome being a particularly aggressive throm-
botic manifestation. LT can partially modulate this thrombophilia by synthesis of normal factor V, but LT is used primarily to reverse
the hepatic failure caused by the Budd-Chiari syndrome.

resulted in renal failure, microangiopathic hemolysis, (MPNs), diseases resulting from abnormal clonal expan-
and fibrinolysis. Anticoagulation with warfarin was com- sion of bone marrow elements. MPNs have an incidence
plicated by intracranial hemorrhage.68 Postoperatively rate of 2.1 per 100,000, and ET and PV constitute 24%
the child suffered hepatic artery and portal vein throm- and 44.6% of MPNs, respectively.78 Most cases of PV
bosis but gradually improved with anticoagulation as the and about 50% of ET are due to a constitutively activat-
allograft restored protein C levels to normal. A second ing mutation in the JAK2 gene, a tyrosine kinase in the
case concerned an 8-year-old child who was a compound JAK/STAT signaling pathway.79 Increased red blood
heterozygote for protein C deficiency and dysfunction69 cell mass in PV or the increased platelet production in
and who developed renal failure secondary to bilateral ET can result in increased risk for venous and arterial
renal vein thrombosis, and intracranial hemorrhage and clots, with 12% to 39% of patients with PV and 11% to
gastrointestinal bleeding complicating chronic anticoag- 25% of ET patients presenting with thrombosis, and a
ulant therapy. After a combined renal/liver transplant the follow-up prevalence of 8% to 19% for PV and 8% to
patient was weaned off protein C concentrate by 2 weeks 31% for ET patients.80,81 In addition to arterial clots,
after transplant, when plasma protein C activity was including peripheral arterial clots, myocardial infarction,
maintained at greater than 70%. Follow-up 1 year after and cerebral vascular accidents, PV and ET result in
transplantation demonstrated normal protein C activity increased risk for deep venous thromboses, cerebral
and graft function. In a third case, protein C activity venous thrombosis, mesenteric vein thrombosis, portal
reached 98% by the fifth day after LT in a 6-month-old vein thrombosis, or hepatic venous outflow obstruction
who received a living donor liver transplant. Normal from hepatic vein or inferior vena cava occlusion, also
protein C activity and antigen and excellent graft func- termed Budd-Chiari syndrome.80,81
tion continued 8 years after transplantation.70 BCS is the indication for LT (Fig. 19-5) in approxi-
Patients who are heterozygous for the factor V Leiden mately 1% to 2% of all LT patients,82-84 and about 50% of
(FVL) mutation have a sevenfold increased risk for venous such patients have an underlying MPN.83-89 A significant
thrombosis, and patients homozygous for this condition proportion (15% to 35%) of patients with MPN-related
have an eightyfold higher risk.71 This mutation affects BCS have a concurrent thrombotic risk factor, including
coagulation factor V so that it cannot be degraded by oral contraceptive use, antiphospholipid antibody, protein
activated protein C (hence the term activated protein C C or S deficiency, and FVL mutation or prothrombin
resistance), producing a hypercoagulable state because of 20210 gene mutation.85,88 LT for BCS is reserved for
unregulated coagulant activity. Transplantation for FVL patients for whom medical management with diuretics,
is usually not warranted, because the thrombophilia can anticoagulation, recanalization procedures (local throm-
be managed with long-term warfarin (Coumadin) antico- bolysis and/or percutaneous transluminal angioplasty with
agulation. However, FVL represents a significant risk stent placement) and transjugular intrahepatic portosys-
factor for Budd-Chiari syndrome (BCS), and six such temic or surgical shunting procedures have failed.85,86
patients have been submitted to LT, all with normaliza- Outcomes of LT for BCS are similar to those for other
tion of activated protein C resistance ratio thereafter.72-77 indications. Halff et al reported 1-, 3-, and 5-year survival
Rarely, thrombophilia can be acquired after LT (see rates of 68.8%, 44.7%, and 44.7%, compared to 69%,
Liver Transplantation–Acquired Disorders). 61%, and 57.6%, respectively, for LT for other indica-
tions,82 and 5- and 10-year actuarial survival rates among
39 patients after LT for BCS were 89.4% and 83.5%,
MYELOPROLIFERATIVE NEOPLASMS compared to 80.7% and 71.4%, respectively, in 1742
patients who had LT for other indications.84 Anticoagula-
Essential thrombocythemia (ET) and polycythemia vera tion is administered routinely immediately after LT for
(PV) are two subtypes of myeloproliferative neoplasms BCS, but long-term anticoagulation will reflect rational
 19 Transplantation for Hematological Disorders 223

MYELOPROLIFERATIVE NEOPLASMS

Hepatic vein thrombosis

(Budd-Chiari syndrome)

LT

Fulminant hepatic failure

Intestinal edema, Reversal of hepatic failure
ischemia Thrombotic risk remains
Ascites
FIGURE 19-5 n Myeloproliferative neoplasms. Polycythemia vera and essential thrombocythemia often arise from constitutively acti-
vated, mutated JAK2 kinase, which may have unusually severe thrombotic manifestations, such as Budd-Chiari syndrome. Liver
transplantation (LT) can be lifesaving, but the risk for thrombotic events remains because LT does not address the underlying throm-
bophilic propensity.

considerations such as elimination of comorbid conditions LT can be lifesaving (Fig. 19-6),99-101 but not without
of protein C, protein S, or prothrombin gene mutation by significant operative problems.102 Bloomer et al103 reported
transplantation of a liver that synthesizes these factors a cohort of nine such patients, two of whom died within
normally. the first 2 months from operative complications, two
developed skin burns from operating room lights, three
developed axonal neuropathies, and two had recurrent
ERYTHROPOIETIC PROTOPORPHYRIA protoporphyric liver damage. Phototoxic burns on the
abdomen and viscera resulting from intense light exposure
The porphyrias are divided into hepatic and erythropoi- during surgery are caused by exposure of protoporphyrin
etic, depending on whether the liver or bone marrow is to ultraviolet light and can result in biliary fistula, intesti-
responsible for producing the excess porphyrins. Erythro- nal perforation, and even death.96,102,103 Polyneuropathy
poietic protoporphyria (EPP) is a porphyria of the erythro- may be exacerbated postoperatively102 as in the case of a
poietic class, in which a rare genetic disorder of heme 54-year-old man in whom profound postoperative axonal
metabolism results in the accumulation of protoporphyrin neuropathy developed despite a reduction in operating
IX, the lipid soluble, photosensitive precursor of hemoglo- room light and halogen head lamp intensity with filters.104
bin.87 EPP is caused by the absence of ferrochelatase and Plasmapheresis and exchange transfusion have been used
the subsequent disruption of the last step in the heme path- preoperatively to reduce protoporphyrin levels, but even
way.88 The ferrochelatase gene has been mapped to chro- an 80% reduction in circulating protoporphyrins may not
mosome 18, region q21.3,89,90 and has significant genetic guarantee a safe outcome.102,104
heterogeneity that allows phenotypic expression of more LT is not curative, because protoporphyrins are still
than 65 different mutations.91 Ferrochelatase levels in produced by the bone marrow and systemic levels usually
affected individuals are lower than would be expected by a remain elevated. It is not uncommon for porphyrins to
simple autosomal dominant inheritance pattern, and some accumulate in the liver allograft, sometimes leading to ful-
cases are transmitted in an autosomal recessive pattern, minant allograft failure. The liver allograft may outper-
though still associated with severe hepatic dysfunction.92 form the native organ in protoporphyrin clearance, so in
EPP is a devastating disease, resulting in an increase some patients serum protoporphyrin levels fall after LT,
in erythrocyte, hepatic, plasma, and fecal protoporphy- even while the erythrocyte protoporphyrin concentration
rin concentrations.93 The disease usually manifests with remains high.103 Hematin has been administered preopera-
childhood photosensitivity, erythema, edema, pruritus, tively to decrease protoporphyrin levels.105,106 This iron-
and chronic deforming skin damage, because of ultravi- containing metalloporphyrin decreases hepatic and marrow
olet light–initiated photoreaction of protoporphyrin in heme synthesis by inhibiting δ-aminolevulinic acid (ALA)
dermal blood vessels and skin.94 The accumulation of synthase, the rate-limiting enzyme in heme production.
lipid-soluble protoporphyrin also causes axonal neurop- The effect that hematin has on hepatic disease is still
athy, abdominal pain, anemia, and hepatic dysfunc- unclear, but a decrease in postadministration plasma proto-
tion.95-97 Excess protoporphyrin is excreted in the feces porphyrin levels has been correlated with increased excre-
via the biliary system and may precipitate in the bile and tion in feces and urine.107 Hematin has been used in the
crystallize in the hepatic parenchyma,98 leading to postoperative setting for cholestasis and allograft salvage.108
micronodular cirrhosis and panlobular necrosis and Murine bone marrow transplant models are being evalu-
end-stage liver disease. Worsening hepatic injury may ated as therapy for EPP,109 which may be a target for gene
further decrease ferrochelatase activity, creating a therapy.110 LT remains a potential lifesaving option, but it
vicious cycle that promotes progressive hepatic failure.99 is not curative, and currently only reactive measures such as
Hepatic failure occurs in only 5% of patients but can be hematin infusion and plasma exchange are available for
life-threatening and warrant LT. managing the devastating clinical outcomes of the disease.
224 PART II Patient Evaluation: Adult

ERYTHROPOIETIC PROTOPORPHYRIA

ALA synthase

Absent PROTOPORPHYRIN
feedback ACCUMULATION
Protoporphyrin IX
inhibition (hepatic and marrow synthesis) • Skin (exposed to UV)
• Neuropathy
+iron • Hepatic cirrhosis
Mutated
ferrochelatase LT

Porphyrin
UV
Decreased heme formation reaccumulation
light

Short-term Intraoperative Recurrent

hepatic complications organ
improvement (skin, neuropathy) damage
FIGURE 19-6 n Erythropoietic protoporphyria. A mutated ferrochelatase prevents heme synthesis and causes accumulation of proto-
porphyrin IX. Without heme, there is insufficient feedback inhibition of aminolevulinic acid (ALA) synthase to modulate the multiple-
step pathway of heme synthesis. The toxic product, protoporphyrin IX, accumulates and causes skin reactions secondary to ultraviolet
(UV) exposure, neuropathy, and cirrhosis. Liver transplantation (LT) can be lifesaving, but because protoporphyrin IX production
occurs in the bone marrow as well as the liver, reaccumulation occurs. Intraoperative precautions are required to prevent patient
exposure to UV light, which can induce acute skin and neurological complications.

GIANT HEMANGIOMAS Giant hemangiomas and KMS remain a rare indica-

tion for LT (Fig. 19-7). To date fewer than 20 cases have
Hepatic hemangiomas occur with an incidence of 0.4% to been reported.115,128-136 Preoperative management
20% in the general population.111-113 Although most are involves management of coagulopathy with infusions of
asymptomatic and require no intervention, giant-sized fresh frozen plasma, cryoprecipitate, and aggressive
hemangiomas (>4 cm)114 may present with symptoms of replacement of blood products, as well as low-dose hepa-
abdominal fullness, respiratory distress from diaphrag- rin129 and serine protease inhibitors116-118 as adjunctive
matic compression, hemorrhage within the hemangioma medications for coagulopathy. Intraoperative blood loss
or abdomen, jaundice from biliary compression, arterio- is high, mean 12 L, and the large size of the hemangioma
venous shunting and cardiac failure, liver failure, and and the native liver present additional technical chal-
consumptive coagulopathy. This syndrome has been lenges. Arterial ligation before mobilization of the liver
termed Kasabach-Merritt syndrome (KMS)115 and was first can be helpful in reducing the hemangioma size.128 LT
described in children with cutaneous hemangiomas in results in improvement in platelet count and fibrinogen
1940.116 KMS reflects platelet sequestration, clotting, and within 24 hours after transplant and eventual resolution
fibrinolysis within the hemangioma, resulting in microan- of the coagulopathy of KMS.115,128-136
giopathic hemolytic anemia and consumptive coagu-
lopathy. Nonsurgical strategies include transarterial
embolization,117 radiofrequency ablation,118-120 and radi- LIVER TRANSPLANTATION–ACQUIRED
ation,121,122 although these may not effectively manage
KMS. Reduction in the size of hemangiomas has been
DISORDERS
observed with antiangiogenic agents interferon alpha-
2115,123 and bevacizumab,124 corticosteroids, and cyclo-
Acquired Thrombophilia
phosphamide,125 but no randomized, controlled trials Because the prevalence of FVL in the white population
have been conducted. In addition, antifibrinolytics such is 4% to 6%, transplantation of a liver that synthesizes
as aminocaproic acid has been used in the management of this mutant would not be unexpected. In a retrospective
coagulopathy from KMS.126,127 Surgical management survey of 276 donor livers, 19 were heterozygous and
includes resection and enucleation if technically feasible. none were homozygous for the FVL mutation. There
However, LT may be indicated in symptomatic cases were 41 episodes of thrombosis, 6 in patients who were
where lesions are multiple, involving the hepatic hilum or heterozygous for the FVL mutation, and the FVL muta-
are otherwise unresectable, and in KMS, where LT can tion was present in 4 of 31 cases of hepatic vessel throm-
result in complete reversal of coagulopathy and may be bosis.137 The presence of FVL confers an increased risk
lifesaving.115,128 for postoperative thrombosis, but the relative risk for
 19 Transplantation for Hematological Disorders 225

KASABACH-MERRITT SYNDROME

Hepatic hemangioma (>4 cm)

LT

Compressive symptoms
Abdominal fullness
Jaundice
Hepatic failure Complete correction
Increased bleeding
Risk of hemangioma rupture
Kasabach-Merritt syndrome
FIGURE 19-7 n Giant hemangiomas and Kasabach-Merritt syndrome (KMS). Giant hepatic hemangiomas can cause compressive
symptoms and consumptive coagulopathy because of platelet sequestration, clotting, and fibrinolysis within the hemangioma. Liver
transplantation (LT) can be lifesaving with complete reversal of both coagulopathy and symptoms, though surgery may be compli-
cated by significant blood loss caused by KMS.

TABLE 19-1 Anticipated Results of Liver Transplantation in Hematological Disorders

Disorder Underlying Defect Clinical Result Potential Problems
Hereditary amyloidosis Almost completely Stabilization or improvement in Cardiac and other organ function
corrected organ function if further may not improve (deposition of
amyloid deposition prevented wild-type transthyretin)
Hemochromatosis Probably not corrected Immediate correction of hepatic Reaccumulation of tissue iron
(hereditary or failure
secondary)
Hemophilia A and Correction of factor Hepatic failure corrected May still require factor for
hemophilia B deficiency to variable Prevention of spontaneous surgical procedures
degree bleeding Recurrent viral hepatitis
Protein C deficiency Completely corrected Thrombophilia cured, no need
for anticoagulation
Myeloproliferative Not corrected Hepatic failure corrected Risk for vascular complications
neoplasms Likely will require ongoing
antithrombotic therapy
Erythropoietic Partial correction (liver Resolution of hepatic failure Possible phototoxic injury
protoporphyria but not other tissues) (neuropathy) during surgery
Recurrent disease
Giant hemangioma, Completely corrected if Resolution of compressive Perioperative bleeding and
Kasabach-Merritt hemangiomas primarily hepatic symptoms, coagulopathy
syndrome in liver coagulopathy
LT-acquired disorders Transplantation of Induction of thrombophilia or Rare occurrence
defective liver hemophilia

LT, Liver transplantation.

hepatic vessel thrombosis is low. Acquired protein S hemophilia A resulting from a factor VIII inhibitor was
deficiency138 and combined protein C deficiency and caused by transport of antibody-producing “passenger”
dysfibrinogenemia139 resulting in thrombosis have also lymphocytes in the transplanted liver.143
been reported.

Acquired Bleeding Disorders SUMMARY (Table 19-1)

LT-related transmission of a hemorrhagic diathesis has LT is the only current curative modality for patients with
been described in a case of a young female who developed hereditary forms of amyloidosis. This treatment is appro-
a prolonged prothrombin time after transplantation of a priate for hereditary hemochromatosis with advanced
liver that was deficient in factor VII synthesis140; factor liver disease, but it may not alleviate iron-related damage
XI and factor XII deficiencies via this mechanism have in other organs or the underlying genetic defect. LT may
also been described.141,142 An unusual case of acquired be employed in severe hemophilia A and B for liver failure
226 PART II Patient Evaluation: Adult

caused by viral infection after transfusion of contaminated 8. Holmgren G, Steen L, Suhr O, et al. Clinical improvement and
blood products; in these cases LT relieves the sequelae of amyloid regression after liver transplantation in hereditary trans-
thyretin amyloidosis. Lancet. 1993;341:1113-1116.
hepatic injury and may also cure the hemorrhagic disor- 9. Snanoudj R, Durrbach A, Gauthier E, et al. Changes in renal
der. LT has cured the life-threatening thrombophilia function in patients with familial amyloid polyneuropathy treated
caused by homozygous protein C deficiency, but in with orthotopic liver transplantation. Nephrol Dial Transplant.
patients with underlying myeloproliferative neoplasms, 2004;19:1779-1785.
10. Ikeda S, Takei Y, Yanagisawa N, et al. Peripheral nerves regener-
thrombotic risk remains. LT is appropriate for EPP with ated in familial amyloid polyneuropathy after liver transplanta-
liver failure, although the metabolic defect is not cured tion. Ann Intern Med. 1997;127:618-620.
and attention must be paid to avoiding phototoxic injury 11. Hornsten R, Wiklund U, Olofsson BO, et al. Liver transplantation
during surgery. KMS resulting from giant hepatic heman- does not prevent the development of life-threatening arrhythmia
giomas can be completely cured by LT. in familial amyloidotic polyneuropathy, Portuguese-type (ATTR
Val30Met) patients. Transplantation. 2004;78:112-116.
12. Sousa MM, Ferrao J, Fernandes R, et al. Deposition and passage of
transthyretin through the blood-nerve barrier in recipients of famil-
ial amyloid polyneuropathy livers. Lab Invest. 2004;84:865-873.
13. Koike H, Kiuchi T, Iijima M, et al. Systemic but asymptomatic
Pearls and Pitfalls transthyretin amyloidosis 8 years after domino liver transplanta-
tion. J Neurol Neurosurg Psychiatry. 2011;82:1287-1290.
• 
Amyloidosis: LT halts further amyloid deposition, but 14. Goto T, Yamashita T, Ueda M, et al. Iatrogenic amyloid neu-
cardiac and other organ dysfunction may not improve. ropathy in a Japanese patient after sequential liver transplantation.
• 
Hemochromatosis: LT immediately corrects hepatic fail- Am J Transplant. 2006;6:2512-2515.
ure, but cardiac dysfunction and endocrinopathies may be 15. Barreiros AP, Geber C, Birklein F, et al. Clinical symptomatic de
irreversible, and tissue iron deposition may reaccumulate. novo systemic transthyretin amyloidosis 9 years after domino liver
• 
Hemophilia: LT corrects clotting factor deficiency so that transplantation. Liver Transpl. 2010;16:109.
spontaneous bleeding does not occur, but factor supple- 16. Zeldenrust S, Gertz M, Uemichi T, et al. Orthotopic liver trans-
mentation may still be required for surgical procedures. plantation for hereditary fibrinogen amyloidosis. Transplantation.
2003;75:560-561.
Viral hepatitis may recur. 17. Simon M, Bourel M, Genetet B, Fauchet R. Idiopathic hemochro-
• 
Thrombophilia: LT cures hypercoagulability, because matosis. Demonstration of recessive transmission and early detec-
transplanted liver synthesizes the missing natural coagu- tion by family HLA typing. N Engl J Med. 1977;297:1017-1021.
lation inhibitor (protein C, protein S). 18. Brandhagen DJ. Liver transplantation for hereditary hemochro-
• 
Myeloproliferative neoplasms: LT corrects hepatic failure, matosis. Liver Transpl. 2001;7:663-672.
but long-term antithrombotic therapy is required. 19. Phatak PD, Bonkovsky HL, Kowdley KV. Hereditary hemochro-
• 
Erythropoietic protoporphyria: LT resolves hepatic failure matosis: time for targeted screening. Ann Intern Med. 2008;149:
but not other tissue injury; intraoperative phototoxic in- 270-272.
jury can occur, and recurrence is possible. 20. Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like
gene is mutated in patients with hereditary haemochromatosis.
• 
Kasabach-Merritt syndrome: LT completely corrects co- Nat Genet. 1996;13:399-408.
agulopathy and compressive symptoms; risk for excessive 21. Enns CA. Pumping iron: the strange partnership of the hemo-
intraoperative blood loss exists. chromatosis protein, a class I MHC homolog, with the transferrin
• 
LT-acquired disorders: Transplanted liver may synthe- receptor. Traffic. 2001;2:167-174.
size inadequate or abnormal clotting factor, resulting in 22. Pietrangelo A. Hereditary hemochromatosis—a new look at an old
thrombophilia or hemophilia. disease. N Engl J Med. 2004;350:2383-2397.
23. Bacon BR, Adams PC, Kowdley KV, et al. Diagnosis and man-
agement of hemochromatosis: 2011 practice guideline by the
American Association for the Study of Liver Diseases. Hepatology.
2011;54:328-343.
24. Fleming RE, Britton RS, Waheed A, et al. Pathophysiology of
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39. Tuomainen TP, Kontula K, Nyyssonen K, et al. Increased risk of deficiency by liver transplantation. N Engl J Med. 2005;352:
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48. Weinberg ED. Iron, infection, and neoplasia. Clin Physiol Biochem. 74. Karasu Z, Nart D, Lebe E, et al. Liver transplantation in a patient
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50. Powell LW. Does transplantation of the liver cure genetic hemo- treated by liver transplantation in a woman homozygous for factor
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51. Parolin MB, Batts KP, Wiesner RH, et al. Liver allograft iron 76. Fickert P, Ramschak H, Kenner L, et al. Acute Budd-Chiari syn-
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hepatic hemosiderosis. Liver Transpl. 2002;8:331-339. factor V Leiden mutation. Gastroenterology. 1996;111:1670-1673.
52. Stuart KA, Fletcher LM, Clouston AD, et al. Increased hepatic 77. Avenhaus W, Ullerich H, Menzel J, et al. Budd-Chiari syndrome
iron and cirrhosis: no evidence for an adverse effect on patient in a patient with factor V Leiden–successful treatment by TIPSS
outcome following liver transplantation. Hepatology. 2000;32: placement followed by liver transplantation. Z Gastroenterol.
1200-1207. 1999;37:277-281.
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Haematol. 1994;87:555-561. ders in the United States, 2001-2004, using data from the
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746-752. tyrosine kinase JAK2 in human myeloproliferative disorders. Lan-
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57. Merion RM, Delius RE, Campbell Jr DA, Turcotte JG. Ortho- JAK2V617F. Semin Thromb Hemost. 2007;33:313-320.
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hemophilia B. Surgery. 1988;104:929-931. Budd-Chiari syndrome. Ann Surg. 1990;211:43-49.
58. Gordon FH, Mistry PK, Sabin CA, Lee CA. Outcome of ortho- 83. Mentha G, Giostra E, Majno PE, et al. Liver transplantation for
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59. Gane EJ, Portmann BC, Naoumov NV, et al. Long-term out- 84. Ulrich F, Pratschke J, Neumann U, et al. Eighteen years of liver
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quent medium-term follow-up. J Hepatol. 1992;16:203-207. gioma and Kasabach-Merritt syndrome with aminocaproic acid.
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102. Herbert A, Corbin D, Williams A, et al. Erythropoietic protopor- cryoprecipitate. N Engl J Med. 1985;313:309-312.
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106. Reichheld JH, Katz E, Banner BF, et al. The value of intravenous 131. Klompmaker IJ, Sloof MJ, van der Meer J, et al. Orthotopic liver
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109. Pawliuk R, Bachelot T, Wise RJ, et al. Long-term cure of the 135. Ferraz AA, Sette MJ, Maia M, et al. Liver transplant for the treat-
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 19 Transplantation for Hematological Disorders 229

137. Hirshfield G, Collier JD, Brown K, et al. Donor factor V Leiden 141. Clarkson K, Rosenfeld B, Fair J, et al. Factor XI deficiency acquired
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278-280.
 CHAPTER 20

Transplantation for Budd-Chiari

Syndrome
Marvin J. Stone • James F. Trotter • James M. Fulmer • Göran B. Klintmalm

CHAPTER OUTLINE

ETIOLOGY Long-Term Results

Graft and Patient Survival
PATHOLOGY AND PATHOPHYSIOLOGY
ANTITHROMBOTIC THERAPY
CLINICAL PRESENTATION AND DIAGNOSTIC
EVALUATION CASE HISTORIES
Diagnostic Imaging Case 10—Undiagnosed Myeloproliferative
Disorder (Essential Thrombocythemia)
ETIOLOGICAL DIAGNOSIS: MYELOPROLIFERATIVE
Case 6—Polycythemia Vera in a 16-Year-Old
DISORDERS AND OTHER CONDITIONS
Girl
LIVER TRANSPLANTATION Case 16—Unclassified Myeloproliferative
Consideration for Transplantation: Indications Disorder and Factor V Leiden
and Contraindications Case 17—Prothrombin Gene Mutation
Surgical Considerations Case 15—Sarcoidosis
Postoperative Vascular Complications
SUMMARY

In 1845 George Budd, a British internist, described a proportion of idiopathic BCS should be no greater than
patient with hepatic venous thrombosis who developed 10% of all cases.
abdominal pain, hepatomegaly, and ascites.1 William
Osler reported the first case of a membranous web caus-
ing vena caval and hepatic vein obstruction in 1879.2 The ETIOLOGY
Austrian pathologist, Hans Chiari, specified the clinico-
pathological features of the syndrome, emphasizing BCS results from diverse causative factors (Table 20-1).4-24
occlusion of the intrahepatic veins in 1899.3 Their incidence varies significantly in different parts of
Budd-Chiari syndrome (BCS) results from obstruc- the world. In India and other parts of Asia, many cases are
tion of hepatic venous drainage due to various causes and idiopathic or caused by vena cava webs. Thus, in a study
leads to progressive liver damage and portal hyperten- of 71 BCS patients in India seen between 1992 and 1997,
sion. The venous occlusion is usually thrombotic and 42 were idiopathic and 18 had vena caval membranes.18
occurs at the level of the major hepatic veins or the infe- Membranous webs may be congenital or caused by fibro-
rior vena cava at any point proximal to the right atrium.4,5 sis from chronic thrombosis. Hepatic vein obstruction
Right heart failure or constrictive pericarditis can pro- because of hepatocellular carcinoma is common in South
duce similar findings. Histologically there is centrolobu- Africa. Myeloproliferative disorders (MPDs) and other
lar congestion, sinusoidal dilatation, hepatocyte necrosis, definable hypercoagulable states account for the majority
and varying degrees of fibrosis.5-7 Portal vein areas remain of BCS cases in Europe and Western countries.4-5,8-17,22-42
intact. The clinical presentation depends on the tempo The recent discovery of the V617F JAK2 mutation is
and extent of hepatic vein occlusion. As recently as 1996 helpful in identifying an MPD cause of BCS but does not
it was stated that “as many as 70% of patients with occlu- distinguish between the different disease entities in this
sion of the hepatic veins may not have a primary detect- group. JAK2 mutation is present in 95% of patients with
able cause."7 This is no longer true. A variety of causative polycythemia vera and approximately 50% with essential
mechanisms have been identified in BCS. Because these thrombocythemia (ET) or primary myelofibrosis.43-45
mechanisms have important bearing on long-term patient The specific cause should be sought in every patient
management and outcome, it is important to identify the because the presurgical and postsurgical management
specific cause responsible for hepatic vein occlusion in and outcome are to a large extent dependent on preven-
individual patients. With thorough evaluation the tion of further hepatic vein occlusion.

230
 20 Transplantation for Budd-Chiari Syndrome 231

TABLE 20-1 E
 tiological Considerations in the
Budd-Chiari Syndrome
Myeloproliferative disorders
Polycythemia vera
Essential thrombocythemia
Paroxysmal nocturnal hemoglobinuria
Others rare
Factor V Leiden mutation
Prothrombin gene mutation G20210A
Protein C deficiency
Protein S deficiency
Antithrombin III deficiency
Antiphospholipid syndrome
Lupuslike anticoagulant
Anticardiolipin antibodies
Pregnancy and postpartum FIGURE 20-1 n Native liver from patient 11 showing extensive
Oral contraceptives hepatocellular necrosis, hemorrhage, and architectural collapse
characteristic of Budd-Chiari syndrome (hematoxylin-eosin, ×100).
Dysfibrinogenemia
Hyperhomocysteinemia
Membranous webs autopsy studies demonstrating fibrous obstruction as the
Behçet’s disease final product of thrombus organization.46
Polycystic liver disease Histological findings characteristic of rapidly progres-
Myeloma/amyloidosis sive hepatic vein occlusion include intense congestion
Sarcoidosis and cellular atrophy (Fig. 20-1). Areas of necrosis and cell
Benign and malignant tumors dropout are often superimposed. Centrilobular extrava-
Infections sation of red cells and necrosis can extend to the periph-
Trauma ery of the lobules; however, the portal areas are
Venoocclusive disease preserved.5,7 In patients with chronic hepatic vein throm-
Herbal teas (pyrrolizidine alkaloids) boses, cardiac cirrhosis develops. The typical finding in
After gemtuzumab and high-dose chemotherapy with this group of patients is pericentral vein fibrosis.10
hematopoietic stem cell transplantation Hepatic venoocclusive disease is a distinct form of BCS
Combinations of above characterized by central venous dilatation, centrilobular
necrosis, and intimal thickening throughout the smaller
liver venules at the microscopic level. The principal cause of
this disease is continuous exposure to hepatotoxic pyrroli-
PATHOLOGY AND PATHOPHYSIOLOGY zidine alkaloids.11 Hepatic venoocclusive disease has also
been reported to develop after high-dose chemotherapy and
The multiple underlying conditions listed in Table 20-1 in the setting of hematopoietic stem cell transplantation.47
do not define the morphological characteristics of the The wide range of topographical and pathological
obstruction or the site involved. In Asian countries the causes encompassed under the BCS label merits a bet-
common finding is a membranous web in the inferior vena ter classification to facilitate patient evaluation, prog-
cava, specifically at the suprahepatic region, resulting in nostic prediction, and rational treatment. Ludwig
progressive thrombosis of the inferior vena cava and the et al48 suggested a more accurate and simplified classifi-
liver ostia.* In the United States and Europe, hematologi- cation of BCS on the basis of morphological features
cal disorders leading to thrombosis are the most frequent (thrombotic versus nonthrombotic), site of the lesion
underlying mechanisms responsible for occlusion of the (inferior vena cava, major or small hepatic veins), and
main hepatic veins.8-14,22-40 This thrombotic form of the cause. Such a classification would help clarify the
syndrome accounts for up to 80% of the patients present- pathophysiological abnormalities, histopathological
ing for surgical treatment of BCS.8,22 Compression or characteristics, and spectrum of diseases that lead to the
invasion of the hepatic veins by tumors or granulomas hepatic venous outflow obstruction and would aid in
occasionally results in acute or chronic occlusion or the selection of the appropriate medical management
thrombosis of the hepatic vein, leading to clinical expres- of patients with BCS.
sion of BCS.17,18,39-42 The reason for the predominant
localization of thrombosis at the level of the liver portion
of the vena cava is not known, although for many years the CLINICAL PRESENTATION AND
underlying mechanism was believed to be an endophlebi- DIAGNOSTIC EVALUATION
tis of the hepatic vein. The weight of the clinical evidence
now indicates that the primary process is thrombotic The clinical picture depends on the tempo and extent of
rather than inflammatory. This conclusion is supported by hepatic vein occlusion and is directly related to liver con-
gestion with subsequent hepatocyte necrosis and ulti-
*References 2, 3, 6, 7, 13, 18. mately fibrosis.
232 PART II Patient Evaluation: Adult

A B

C
FIGURE 20-2 n A, Sagittal color Doppler image of the liver demonstrates lack of flow within the intrahepatic inferior vena cava. B,
Sagittal gray-scale ultrasonographic image demonstrates coarse echotexture of the hepatic parenchyma with no visualization of the
intrahepatic inferior vena cava. C, Sagittal gray-scale ultrasonographic image demonstrates the presence of the transjugular intrahe-
patic portosystemic shunt in a patient with Budd-Chiari syndrome.

Although the presentation of patients suffering from portal hypertension in this patient population, variceal
BCS is variable, the clinical history correlates with the bleeding is uncommon.
acuity of disease onset. A minority of BCS patients pres- Routine laboratory test results indicate variable
ent with the classical symptoms and findings of gradual degrees of liver dysfunction. Serum transaminase, bili-
onset of right upper quadrant abdominal pain, tender rubin, and alkaline phosphatase levels are normal or
hepatomegaly, and ascites.5 The right upper quadrant mildly elevated. Serum albumin level may be decreased,
pain is often preceded by weeks to months of vague and albumin levels correlate well with the severity of
abdominal distress. Splenomegaly and an enlarged cau- liver injury and the magnitude of protein loss into
date lobe (palpable epigastric mass) are frequent addi- ascitic fluid. Prothrombin time may be mildly
tional findings. Patients with occlusion of the inferior prolonged.
vena cava have lower extremity edema, distended abdom- Liver biopsy typically demonstrates intense centrilobu-
inal flank and back veins, and albuminuria. Sudden-onset lar congestion and pressure necrosis of the liver paren-
upper abdominal pain with vomiting and rapid accumula- chyma. Cardiac cirrhosis is seen in the advanced stage of
tion of ascites with an enlarged, tender liver are less com- the disease. Liver biopsy may not be necessary in every
mon and are associated with acute onset of disease. Only patient; however, chronic BCS patients with biopsy find-
rarely will these patients experience fulminant liver fail- ings of cirrhosis and marginal liver reserve should be con-
ure, which is characterized by massive liver necrosis and sidered for liver transplantation rather than a decompressive
consequent liver coma, severe coagulopathy, and hypo- procedure.
glycemia.49 In the chronic type of BCS the development
of end-stage liver disease may not be associated with the
typical stigmata of chronic liver disease seen in cirrhotic
Diagnostic Imaging
patients. Fatigue and poor nutritional status are common; Noninvasive hepatic imaging has assumed a progressively
however, spider angiomas and palmar erythema are important role in the diagnostic evaluation of BCS.
unusual, and jaundice is usually mild. A common physical Duplex ultrasonography and color Doppler ultrasound
finding is lower extremity edema resulting from partial or imaging accurately define the flow parameters of the
complete occlusion of the retrohepatic vena cava by the hepatic veins, the portal vein, and the inferior vena cava
hypertrophied caudate lobe. Caval obstruction may in most patients (Fig. 20-2). Often ultrasonography is the
decrease kidney perfusion pressure, thereby contributing initial imaging modality in patients being evaluated for
to the development of kidney failure. Despite severe hepatic venoocclusive disease. However, the sensitivity of
 20 Transplantation for Budd-Chiari Syndrome 233

technique for contrast-enhanced MRI includes multiple

phases of enhancement. In the preoperative evaluation,
specific flow-sensitive sequences are often employed to
evaluate splenoportal morphological features and hepa-
tovenous morphological characteristics. Although not
routinely necessary, magnetic resonance cholangiopan-
creatography may be added to preoperative protocols in
those patients who are suspected of harboring biliary
pathological conditions.
In patients with known or suspected BCS the noninva-
sive imaging evaluation is used to confirm the diagnosis
and uncover unsuspected malignancies. This is particu-
larly important because hepatic malignancy is more com-
mon in patients with BCS than in the general
population.
FIGURE 20-3 n Computed tomographic image demonstrates typi- Hepatic venography remains the gold standard for
cal morphological changes in the hepatic shape, with lack of the imaging diagnosis of BCS. The hepatic veins may
visualization of the intrahepatic inferior vena cava and the pres- be cannulated from a femoral or jugular approach. A
ence of ascites.
spiderweb appearance of the intrahepatic veins is con-
firmatory (Fig. 20-5). Hepatic venography also allows
measurement of the hepatic wedge pressure, and infe-
rior venacavography can be performed during the same
catheterization in the rare occasion shunt surgery is
contemplated.
Thorough radiological evaluation of BCS is best
accomplished with a multimodality approach. Cross-
sectional imaging (CT or MRI) is used to examine the
entire abdominal contents, as well as to confirm and
characterize hepatic blood flow. The measurement of
flow parameters is usually accomplished with ultraso-
nography. In patients who are not transplant candidates,
venography confirms the diagnosis of BCS and provides
preoperative assessment before the transjugular intrahe-
patic portosystemic shunt (TIPS) procedure. Surgical
shunts are rarely used now.
FIGURE 20-4 n Axial T2-weighted image in a patient with Budd- Once hepatic vein obstruction is demonstrated, its
Chiari syndrome secondary to extramedullary hematopoiesis. cause should be established. Table 20-2 lists suggested
Notice the splenomegaly, ascites, and altered hepatic morpho- diagnostic studies.
logic structures typical of Budd-Chiari syndrome.

ultrasonography is affected by the patient’s body habitus,

ETIOLOGICAL DIAGNOSIS:
echo density of the liver, and the amount of upper abdom- MYELOPROLIFERATIVE DISORDERS AND
inal bowel gas. Ultrasonography does provide valuable OTHER CONDITIONS
information in most patients, but it is less sensitive for the
detection of hepatic masses than computed tomography In Western countries the recognition of overt or occult
(CT) or magnetic resonance imaging (MRI). MPDs—especially polycythemia vera, ET, and paroxys-
Multiphase infusion CT evaluation accurately mal nocturnal hemoglobinuria—as causes of BCS has
images the hepatic parenchyma and gives valuable been documented for more than 20 years. Other MPDs
information regarding hepatic venous and portal venous (agnogenic myeloid metaplasia or primary myelofibrosis,
flow (Fig. 20-3). An enlarged caudate lobe is character- chronic granulocytic leukemia, and erythroleukemia) are
istically observed. CT arteriography and venography rarely associated with BCS. MPDs are the cause of 40%
accurately assess the anatomical features of hepatic vas- to 70% of BCS cases in the United States and
culature. CT also defines hepatic morphological fea- Europe.8,22-24 Coagulation abnormalities, both heredi-
tures and helps distinguish BCS from other processes tary and acquired, are also causes of BCS. Some of these
that may mimic venoocclusive disease.50 disorders were recognized during the 1990s. If preven-
MRI is also very sensitive in the detection of hepatic tion of further thrombosis is to be achieved, complete
mass disease, as well as in evaluating flow characteristics hematological evaluation of each patient with BCS for
in the hepatic vasculature (Fig. 20-4). MRI can provide evidence of MPDs and other hypercoagulable states
insight into diffuse hepatic disease.51 Gadolinium-based becomes imperative. Consideration of one series of
contrast agents are commercially available and are rou- patients studied serially illustrates several pertinent
tinely employed in liver imaging. As with CT, the points in this regard.
234 PART II Patient Evaluation: Adult

A B
FIGURE 20-5 n A, Hepatic venogram demonstrates cannulation of right hepatic vein. Middle and left hepatic veins are completely
occluded. B, Hepatic venogram on another patient demonstrates irregular spiderweb appearance of Budd-Chiari syndrome. (B, From
Shaked A, Goldstein R. Transplantation for Budd-Chiari syndrome. In: Busuttil RW, Klintmalm GB, eds. Transplantation of the Liver. Philadelphia:
Saunders; 1996:130.)

colony-forming assays were not done.25,26 The JAK2 muta-

TABLE 20-2 D
 iagnostic Tests for Evaluation of tion was not identified until 2005, and so analysis for this
Cause of Budd-Chiari Syndrome abnormality was not carried out in these patients. Hyperco-
Complete blood count and peripheral blood smear
agulability evaluation was conducted in all patients. An
Liver function blood tests
expanded battery of studies was used as new causes for
Liver imaging studies
thrombophilia were established (see Table 20-2). The first
Liver biopsy
13 patients underwent transplantation before 1996, before
V617F JAK2 mutation in peripheral blood or bone marrow
widespread recognition of factor V Leiden, the prothrom-
Bone marrow aspiration and biopsy
bin gene mutation, and hyperhomocysteinemia as causes of
Factor V Leiden mutation
the hypercoagulable state. Laboratory studies performed
Prothrombin gene mutation (G20210A)
on the earlier patients included functional and total protein
Antithrombin III
C and protein S, antithrombin III, anticardiolipin immu-
Protein C (total and functional)
noglobulin G and M antibodies, lupuslike anticoagulant,
Protein S (total and functional)
sucrose hemolysis, and serum protein electrophoresis. This
Lupuslike anticoagulant (anti-beta 2 glycoprotein 1 antibodies)
protocol was not in place when the first patient with BCS
Anticardiolipin antibodies
was seen, but it was used subsequently. Causative diagnoses
Homocysteine level
were established in 22 of the 24 remaining patients (92%).
Serum protein electrophoresis
The purpose of this study was to identify the origin of
Flow cytometry for CD55, CD59 expression (paroxysmal
BCS and to determine whether antiplatelet treatment
nocturnal hemoglobinuria) rather than anticoagulation would be effective in patients
with underlying MPDs.
Table 20-3 lists the diagnosis, treatment, and outcome
of the 25 patients in the Dallas study. Seventeen patients
Between 1987 and 2007, 25 patients with BCS under- were women, and 8 were men. Age at time of OLT
went orthotopic liver transplantation (OLT) at Baylor Uni- ranged from 9 to 61 (mean 33) years. Time from onset of
versity Medical Center in Dallas, Texas (Table 20-3).8,28,52 BCS to OLT ranged from approximately 4 months to 4
Data for this study were collected through a prospectively years. Seventeen patients (68%) had evidence of an MPD
maintained longitudinal database and chart review. The as the cause of their BCS. Seven of these patients had a
diagnosis of BCS was confirmed by imaging studies, includ- clinical picture consistent with polycythemia vera, 2
ing MRI, CT, Doppler ultrasonography, and angiography. patients had ET, and 8 patients had unclassifiable MPDs.
Pathological examination of the native liver after transplan- Cytogenetic analysis was performed in 5 patients (patients
tation was accomplished in all cases. 2, 7, 8, 11, and 16), and all were normal. Two patients
Bone marrow examination was performed in all patients (patients 1 and 19) were classified as having idiopathic
except the first. The diagnosis of MPD was based on bone BCS. The 3 remaining patients had protein C deficiency
marrow morphological abnormalities in conjunction with (patient 13), sarcoidosis (patient 15), and the prothrom-
peripheral blood counts.53,54 Spontaneous erythroid bin gene (G20210A) mutation (patient 17). Three
 20 Transplantation for Budd-Chiari Syndrome 235

TABLE 20-3 D
 iagnosis, Treatment, and Outcome of Patients After Liver Transplantation for
Budd-Chiari Syndrome
Case Number Etiology Posttransplant Treatment Follow-up (Year)
1 Idiopathic Warfarin 22
2 Polycythemia vera Hydrox + asp, later Warfarin 22
3 MPD unclassified Hydrox + asp 22
4 Polycythemia vera Hydrox + asp 0.6
5 Polycythemia vera Hydrox + asp 20
6 Polycythemia vera Hydrox + asp 10
7 MPD and later Hydrox + asp, later folic acid 15
hyperhomocysteinemia
8 MPD unclassified Hydrox + asp 17
9 MPD unclassified Hydrox + asp 17
10 Essential thrombocythemia Warfarin initially and later 16
Hydrox + warfarin
11 Polycythemia vera Hydrox + asp 14
12 Polycythemia vera Hydrox + asp 8
13 Protein C deficiency None 8.5
14 Essential thrombocythemia Hydrox + asp 4.5
15 Sarcoidosis None 9.8
16 MPD unclassified and factor Hydrox + asp 8
V Leiden
17 Prothrombin gene mutation None 6.6
18 Polycythemia vera Hydrox + asp 6.3
19 Idiopathic Warfarin 6
20 Antiphospholipid syndrome Warfarin 6
21 Idiopathic Warfarin 5.8
22 MPD and factor V Leiden Hydrox + asp 4.3
23 MPD unclassified Hydrox + asp 4.2
24 MPD and factor V Leiden Hydrox + asp 4
25 Factor V Leiden and Warfarin 0.75
antiphospholipid syndrome

Modified from Chinnakotla S, Klintmalm G, Kim P, et al. Long-term follow-up of liver transplantation for Budd-Chiari syndrome with
antithrombotic therapy based on the etiology. Transplantation 2011;92:341-345.
*Had a stroke resulting from intracranial bleeding from anticoagulation but still has good liver function.
†First liver graft lost because of cholestatic liver failure in 1 month, retransplanted.
‡Cause of death: patient 4, hepatitis B cirrhosis (no thrombotic complications); patient 6, chronic rejection and portal vein thrombosis; patient

7, renal cell carcinoma; patient 12, hepatitis C cirrhosis; patient 13, stroke with a functioning liver allograft; patient 14, intracranial
aneurysm bleeding with a functioning liver allograft.
asp, Aspirin; Hydrox, hydroxyurea; MPD, myeloproliferative disorder.

patients (patients 16, 22, and 24) were heterozygous for versus portosystemic shunting are similar in terms of
factor V Leiden in addition to having an MPD. One patient outcome.* Although surgical shunts were a main-
patient (25) had factor V Leiden plus antiphospholipid stay of BCS therapy in the past, their application has been
antibody syndrome. virtually replaced by TIPS. In almost all cases TIPS may
It was possible to arrive at a causative diagnosis in be considered as the primary therapy of choice over shunt
nearly all patients with BCS. Sixty-eight percent (17 of surgery. In the hands of experienced radiologists, TIPS
25) had evidence of MPD.8 Antiplatelet therapy with offers the advantage as a minimally invasive procedure with
hydroxyurea and aspirin was employed as the antithrom- all the benefits of shunt decompression. With the
botic regimen in the MPD patients (see Table 20-3).8,28,52 development of covered stents, the patency rate and
consequently the efficacy of TIPS have greatly improved.
Once the diagnosis of BCS has been made, every
LIVER TRANSPLANTATION patient should be considered for decompressive shunt
therapy. Historically this was done with a surgical
Consideration for Transplantation: shunt. However, with the advent of TIPS and in
Indications and Contraindications particular the covered TIPS stent, TIPS has virtually
supplanted surgical shunting as the preferred
The first liver transplant for BCS was performed in 1974.55 decompressive therapy. Consideration for TIPS
The selection of patients to undergo OLT for BCS must
be made on an individual basis. Long-term results of OLT *References 4, 12, 17, 19-21, 50-52, 56-58.
236 PART II Patient Evaluation: Adult

includes (1) technical feasibility and (2) considerations OLT is indicated when liver synthetic function is
of hepatic decompensation. The technical feasibility of poor.56-59 Assessment of liver reserve is critical; patients
TIPS must include assessment of the patient and his or with no reserve (i.e., irreversible parenchymal injury)
her hepatic venous anatomy by a radiologist experienced may rapidly decompensate after portosystemic shunt,
in the placement of TIPS. Some patients are not resulting in high mortality.57,60,61 Acute or chronic liver
amenable to TIPS because anatomical considerations, failure after portosystemic shunt or TIPS therefore indi-
including portal vein thrombosis, vena caval thrombosis, cates poor liver reserve and signals the need for urgent
or pulmonary hypertension. In many cases the TIPS liver transplantation.
shunt is placed between the vena cava and the portal Development of encephalopathy in end-stage liver
vein if the hepatic venous anatomy does not allow disease is generally regarded as an indicator of poor resid-
standard hepatic venous-to-portal venous stent ual liver function. Portosystemic shunt is usually contra-
placement. Once the technical feasibility of TIPS has indicated in encephalopathic patients because further
been established, patients deemed as candidates for the neurological deterioration may be a consequence of the
procedure should be evaluated for liver transplantation. procedure. For this reason encephalopathy complicating
Because hepatic decompensation is a recognized acute or long-standing BCS should be considered an
complication of shunting procedures in general and indicator for OLT.
TIPS in particular, liver transplantation serves as a The role of liver biopsy in determining the extent of
required “safety net” should this problem develop after injury caused by long-standing hepatic venous occlusion
TIPS. Patients at greatest risk for decompensation are is not clear. However, liver biopsy alone should not be
those with encephalopathy or marked jaundice before the dominant focus of decision making. The ambiguity of
the procedure. In patients who are anatomically eligible biopsy findings is illustrated by the favorable clinical
for TIPS, there are no strict criteria for selecting BCS course of some shunt patients whose biopsies showed
patients for the procedure. Careful consideration fibrosis at initial presentation.57,62 There are conflicting
should be given to the potential risk for decompensation reports about the role of portosystemic shunting in
after decompression versus the potential benefit. arresting the progression of cirrhosis, but progressive
However, TIPS may be considered in carefully selected fibrosis and cirrhosis dominate the course of at least a
patients with these problems if they are listed for small group of shunt patients.62-64
transplantation. Some patients demonstrate remarkable The primary disease causing obstruction of the hepatic
improvement in liver function after decompression, vein may also determine appropriate surgical interven-
especially young ones. In the symptomatic patients with tion. A number of reports have identified BCS as a poten-
tender hepatomegaly and ascites, TIPS should be tial risk factor for the development of hepatoma.65,66 The
performed unless there is compelling evidence to do finding of a small incidental hepatoma should prompt
otherwise. Most patients improve after the procedure, consideration of OLT. In contrast, results of transplanta-
and if the patient is listed, transplantation may be tion for stage IV hepatocellular carcinoma (tumor invad-
performed in the event of decompensation. ing the portal or hepatic veins) are dismal, and shunt
Several liver transplantation centers have reported surgery is more appropriate therapy. Other similar exclu-
good results in BCS patients undergoing OLT.7,8,12-21,56-59 sion criteria for transplantation are hepatic venous occlu-
The 3-year survival rate after transplantation was greater sion secondary to locally invasive tumors or metastatic
than 75%, with surviving patients returning to a func- extrahepatic malignancies.
tional lifestyle. Although these reports may be interpreted Several studies outline critical criteria to distinguish
as an unequivocal recommendation for OLT as therapy shunt versus transplantation candidates.57,58 These
for patients with BCS, excellent long-term results have studies suggest that patients with fulminant or chronic
also been reported after portosystemic shunts.13,56-59 Fur- forms of BCS should undergo transplantation, and
thermore, liver function test results may return to normal those with acute or subacute BCS should undergo
after shunting, with stabilization or even improvement of decompressive procedures. These clinical criteria, when
the parenchymal injury, as indicated by postoperative considered with assessment of residual liver function,
liver biopsies. These reports pose a central dilemma in provide a therapeutic framework for successful manage-
the management of patients with BCS and indicate the ment of this otherwise fatal syndrome. Screening for
need to establish standards for determining which coexisting medical conditions in this group of patients
patients should undergo decompressive procedures ver- is similar to that in other OLT candidates. In addition,
sus liver transplantation. Such criteria should include thrombosis of the hepatic veins in the setting of a hyper-
reversibility of liver injury, primary disease leading to the coagulable state mandates careful evaluation of the por-
hepatic venous obstruction, and fitness of the patient to tal system, and the absence of clots in the cava and iliac
withstand either surgical procedure. veins should be confirmed before surgery to anticipate
The severity of liver failure and the functional liver the need for portal venous grafts and access sites for
reserve should be determined by clinical and laboratory venovenous bypass.
data, aided by liver biopsy. Hepatocyte synthetic failure is In summary, appropriate surgical therapy for BCS
reflected by serum levels of albumin less than 3 g/dL, should be performed only after consideration of the
prolonged coagulation (prothrombin time greater than 3 reversibility of the liver disease and the fitness of the
seconds more than control), and the inability to conjugate candidate to withstand surgery. The operation must be
bilirubin and secrete bile (conjugated bilirubin level individualized to the unique expression of the disease for
greater than 3 mg/dL). each patient.
 20 Transplantation for Budd-Chiari Syndrome 237

anticoagulation. We commence hydroxyurea/aspirin, or

Surgical Considerations Coumadin when indicated, 1 week after transplantation;
The standard operative technique of liver transplantation heparin is never used.
is recommended for most cases of BCS.4 The dissection None of the BCS patients in the Dallas series devel-
is characteristically difficult when approaching the supra- oped hepatic vein thrombosis postoperatively; however,
hepatic vena cava because of dense adhesions between the hepatic artery stenosis was seen in three patients (12%).
liver and the diaphragm. In most cases the suprahepatic This incidence was not significantly different from that
vena cava can be encircled and a clamp applied. Occa- in non-BCS patients. Portal vein thrombosis developed
sionally the diaphragm must be dissected off the inferior in one patient, after the second graft (7 years after
vena cava up to the right atrium. This approach avoids retransplantation for hepatitis C) and following 11 years
splitting of the diaphragm or thoracic extension. of posttransplant antithrombotic therapy with hydroxy-
The surgical approach can be modified in the presence urea and aspirin. Intra-abdominal bleeding in the imme-
of complete obstruction of the suprahepatic vena cava diate posttransplant period occurred in two patients in
caused by an organized thrombus that is not amenable to the BCS group. Both patients required return to the
thrombectomy. The suprahepatic clamp is removed, and operating room for an evacuation of clots with no source
a curvilinear incision through the tendinous portion of of bleeding identified. One hundred thirty-three liver
the diaphragm exposes the pericardium. An end-to-end biopsies were performed to evaluate liver dysfunction in
anastomosis is performed to the intrapericardial portion the 16 patients on hydroxyurea/aspirin antithrombotic
of the inferior vena cava.67 Similarly a previous hepa- therapy at various times during the entire follow-up with
toatrial anastomosis can be taken down via an inferior no bleeding complications.52
medical sternotomy and median laparotomy.68 To avoid
venous air embolism during dissection, place the patient Long-Term Results
on cardiopulmonary bypass with short periods of induced
fibrillation. The diaphragm is split through the central Reported 3-year survival of patients who underwent
fibrous body, and the cuff of the donor atrium is brought transplantation for BCS ranges from 45% to 88%. The
to the chest followed by standard anastomosis. (Despite European Liver Transplant Registry recorded 82 patients
removal of the liver with a long suprahepatic or atrial who underwent transplantation for BCS, with a 3-year
cuff, transplantation of the heart from the same donor is survival of 57%.71 These long-term results are compara-
still possible.) ble to survival after portosystemic shunt procedures, but
As noted previously, it is not uncommon to perform these data should be interpreted with the knowledge that
transplantation in patients with prior portosystemic different patient populations undergo shunt versus OLT
shunting, most commonly end-to-end portacaval or and that selection criteria for OLT may vary among cen-
mesoatrial shunts. Dissection of end-to-side portacaval ters. Furthermore, OLT may not be an option in some
shunts is performed as previously described.69 If veno- centers performing shunt procedures.
veno bypass is used, recent modifications include the In our study, with both options available, proper pre-
placement of a portal cannula through the inferior mes- operative assessment of liver reserve resulted in similar
enteric vein followed by simple ligation of any mesopor- survival in both groups. Furthermore, patients who dete-
tacaval shunt immediately after reperfusion. A mesoatrial riorated after shunting could be rescued by urgent OLT.
shunt should be ligated because it jeopardizes the portal The pattern of liver function test results after shunt sur-
blood flow and patency if left intact. The portal outflow gery was variable. In some patients, liver function test
can usually still be used in case of portal vein occlusion. results stabilized, but others showed further deterioration
The incidence of portal vein thrombosis or occlusion of in synthetic function; in a few patients extensive fibrosis
the infrahepatic inferior vena cava is reported to be higher developed. In contrast, successful OLT resulted in com-
in patients with BCS than in other transplant recipients.70 pletely normal liver function. Patients undergoing OLT
Restoration of portal blood flow is usually successful after for curable parasitic disease had no evidence of recurrence
thrombectomy; rarely is a portal vein graft required.69 within 2 years after surgery, whereas disseminated disease
The infrahepatic inferior vena cava can either be throm- recurred and progressed slowly over 3 to 19 months after
bectomized or allowed to remain occluded if the orga- transplantation.72 Despite these advantages of transplan-
nized thrombus extends below the renal veins. tation, significant drawbacks are well known and include
A word of caution: BCS patients can be the most tech- complications related to lifelong immunosuppression and
nically challenging patients for liver transplant surgery, the development of acute or chronic rejection.
especially if they have had previous surgeries that have
caused adhesions to the surface of the liver, producing Graft and Patient Survival
huge and friable varices. Such patients need to be
approached with utmost caution and care. The 1-, 3-, 5-, 10-, and 15-year graft survival rates in
patients transplanted for BCS were 92%, 92%, 88%,
72%, and 72%, respectively; the corresponding patient
Postoperative Vascular Complications survival rates were 96%, 96%, 92%, 81%, and 73%,
Postoperatively BCS patients do not require immediate respectively.52 Both graft survival and patient survival
anticoagulation because recurrent disease thromboses were higher in BCS patients than non-BCS patients who
do not occur during the first postoperative week. Thus underwent liver transplantation (Fig. 20-6). There were
there is no need to risk postoperative hemorrhage by four deaths in the MPD group: one resulting from
238 PART II Patient Evaluation: Adult

100
90
80
70
Survival % 60
50
40
30
Budd-Chiari graft survival
20 Budd-Chiari patient survival
10 Other graft survival
Other patient survival
0
0 5 10 15 20 25
Years

Surviving Patients

Group 1 year 5 years 10 years 15 years 20 years

Budd-Chiari 23 22 12 8 3
(n = 25)

Other 2213 1480 748 297 56

(n = 2609)

FIGURE 20-6 n Kaplan-Meier plot of graft and patient survival after liver transplantation according to indication for transplant: Budd-
Chiari syndrome and other (i.e., non–Budd-Chiari syndrome indications). (From Chinnakotla S, Klintmalm G, Kim P, et al. Long-term
follow-up of liver transplantation for Budd-Chiari syndrome with antithrombotic therapy based on the etiology. Transplantation 2011;92:341-345.)

hepatitis C cirrhosis, one resulting from hepatitis B, one sec- abnormalities in MPDs include qualitative and quantita-
ondary to portal vein thrombosis (see case 6 discussion), and tive platelet defects that are associated with both abnormal
one resulting from an intracranial aneurysm hemorrhage.52 bleeding and clotting. Thus treatment directed toward
A randomized study comparing OLT and shunt pro- altering platelet production and function may be more
cedures is unlikely to be performed for patients suffering rational and effective than anticoagulation.
from various types of BCS in a single center, in part In the Dallas study, patients with MPDs (see Table
because of the rarity of the syndrome. The message 20-3) were given aspirin, 325 mg/day, and hydroxy-
emerging from the surgical literature is that patients with urea, 500 to 1500 mg/day, 4 to 7 days after OLT.8,52
BCS must not be inserted into any preconceived surgical Neither heparin nor any other anticoagulation was
approach. Various options for the treatment of the BCS routinely given after OLT. The hydroxyurea dose was
should be individualized to the particular underlying titrated to maintain platelet counts between 100 ×
causative disease and clinical presentation. 103/μL and 250 × 103/μL. Patients were maintained on
these medications. Those who were recognized as hav-
ing an MPD before transplantation received the same
ANTITHROMBOTIC THERAPY regimen. Thrombolytic therapy was attempted unsuc-
cessfully in two patients thought to have acute BCS.
The effectiveness of OLT in patients with BCS has been Such thrombolytic treatment has been reported to
complicated by recurrent thrombosis and difficulties in have efficacy in occasional patients.20 After anagrelide
establishing a cause for the thrombosis.6,19-24,59,73-80 Anti- became available, it was used in place of hydroxyurea in
coagulation with heparin followed by warfarin has been two patients who developed anemia or granulocytopenia
the therapy of choice to prevent posttransplant on the latter agent. Patients without MPDs were
thrombosis.* Recent advances in understanding the patho- treated according to identification of their underlying
genesis of BCS indicate that overt or occult MPDs are fre- condition. Standard immunosuppressive therapy was
quent causes in the United States and Europe.23-27 Despite used after OLT and consisted of cyclosporine and
the recognition that MPDs often underlie BCS in West- prednisolone for the first 12 patients and cyclosporine
ern countries, therapeutic recommendations continue to microemulsion and prednisolone thereafter.
focus on anticoagulation.22-24,81 The pathophysiological Anticoagulation with heparin and warfarin has
generally been the therapy used to prevent recurrent
*References 6, 12, 19-24, 73, 75, 76, 78-80. thrombosis in patients with BCS undergoing OLT or
 20 Transplantation for Budd-Chiari Syndrome 239

portosystemic shunting.* In 1991 we reported the use of Both graft and patient survival were higher in the
hydroxyurea and aspirin in five patients who underwent BCS patients than in non-BCS patients who underwent
transplantation for BCS associated with MPDs.28 This OLT (see Fig. 20-6). The majority of the BCS patients
treatment approach was predicated on our experience had MPD and were treated after OLT with only
and that of others that MPDs were a common cause of hydroxyurea and aspirin. One patient (patient 6) had a
BCS. Seventeen of 25 patients (68%) in the expanded recurrent thrombus manifested as portal vein thrombosis
Dallas study had evident MPDs, which are hematopoi- 124 months after the first OLT. No other instances of
etic clonal stem cell disorders associated with a paradoxi- thromboembolic complications occurred in this group,
cal propensity to both bleed and clot abnormally.8 A and no major bleeding complications were identified.
classification system has been proposed that relies heav- Moreover, the patients treated with antiplatelet therapy
ily on megakaryocyte morphological features in diagnos- only underwent 133 liver biopsies to monitor allograft
ing MPDs.54 In polycythemia vera patients with BCS, status with no bleeding complications. In 2 patients from
peripheral blood counts may not be elevated because of the group of 17 (patients 14 and 16), anagrelide was
splenomegaly and hypersplenism. Therefore bone mar- administered after initial therapy with hydroxyurea;
row morphological findings are crucial. Several authors aspirin was continued in both patients. Observed side
have reported finding a high percentage of occult MPDs effects included transient cytopenias secondary in part to
by using spontaneous erythroid colony-forming assays hydroxyurea. No clinical sequelae were noted, and these
in vitro.25-27,82 All of our patients with MPDs had mor- cytopenias were managed by temporarily discontinuing
phological abnormalities of the megakaryocyte lin- hydroxyurea or, in the later patients, by substituting
eage.28,52 Thus spontaneous erythroid colony-forming anagrelide for hydroxyurea.
assays were not used for diagnosis of MPDs in these In patients presenting with BCS a complete hemato-
patients. However, such studies may have been helpful in logical workup, including assay for JAK2 mutation and
the patients with idiopathic BCS. bone marrow examination, is mandatory, because these
Identification of the gain-of-function JAK2 mutation procedures may yield important information for guiding
has been a major advance in detection of MPD because therapy.8,52 None of our patients had paroxysmal noctur-
it is present in 95% of polycythemia vera patients and nal hemoglobinuria, a rare MPD that can present as
about 50% of those with ET and primary myelofibrosis. abdominal thrombosis, including BCS.22-24,83 A mono-
However, it should be borne in mind that a positive clonal antibody is available for this disorder that appears
result for JAK2 does not indicate which MPD a patient to reduce hemolysis and thrombotic risk.
has and a negative test result does not rule out an The underlying drive to thrombosis in patients with
MPD.23,24,43-45 MPDs may not be adequately treated using heparin and
Of the 25 patients in the Dallas study, 5 were given warfarin. These agents also expose patients to risk associ-
warfarin after OLT for various reasons. Patient 1 was ated with anticoagulation. Our approach consisted of
receiving warfarin before this study was initiated. Patient managing patients diagnosed with BCS secondary to an
2 had recurrent thrombus in a brachial artery that had MPD in a different manner. The use of hydroxyurea and
been damaged at cardiac catheterization during pretrans- aspirin directed treatment toward abnormal platelets and
plant evaluation. She developed recurrent thrombosis in is a safe and effective alternative to anticoagulation ther-
this artery while receiving aspirin and hydroxyurea ther- apy. Hydroxyurea appears to have little leukemogenic
apy, so warfarin was resumed. Patient 10 had a pretrans- risk. The action of anagrelide is primarily on megakaryo-
plant diagnosis of cryptogenic cirrhosis but was later cytes and platelets, with less effect on normal erythroid
determined to have BCS. The diagnosis of an MPD (ET) and granulocytic precursors. None of our MPD patients
in patient 10 was subsequently made on histological has developed leukemia, although this remains a future
review of the spleen (removed 1 month after OLT) possibility.22,84,85
and after she had two episodes of thrombosis following The recurrent thrombosis rate in Baylor Dallas
OLT with retained thrombus in the portal vein (see case patients treated with hydroxyurea and aspirin compares
10 later). Therefore warfarin was continued. These favorably with other series. Only one patient developed
patients were not given aspirin because of warfarin recurrent thrombosis and that was 124 months after
anticoagulation. OLT. One series in which seven patients on warfarin
Follow-up of the 25 patients ranged from 7 months to were followed after OLT revealed that all seven patients
22 years. Six of the 25 patients died. Patient 4 died sec- remained alive, but two patients required retransplanta-
ondary to acute hepatitis B and multisystem organ failure tion because of recurrent BCS, and one patient had major
7 months after OLT while receiving hydroxyurea. Patient gastrointestinal bleeding.75 Another study73 examined 16
6 died secondary to portal vein thrombosis while receiv- patients with BCS who has undergone anticoagulation
ing hydroxyurea and aspirin 124 months after initial after OLT. Mean follow-up was 28.2 months. The
OLT (see case report later). Two allografts were lost— authors found a 31% rate of thrombosis (three in the por-
one secondary to hepatitis C 78 months after OLT tal vein, one in the hepatic artery, and one in the axillary
(patient 6) and the other as a result of vanishing bile duct vein). A 44% rate of bleeding complications also was
syndrome 1 month after OLT (patient 2). Neither observed.
allograft showed evidence of recurrent thrombosis. Antiplatelet therapy with hydroxyurea and aspirin
appears to be an effective, safe, and preferable alternative
to anticoagulation in preventing recurrent thrombosis in
*References 6, 12, 19-24, 58, 59, 73, 75. transplant recipients who have BCS associated with an
240 PART II Patient Evaluation: Adult

ETIOLOGY

MPD Non-MPD Hypercoagulable States Idiopathic

AC with heparin,
warfarin, or other
agent
Antiplatelet Rx with Corrected by OLT Not Corrected by OLT AC with heparin,
hydroxyurea, aspirin warfarin, or other
agent

No Rx AC with heparin,
warfarin, or other
agent
FIGURE 20-7 n Decision tree for antithrombotic treatment in Budd-Chiari syndrome (BCS). Note: Thrombolytic therapy is a consider-
ation for patients presenting with acute BCS. Some patients with BCS, because of polycythemia vera, do not have elevated hemato-
crit levels. If the hematocrit is greater than 45%, phlebotomy should be performed with antiplatelet medications. AC, Anticoagulation;
MPD, myeloproliferative disorder; OLT, orthotopic liver transplantation; Rx, therapy.

MPD (see Fig. 20-6). Patients treated with warfarin ther- cryptogenic cirrhosis. Pretreatment platelet count was
apy to prevent recurrent thrombosis are at substantial risk normal. This patient developed a thrombus in the portal
when their prothrombin time falls to subtherapeutic lev- and splenic veins 1 month after OLT, and splenectomy
els.10,73,75 Warfarin was discontinued in a patient who was was performed. Recurrent thrombus of the portal vein
seen in 1981 by one of this textbook’s editors (G.B.K.) in graft and marked postsplenectomy thrombocytosis
preparation for liver biopsy and experienced recurrent aroused suspicion of an MPD. Additional histological
thromboses. The patient was hospitalized and died after a review of the spleen disclosed trilineage extramedullary
short course. This experience was one of the initial moti- hematopoiesis, a finding strongly suggestive of an MPD.
vating factors in our current therapeutic approach to Subsequent bone marrow examination was consistent
patients who have BCS undergoing OLT. with ET. Administration of warfarin had begun when the
In patients not having an MPD, posttransplant anti- recurrent thrombus in the portal vein occurred. Hydroxy-
thrombotic therapy may not be necessary if an underly- urea was added after the diagnosis of ET was made.
ing hereditary defect is corrected by liver transplantation, This case illustrates the value of complete hematologi-
for example, protein C deficiency or the prothrombin cal evaluation to establish the diagnosis of MPDs in
gene mutation.8,86 For patients with acquired thrombo- patients who present with BCS. Had the underlying
philia, posttransplant therapy will vary (Fig. 20-7). The MPD been recognized earlier, splenectomy would not
patient with sarcoidosis was followed without anti- have been performed. Despite multiple thromboses soon
platelet or anticoagulant treatment. By contrast, indi- after OLT, this patient has not had a recurrent thrombo-
viduals with BCS caused by antiphospholipid antibodies sis since starting hydroxyurea.
should be maintained on anticoagulation. For BCS
patients in whom a thorough hematological and hyper- Case 6—Polycythemia Vera in a
coagulable evaluation are negative and who therefore
have idiopathic BCS, long-term anticoagulation seems
16-Year-Old Girl
prudent. This young patient abruptly developed abdominal pain
and nausea in April 1988. She was found to have ascites
and elevation of liver enzyme levels. CT, MRI, and a
CASE HISTORIES Doppler ultrasonogram revealed hepatic venous throm-
bosis. A complete blood count disclosed a white blood
The following case reports illustrate a causative spectrum cell count of 14 × 103/μL, a hematocrit of 41%, and a
and diverse clinical presentations of patients with BCS.8,52 platelet count of 600 × 103/μL. Leukocyte alkaline phos-
Table 20-3 lists the case numbers. phatase score was elevated at 200 (normal 16 to 77). Bone
marrow examination showed a hypercellular marrow
Case 10—Undiagnosed Myeloproliferative with erythroid hyperplasia and absent iron stores. Mega-
karyocytes were increased in number and clustered in
Disorder (Essential Thrombocythemia) multiple areas. The diagnosis of polycythemia vera was
This 34-year-old white woman began having symptoms made. Treatment with hydroxyurea and aspirin was
of liver dysfunction in March 1990. Evaluation failed to instituted.
reveal the cause of her liver failure, and she underwent The patient underwent liver transplantation in
transplantation in April 1992 with the diagnosis of December 1988. Pathological examination of the native
 20 Transplantation for Budd-Chiari Syndrome 241

liver confirmed hepatic venous thrombosis. A second Case 17—Prothrombin Gene Mutation
transplant 78 months after the first was necessitated by
the development of hepatitis C. The excised allograft This 25-year-old man from Israel was transferred to our
showed no evidence of recurrent thrombosis. Liver institution for urgent OLT as a result of refractory ascites,
biopsy in March 1998 disclosed ductopenia and fibrosis renal insufficiency, and hepatic encephalopathy. The
consistent with chronic rejection. One year later the patient was first diagnosed with BCS 18 months previ-
patient developed abdominal pain as a result of portal ously when he presented with ascites. Hematological eval-
vein thrombosis. She died while waiting for her third uation, including bone marrow examination, was negative
liver transplant. Hydroxyurea and aspirin therapy were for MPD. Warfarin therapy was initiated. Multiple surgi-
well tolerated for 10 years until she became symptom- cal procedures were unsuccessful in controlling the asci-
atic from a portal vein thrombus and eventually died of tes. Evaluation at Baylor University Medical Center in
this complication. This patient was the only one with Dallas disclosed normal bone marrow. However, a
an MPD in our study to experience documented recur- G20210A mutation of the prothrombin gene was detected.
rent thrombosis. It occurred more than 10 years after Results of other hypercoagulable studies were negative.
the institution of antiplatelet therapy and developed in The patient underwent OLT in March 2000 and
the setting of liver dysfunction from recurrent hepatitis returned to Israel 1 month after OLT in good condition.
C and chronic rejection. He was not given hydroxyurea or warfarin after trans-
plantation because it is probable that the hypercoagulable
Case 16—Unclassified Myeloproliferative defect was corrected by the liver allograft. The prothrom-
bin gene mutation has been reported in patients with
Disorder and Factor V Leiden BCS,37,38 but its incidence is unknown.
A 36-year-old white woman presented with a 1-year his-
tory of nausea and vomiting and intermittent right upper Case 15—Sarcoidosis
quadrant pain. Her only medication at the time of pre-
sentation in March 1997 was an oral contraceptive. This 44-year-old black man received a transplant because of
Hepatic venogram showed thrombosed hepatic veins. BCS 3.5 years after elevated liver biochemistry values were
Bone marrow examination disclosed a 75% cellular spec- detected. Six months before OLT, liver function worsened
imen, megakaryocytic hyperplasia with clustering, and and a Doppler study disclosed thrombosis of the hepatic
an increase in reticulin. She was believed to have an early veins. Results of hypercoagulable workup and bone marrow
MPD of unclassified type. A DNA assay for factor V examination were normal. OLT was performed in January
Leiden mutation was reported as heterozygous positive. 1997. Native liver pathological examination revealed non-
The patient underwent OLT in October 1998. Native caseating granulomas that compressed veins within the liver
liver pathological examination confirmed hepatic vein and thrombosis of the hepatic veins. Stains for acid-fast
thrombosis. Hydroxyurea and aspirin were continued bacilli and fungi were negative. The diagnosis of sarcoidosis
after surgery. Anagrelide was substituted subsequently was made, and the patient did well after OLT. To our
because of the development of anemia on hydroxyurea. knowledge, this is the third reported case of sarcoid involve-
This patient had evidence of an MPD and also factor ment of the liver causing BCS.41,42 In this circumstance,
V Leiden mutation. Combinations of MPDs and other neither warfarin nor antiplatelet therapy was given to pre-
hypercoagulable states have been reported.29-31 The fac- vent recurrent thrombosis because the granulomas that
tor V Leiden mutation was recognized in patients with compressed the hepatic veins were removed.
BCS in 1997.29 Homozygous factor V Leiden has also
been described as the cause of BCS.32-34 Therefore it is
important to perform a thorough hypercoagulable SUMMARY
workup in addition to a bone marrow evaluation in
patients with BCS. Thorough evaluation will establish the cause of hepatic
Oral contraceptives, pregnancy, and the postpartum vein thrombosis in nearly all patients who present with
state may be risk factors for BCS.23,35,36 Valla et al36 BCS. In Western countries, MPDs and other definable
examined 33 women with BCS who were 15 to 45 years hypercoagulable states account for the majority of BCS.
of age and found that 21 had underlying MPDs or sus- Treatment of patients with MPDs using hydroxyurea
pected early MPDs on the basis of the spontaneous and aspirin appears to be a safe and effective regimen,
proliferation of erythroid progenitor cells of colony- without exposing them to the risks of anticoagulation
forming assays. Fifty-four percent of these women with warfarin. After transplantation, patients can con-
were oral contraceptive users, and their relative risk for tinue antiplatelet therapy when undergoing liver biopsy
developing BCS was 2.37 when compared to controls. to monitor allograft function, which is another major
In another report, Valla et al36 noted a female prepon- advantage of this approach. Some patients who present
derance of BCS in patients younger than 50 years and with BCS have other hypercoagulable states and require
suggested that this finding may be related to the throm- warfarin therapy after OLT. The type of antithrombotic
bogenic effect of estrogen. Of the 11 women in our therapy used should be based on the cause of the BCS.
study younger than 45 years of age, 4 were taking oral Patients in whom there is correction of the
contraceptives (36%) and 1 patient (patient 8) had hypercoagulable state by liver allografting probably do
delivered a child only 2 months before the onset of not require anticoagulation or other antithrombotic
symptoms. treatment after transplant.
242 PART II Patient Evaluation: Adult

20. Slakey DP, Klein AS, Venbrux AC, et al. Budd-Chiari syndrome:
Pearls and Pitfalls Current management options. Ann Surg. 2001;233:522-527.
21. Srinivasan P, Rela M, Prachalias A, et al. Liver transplantation for
• Clinical presentation depends on extent and rapidity of Budd-Chiari syndrome. Transplantation. 2002;73:973-977.
hepatic venous outflow obstruction. 22. Valla DC. Hepatic vein thrombosis (Budd-Chiari syndrome).
• Imaging studies show the following: Semin Liver Dis. 2002;22:5-14.
• Hypertrophied caudate lobe 23. Valla DC. Primary Budd-Chiari syndrome. J Hepatol. 2009;
• Spiderweb pattern of hepatic veins 50:195-203.
• Complete hematological evaluation, including bone 24. Murad SD, Plessier A, Hernandez-Guerra M, et al. Etiology,
management, and outcome of the Budd-Chiari syndrome. Ann
marrow, JAK2 determination, and hypercoagulable
Intern Med. 2009;151:167-175.
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patients with Budd-Chiari syndrome in Western tive disorder and hepatic vein thrombosis. Ann Intern Med.
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• Optimal antithrombotic treatment depends on cause. colony formation as the clue to an underlying myeloproliferative
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of autonomous growth of erythroid precursors in liquid culture
operatively because thrombotic complications do not
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occur during the first week. 2000;32:574-578.
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liver transplants if the patient has been operated on thrombosis following liver transplantation for Budd-Chiari
   previously. syndrome associated with myeloproliferative disorders: Treatment
with hydroxyurea and aspirin. Transplant Proc. 1991;23:1559-1560.
29. Mahmoud AE, Elias E, Beauchamp N, et al. Prevalence of the fac-
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 CHAPTER 21

Transplantation for
Alcoholic Liver Disease
Michael R. Lucey

CHAPTER OUTLINE

LIVER TRANSPLANTATION AND TREATMENT OF LIVER TRANSPLANTATION AS A TREATMENT FOR

ALCOHOLIC LIVER DISEASE SEVERE ALCOHOLIC HEPATITIS
REFERRAL OF PATIENTS WITH ALCOHOLIC LIVER PROGNOSIS FOR SOBRIETY
DISEASE FOR LIVER TRANSPLANTATION
MANAGEMENT OF ADDICTIONS BEFORE LIVER
EVALUATION
TRANSPLANTATION
PROGNOSIS AFTER LIVER TRANSPLANTATION
MEDICAL MANAGEMENT OF LIVER TRANSPLANT
EVALUATION FOR LIVER TRANSPLANTATION RECIPIENTS WITH ALCOHOLIC LIVER DISEASE
ALCOHOL USE BY CANDIDATES FOR LIVER DRINKING RELAPSES AFTER LIVER
TRANSPLANTATION WITH ALCOHOLIC LIVER TRANSPLANTATION
DISEASE
TREATMENT OF ADDICTION AFTER LIVER
THE SIX-MONTH RULE TRANSPLANTATION
COMPREHENSIVE PSYCHOSOCIAL ASSESSMENT

Alcoholic liver disease (ALD) is the second most com- failure or cancer that is intractable to medical management.
mon diagnosis among patients undergoing liver trans- A therapeutic formulation addressing LT for ALD needs to
plantation (LT) in the United States and Europe.1,2 ALD, encompass the psychological as well as the somatic health of
either alone or in combination with hepatitis C virus the potential candidate. Put another way, LT should be seen
(HCV) infection, accounts for 20% of all the primary as a treatment of end-stage liver failure, within a compre-
transplants that took place in the United States from hensive care program that addresses management of addic-
1988 to 2009, comprising more than 19,000 recipients. tions to alcohol, cigarettes, or any other drugs of addiction.
Moreover, the outcome for patients transplanted for
ALD is at least as good as that for most other diagnoses
and better than that for HCV.3,4 REFERRAL OF PATIENTS WITH
ALCOHOLIC LIVER DISEASE FOR LIVER
LIVER TRANSPLANTATION AND TRANSPLANTATION EVALUATION
TREATMENT OF ALCOHOLIC In view of the prevalence of ALD in the United States and
LIVER DISEASE Western Europe, it has been suggested that ALD patients
are underreferred for LT in the United States.8,9 On the
Medical management of ALD starts with abstinence from other hand, data documenting the process of referral and
alcohol. Alcoholic patients who maintain abstinence can evaluation of patients with problem drinking are inconclu-
recover from advanced liver failure and reestablish stable sive on this point. Julapalli et al10 described a cohort of 199
liver function, with resolution of portal hypertension.5 patients with liver disease who received their medical care at
Unfortunately, alcoholism is a disease of relapses and remis- a large metropolitan Veterans Affairs medical center, albeit
sions, and this pattern persists even after life-­threatening one without an LT program, between October 2001 and
episodes such as a variceal hemorrhage.6 The frequency of September 2003. Even when those patients with a history of
recovery from decompensated liver failure due to ALD is recent alcohol use were removed from consideration, the
restricted by the frequency of relapse to drinking.7 The goal presence of ALD was a significant negative determinant
of LT in patients with ALD is to treat life-threatening liver regarding referral for LT. In contrast, retrospective studies

244
 21 Transplantation for Alcoholic Liver Disease 245

from the United Kingdom and France have documented findings. For example, we have difficulty distinguishing
that the combination of death in the initial hospital stay, hepatic encephalopathy from Wernicke’s encephalopathy,
recovery with abstinence, and alcoholic relapse during and painful peripheral neuropathy due to alcohol from that
immediate follow-up, diminishes the actual number of due to other causes, especially diabetes, whereas the full
ALD patients who remain transplant candidates following a effects of the alcohol-associated myopathic heart may be
thorough evaluation and casts doubt on the contention that masked by the reduced systemic vascular resistance (after-
there is an unmet need for LT among ALD patients.11,12 load) common in patients with advanced liver disease.
If ALD patients are underrepresented in the population
undergoing LT evaluation, a number of possible explana-
tions involving primary care providers, the principal sources
of referrals to LT programs, come to mind. There may be a
ALCOHOL USE BY CANDIDATES FOR
lack of recognition in the primary care community of the LIVER TRANSPLANTATION WITH
contribution of alcohol excess to liver failure of any cause.13 ALCOHOLIC LIVER DISEASE
Primary care providers may hold a pejorative view of patients
with alcohol abuse and dependence in relation to LT, as has The evaluation of the patient with ALD differs from that
been described in the United Kingdom, and these attitudes in other potential candidates for LT because it must take
could account for reluctance to refer ALD patients for LT into account the history of addiction, not only to alcohol,
evaluation.14 It is also possible that many primary care pro- but also often to nicotine and other drugs of addiction,
viders and community gastroenterologists are confused either recently or in the past. One important question is
about when to refer their ALD patients for LT evaluation whether the potential ALD candidate is drinking now. By
and about whether a specific interval of abstinence is needed and large, only stable alcoholics who are thought to be
before referral. The role of an interval of sobriety in the pro- abstinent are referred to transplant programs.17 Two
cess of selecting patients for LT will be considered later. recent studies have shown that a not inconsiderable pro-
portion of these supposedly abstinent ALD patients
undergoing evaluation for LT or on the waiting list con-
PROGNOSIS AFTER LIVER tinue to drink18,19 (Fig. 21-1). The alcoholic patient who
TRANSPLANTATION continues to drink while under evaluation or awaiting LT
is constrained from seeking help to reestablish sobriety.20
The plasticity of ALD, particularly in response to absti-
nence, makes it difficult to determine accurately the prog-
nosis of alcoholic liver injury independent of LT. This THE SIX-MONTH RULE
assessment is crucial, because all LT programs would prefer
to avoid transplantation in those patients who have a good Controversy remains as to whether a minimal interval of
potential for recovery of liver function with abstinence and abstinence, often referred to as the six-month rule, is required
medical therapies. Studies using either mathematical mod- for a patient with ALD to be acceptable for evaluation for
els or a prospective randomized trial have suggested that LT. In 1997 a consensus conference of the American Asso-
ALD patients with Child-­Turcotte-Pugh class C liver fail- ciation for the Study of Liver Diseases (AASLD) and the
ure, but not those with less severe liver failure, derive a ben-
efit in posttransplant survival.15,16 In contrast, a retrospective
analysis of the United Network for Organ Sharing (UNOS) 50
46 45 MET
database, estimating survival benefit, that encompassed sur-
vival/mortality before and after transplantation, showed TAU
that ALD patients with relatively low Model for End-Stage 40
Liver Disease (MELD) scores in the 9 to 11 range derived
a survival benefit.4 The present system of organ allocation 30
in the United States ensures that LT is confined to ALD
patients with severe liver failure or hepatocellular cancer
and high urgency of dying without LT. 20

11 12
EVALUATION FOR LIVER 10 7
6
TRANSPLANTATION 4
2
0
A comprehensive evaluation of an ALD patient should N Any >4 Positive
assess all tissues at risk from alcoholic damage. Cardiac drinking drinks drinking
function, kidney function, the central and peripheral ner- per day at >1 visit
vous system, and the immune system are at risk from FIGURE 21-1 n Drinking while awaiting liver transplantation in 99
chronic alcohol abuse. Each system should be studied care- patients with alcoholic cirrhosis. Alcoholism was treated with
fully, in addition to the standard assessment of liver func- either motivational enhancement therapy (MET) or treatment as
usual (TAU). (From Weinrieb RM, Van Horn D, Lynch KG, Lucey
tion and hepatocellular carcinoma. Interpreting data MR. A randomized, controlled study of treatment for alcohol depen-
testing the integrity of extrahepatic organ systems is often dence in patients awaiting liver transplantation. Liver Transpl.
complicated by competing explanations for abnormal 2011;17:539-547.)
246 PART II Patient Evaluation: Adult

American Society of Transplantation (AST) concluded that

TABLE 21-1 E
 stimating the Prognosis for
“there is a strong consensus for requiring that most alcoholic
Abstinence in Patients Under
patients should be abstinent from alcohol for at least 6
Evaluation for Liver Transplantation
months before they can be listed for liver transplantation.”21
The six-month rule has been widely adopted by the U.S. 1. No single measure is a reliable prognosticator for future
insurance industry. At first it was declared that the primary relapses into harmful drinking after transplantation.
purpose of the six-month interval was to allow time for 2. Alcoholic patients under consideration for LT have a
recovery from alcohol-induced liver failure. However, since conflict of interest regarding admitting recent use.
then the six-month rule has mostly been discussed as a prog- 3. Although duration of abstinence is associated with sub-
nostic tool to predict subsequent alcoholic relapse, often sequent drinking, it is an imprecise prognostic tool.
referred to as recidivism. There are conflicting data on 4. Liver biopsy results provide an unreliable estimate of
recent alcohol use.
whether six-month’s abstinence is predictive of drinking
5. The careful evaluation by a trained addiction specialist
after transplantation.9 Indeed, in the literature on alcohol- with a special interest in transplant medicine is very help-
ism 6 months appears too short to determine meaningful ful.
abstinence, and Vaillant22 has suggested that sobriety is 6. A comprehensive psychosocial assessment segregates
robust only after 5 years. In recent years the emphasis has risk for relapse to harmful drinking into lower and higher
shifted from identifying LT candidates who might relapse to estimates rather than absolute degrees of risk.
any alcohol to predicting which patients will return to harm- 7. The psychological assessment needs to be incorporated
into a more comprehensive consideration of the appro-
ful or addictive drinking, defined as drinking more than five priateness of LT for a particular patient.
drinks a day for a man, four drinks a day for a woman, or 8. The severely ill patient who has been drinking recently
drinking for more than 4 successive days in either sex.23 but who has other favorable prognostic indicators re-
garding addiction poses great difficulty for the transplant
program.
COMPREHENSIVE PSYCHOSOCIAL
LT, Liver transplantation.
ASSESSMENT
In the 1990s Beresford17 proposed a broad-based exami-
nation of psychological health to assess risk for relapse alcoholic hepatitis, a favorable psychosocial assessment,
after liver transplantation. Drawing on studies of alcohol- and no response to maximal medical treatment, demon-
ics in the nontransplant setting, he described a composite strated excellent intermediate-term survival after LT,
checklist of factors that indicate a favorable prognosis for with a low frequency of posttransplant harmful
abstinence (Table 21-1). On completion of an assessment, drinking.28
Beresford advocated that the addiction specialist should
be able to give an estimate of the risk for alcoholic relapse
and to recommend treatment where appropriate.17 It was PROGNOSIS FOR SOBRIETY
then up to the transplant team to integrate this prognostic
assessment into the comprehensive clinical review to In the United States the evaluation process usually results
determine whether to place the patient on the waiting list. in presentation of a comprehensive clinical and psychoso-
cial assessment to the transplant selection committee.
When the transplant program selection committee
decides to recommend transplantation, approval of the
LIVER TRANSPLANTATION AS A third-party payer is necessary before proceeding with
TREATMENT FOR SEVERE ALCOHOLIC placement on the LT waiting list. Table 21-2 outlines
HEPATITIS some of the lessons that can be drawn regarding the place
of sobriety in gauging prognosis and vice versa. Table
Patients with severe alcoholic hepatitis present particular 21-2 lists the factors that indicate that the patient is more
challenges to transplant teams, because they have invari- likely to estabish and maintain sobriety. It remains true
ably consumed alcohol in the previous month. Those that the severely ill patient who has been drinking recently,
patients who fail to respond to medical management but who has other favorable indicators of addiction prog-
carry a very high 90-day mortality. Heretofore, as in the nosis, poses great difficulty for the transplant program.
AST/AASLD 1997 guidelines, alcoholic hepatitis was an
absolute contraindication to placement on the transplant
waiting list.24 In contrast, two retrospective studies have MANAGEMENT OF ADDICTIONS BEFORE
found that that the presence of histological alcoholic hep- LIVER TRANSPLANTATION
atitis in the explanted liver does not correlate with subse-
quent alcohol relapse.25,26 Similarly, a retrospective Although some LT programs recommend requiring
analysis of the small number of patients in the UNOS the candidate to sign a “contract” to remain abstinent
database with alcoholic hepatitis as their declared diagno- and/or encourage attendance at support groups such as
sis indicated similar patient or graft survival compared to Alcoholics Anonymous (AA), data on the efficacy
nonalcoholic LT recipients.27 A prospective European of contracts or AA in LT candidates are lacking.
multicenter pilot study of LT in a small cohort of care- A recently published randomized trial in patients under
fully selected patients with a first episode of severe evaluation for or awaiting LT at two U.S. centers
 21 Transplantation for Alcoholic Liver Disease 247

TABLE 21-2 F
 actors That Indicate a Favorable TABLE 21-3 R
 ecommendations of the American
Likelihood of Future Sobriety Association for the Study of Liver
Diseases Guidelines Regarding
1. Acknowledgment by the patient of his or her addiction to Patients With Alcoholic Liver
alcohol
Disease Who Survive Liver
2. Strong social support (such as a spouse, a job, and a home)
Transplantation
3. Substitute activities to replace time spent drinking
4. A source of improved self-esteem or hope 1. All patients with a prior diagnosis of ALD should be encour-
5. A “rehabilitation relationship” (which overlaps with No. 2) aged to remain abstinent from alcohol. (Grade I level B)
6. The perception by the drinker that negative consequenc- 2. Patients should be encouraged to enter therapy or coun-
es will follow a relapse into drinking seling if they relapse into alcohol use. (Grade I level C)
3. All patients with a prior diagnosis of ALD who are users
of tobacco should be encouraged to undertake smoking
cessation. (Grade I level B)
compared the impact of one such positive reinforcement
4. Careful attention should be given to the risk for cardio-
technique, motivational enhancement therapy, to advice vascular disease and/or new-onset cancers of the aer-
to attend AA or local counseling, referred to as treatment odigestive tract, especially in cigarette smokers. (Grade I
as usual.19 The study revealed considerable hidden level A)
drinking, including harmful drinking, in ALD patients
ALD, Alcoholic liver disease.
awaiting LT, and the effects of motivational enhance-
Modified from Lucey MR, Terrault N, Ojo L, et al. Long-term
ment therapy were modest at best (see Fig. 21-1). management of the successful adult liver transplant: 2012
Although smoking cigarettes is widespread in this practice guideline by the American Association for the Study of
population, we lack data on efficacious strategies to com- Liver Diseases and the American Society of Transplantation.
bat smoking during the evaluation stages before LT. As Liver Transpl. 2013;19:3-26.
will be pointed out, return to smoking is very common,
and smoking-related morbidity and mortality are
increased in alcoholic LT recipients. to 90%.36 These data mostly refer to studies in which
relapse was defined as “any use,” rather than distin-
MEDICAL MANAGEMENT OF LIVER guishing between occasional lapses or “slips” and
harmful or addictive drinking.37 Analysis of the longi-
TRANSPLANT RECIPIENTS WITH tudinal prospective cohort of ALD transplant recipi-
ALCOHOLIC LIVER DISEASE ents maintained by DiMartini et al has yielded five
patterns of alcohol use after transplantation, including
Table 21-3 summarizes the recommendations of the three separate patterns of addictive drinking based on
AASLD 2013 guidelines on posttransplant management the time to relapse, and the subsequent course38
in relation to patients who were transplanted for ALD.29 (Fig. 21-2). Eighty percent of patients either did not
ALD patients selected for LT in the United States have drink or consumed only small amounts occasionally.
similar survival both before and after the operation to LT Conversely, in the remaining 20% there were three
recipients without a diagnosis of ALD, although mortal- patterns of harmful drinking. The patterns varied
ity was increased in patients with comorbid ALD and according to the time to relapse and whether the
HCV.2,4 These data are likely to change with the advent patients demonstrated sustained heavy use or subse-
of more efficacious treatments for HCV infection. quently modified their drinking.
Although ALD patients have similar survival to non- Data on consequences of alcoholic relapse have tended
ALD liver transplant recipients, death from cardiovascu- to be anecdotal and are often based on retrospective
lar causes and de novo malignancies, particularly of the accounts from single centers. These anecdotal reports
aerodigestive tract, are significantly overrepresented in suggest that patients who relapse to harmful drinking are
the patients transplanted for ALD.2,30-34 These studies do at risk for alcoholic liver injury, including alcoholic hepa-
not show an association between new-onset cancers and titis, delirium tremens, alcoholic pancreatitis, pneumo-
alcohol relapse. The stratification of cardiovascular nia, and reduced patient survival.23,39-42
deaths and of new-onset cancers of the aerodigestive tract
in patients receiving LT for ALD strongly hints at a
causal linkage with cigarette smoking. Smoking is preva- TREATMENT OF ADDICTION AFTER
lent in ALD patients undergoing evaluation for LT, and LIVER TRANSPLANTATION
ALD liver transplant recipients who were smokers before
transplantation quickly reestablish smoking at addictive There are several difficulties to overcome when con-
levels.35 templating structured treatment studies in this popula-
tion. First, the alcoholic patients who receive liver
transplants are probably not homogeneous in regard to
DRINKING RELAPSES AFTER LIVER risk for relapse to addiction. Many have a strong sense
TRANSPLANTATION of having recovered from alcoholism, denying craving
and consequently expressing low motivation for under-
There is a wide variation in reported rates of alcoholic going treatment.43 This is in contrast to patients in alco-
relapse after transplantation, ranging from about 10% holism treatment units, where endorsing the treatment
248 PART II Patient Evaluation: Adult

Log 3 week interval of drinks

0 500 1000 1500 2000 2500 3000

Days Post-discharge from LTX Hospitalization
Group 1 Group 2 Group 3 Group 4 Group 5
Confidence bands are displayed around the trajectory lines.
N of each group: group 1=113 (51.3%), group 2=55 (28.6%), group 3=13 (6.4%), group 4=15 (7.9%) and
group 5=12 (5.8%)
FIGURE 21-2 n Patterns of drinking behavior in a prospective cohort of patients with alcoholic liver disease in a single center. LTX, Liver
transplantation. (From DiMartini A, Dew MA, Day N, et al. Trajectories of alcohol consumption following liver transplantation. Am J Trans-
plant. 2010;10:2305-2312.)

model is considered a favorable prognostic indicator. liver transplant recipient, the treatment under study
This resistance to treatment may reflect the fear that a should have no hepatotoxicity, and the end point of the
declaration of a desire for alcohol would be interpreted study should be control of the addictive behavior rather
by the transplant team as a sign of poor candidacy or than patient or graft survival.
lack of commitment to sobriety. It is likely that some of
these responses are genuine and indicate an absence of
internal prompts to consume alcohol. Lack of interest in Pearls and Pitfalls
receiving treatment for alcoholism was one reason for
failure to recruit to a trial of naltrexone in alcoholic LT • Liver transplantation (LT) is a treatment of end-stage liv-
recipients.44 An additional impediment was that LT er failure, within a comprehensive care program that ad-
recipients were unwilling to take a potentially hepato- dresses management of addictions to alcohol, cigarettes,
toxic medication such as naltrexone. In contrast, Björns- or any other drugs of addiction.
• All LT programs would prefer to avoid transplantation
son et al45 introduced into their transplant program a in those patients with alcoholic liver disease (ALD) who
plan for structured management of alcoholism, com- have a good potential for recovery of liver function with
prising assessment by a psychiatrist skilled in care of abstinence and medical therapies.
alcoholics, initiation of treatment in patients who had • A goal of pretransplant evaluation of ALD candidates for
not been treated in the past, encouragement to partici- LT is to exclude patients most likely to return to harmful
pate in motivational enhancement, and use of an absti- or addictive drinking, defined as drinking more than five
nence contract. The protocol was started before and drinks a day for a man, four drinks a day for a woman, or
continued after transplantation with interviews at 3 drinking for more than 4 successive days in either sex.
months, 1 year, 3 years, and 5 years. In consecutive • A comprehensive pretransplant evaluation of an ALD pa-
patients they observed a reduction in the prevalence of tient should assess all tissues at risk for alcoholic damage.
• Although ALD patients have similar survival to non-
alcohol use when compared to a matched historical con- ALD liver transplant recipients, death from cardiovascu-
trol group (48% versus 22%), although they do not lar causes and de novo malignancies, particularly of the
report their data in terms of harmful drinking. Future aerodigestive tract, are significantly overrepresented in
treatment initiatives should be targeted to the subcohort the patients transplanted for ALD.
of ALD patients with persistent cravings, with the goal • Alcoholic liver transplant recipients who relapse to harm-
of preventing harmful drinking. ful drinking are at risk for alcoholic liver injury, including
Similarly, we need studies designed to enable LT alcoholic hepatitis and fibrosis, delirium tremens, alcohol-
recipients to stop smoking cigarettes. Whether the study   
ic pancreatitis, pneumonia, and reduced patient survival.
is considering drinking alcohol or smoking by the ALD
 21 Transplantation for Alcoholic Liver Disease 249

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Gastroenterol. 2005;40:206-216.
CHAPTER 22

Transplantation for
Nonalcoholic Steatohepatitis
Ashwani K. Singal • Michael Charlton

CHAPTER OUTLINE

NONALCOHOLIC STEATOHEPATITIS AS A CAUSE OUTCOMES FOLLOWING LIVER

OF ADVANCED LIVER DISEASE AND AS AN TRANSPLANTATION FOR NAFLD/NASH
INDICATION FOR LIVER TRANSPLANTATION Histological Recurrence of NAFLD and NASH
CLINICAL FEATURES AND DIAGNOSIS OF NASH TREATMENT OF NAFLD BEFORE AND AFTER LIVER
CIRRHOSIS TRANSPLANTATION
Interactions Between the Pathobiology Choice of Immunosuppression
of NAFLD/NASH and Posttransplant Diet
Management
THE ROLE OF POSTTRANSPLANTATION LIVER
BIOPSY

NONALCOHOLIC STEATOHEPATITIS AS A with younger age of onset, the frequency of NASH as an

CAUSE OF ADVANCED LIVER DISEASE indication for liver transplantation seems likely to
increase further. These epidemiological trends for obe-
AND AS AN INDICATION FOR LIVER sity and steatosis and NASH also have implications for
TRANSPLANTATION donor livers. The prevalences of steatosis and NASH
among living donors has been reported to range from
A recent cross-sectional study of patients in a large out- 12% to 51% and 2% to 15%, respectively.5 Living
patient general medical clinic setting observed the prev- donor grafts with steatosis have been reported to be at
alence of nonalcoholic fatty liver disease (NAFLD) to be increased risk for ischemia reperfusion injury, possibly
46%, with nonalcoholic steatohepatitis (NASH) related to reduced hepatic microcirculation secondary to
observed in 12.2% of the total cohort, making NASH sinusoidal space compression by the ballooned fatty and
the most common liver disease in North America.1 The inflamed hepatocytes or oxidative stress–induced sus-
prevalence of advanced fibrosis due to NASH in the ceptibility to hypoxia.6,7
United States should thus be between 3 and 8 million
cases.2 The precise frequency of liver disease related to
NASH as a primary or secondary indication for liver CLINICAL FEATURES AND DIAGNOSIS
transplantation is difficult to know because, unlike other OF NASH CIRRHOSIS
indications such as hepatocellular carcinoma, there are
no rigorous diagnostic criteria required for assigning Most patients who are ultimately diagnosed with NASH
NASH as an indication for liver transplantation. Based are referred for evaluation of abnormal liver biochemistry
on data from the Scientific Registry of Transplant values, often detected serendipitously. In contrast to the
Recipients (SRTR) and the United Network for Organ ratio seen in alcoholic liver disease, aminotransferase lev-
Sharing (UNOS), NASH is the third most common els are typically four times the upper limit of normal or
indication for liver transplantation, after hepatitis C less, with alanine aminotransferase (ALT) usually greater
virus (HCV) and alcohol, with the proportion of trans- than aspartate aminotransferase.8,9 Alkaline phosphatase
plants performed for NASH increasing from 1.2% in level is usually normal or mildly elevated, twice normal or
2001 to 9.7% in 2009 (Fig. 22-1).3,4 In the setting of a less, with bilirubin levels usually within the normal range.
continuing increase in the prevalence and severity of About one in six patients with NASH have normal liver
obesity in North America and worldwide, combined biochemistry values.1

250
 22 Transplantation for Nonalcoholic Steatohepatitis 251

20 2001
2002
2003
2004

Frequency as indication (%)

15
2005
2006
2007
10 2008
2009

0
ALD HBV NASH NASH + CC PSC PBC AIH
50% CC
FIGURE 22-1 n The frequencies of specific indications for liver transplantation among adults in the United States. AIH, Autoimmune
hepatitis; ALD, alcoholic liver disease; CC, cryptogenic cirrhosis; HBV, hepatitis B virus; NASH, nonalcoholic steatohepatitis; PBC,
primary biliary cirrhosis; PSC, primary sclerosing cholangitis.

Ascites can be difficult to detect clinically in patients with 24%), and hypertensive (41% versus 22%); and less likely
cirrhosis secondary to NASH in the context of a high body to have hepatocellular carcinoma (12% versus 19%).3
mass index (BMI), particularly when the fat distribution is There is a high prevalence of MZ (17%) α1-antitrypsin
truncal. An apron of adipose can preclude accurate exami- phenotypes among patients with NASH evaluated for
nation of the abdominal cavity, and the presence of omental liver transplantation. Patients with panhypopituitarism
adipose can mimic ascites. A detailed history is essential in may develop NASH that is rapidly progressive, leading to
order to exclude, or otherwise, the presence of excessive cirrhosis within the second or third decade of life, and is
alcohol consumption, steatohepatitis-inducing pharmaco- relatively commonly associated with severe hepatopul-
therapy, surgical procedures, and occupational exposure to monary syndrome.11
hepatotoxins. Of the clinical conditions that are associated
with NASH that cannot be excluded by simple history tak-
ing, Wilson’s disease, viral hepatitis, and autoimmune liver Interactions Between the Pathobiology
disease require specific serological/biochemical exclusion. of NAFLD/NASH and Posttransplant
The great majority of patients with NAFLD will concomi-
tantly have one or more features of the metabolic syndrome
Management
(increased waist circumference, hypertriglyceridemia, low Obesity, which increases in prevalence and severity fol-
level of high-density lipoprotein cholesterol, hypertension, lowing liver transplantation, is associated with a number
and a fasting glucose level of 110 mg/dL or higher).8,10 A of metabolic effects relevant to the development of
nutritional history, particularly of rapid weight gain or loss, hepatic steatosis. These include increased absolute
is also important. Bariatric surgery in patients with unsus- hepatic FFA uptake, increased esterification of hepatic
pected NASH cirrhosis can produce postoperative hepatic FFAs to form triglycerides, increased FFA synthesis from
decompensation. The typical picture is of rapidly progres- cytosolic substrates, decreased apolipoprotein B-100 syn-
sive cholestasis with encephalopathy. Post–bariatric surgery thesis with subsequent decreased export of FFAs and tri-
hepatic decompensation is probably secondary to the oxida- glycerides, decreased hydrolysis of triglycerides and
tive injury associated with the rapid and large mobilization diminished hepatic triglyceride and FFA export, and
of peripheral free fatty acids (FFAs) that inevitably occurs increased beta oxidation of mitochondrial long-chain
following bariatric surgery. Hyperalimentation is a corner- fatty acids. Although the relative contribution of these
stone of treatment (to decrease mobilization of FFAs). The effects to the net retention of fat within hepatocytes is not
benefits of ursodeoxycholic acid and antioxidants such as known, each of these potential contributing mechanisms
betaine and N-acetylcysteine are unknown in this setting. to hepatic steatosis might be predicted to occur more
Because steatosis may resolve following the develop- commonly following liver transplantation.
ment of cirrhosis because of increased oxidation of FFAs, Obesity is also strongly correlated with insulin resis-
with the loss of steatosis following histological progres- tance, particularly when central or truncal (a distribution
sion to cirrhosis being well described,2 a firm pretrans- that is favored by corticosteroid use).12,13 Obesity is gener-
plant diagnosis is often difficult. ally associated with multiple acquired factors predisposing
Compared to patients transplanted for other indica- to insulin resistance, including sedentary lifestyle, high-fat
tions, NASH patients are older (58.5 ± 8 years versus 53 diets, medications (e.g., cyclosporine and sirolimus), and
± 9 years); more likely to be overweight with BMI of 30 glucose toxicity. Although the precise mechanism of truncal
kg/m2 or higher (63% versus 32%), diabetic (53% versus obesity–associated insulin resistance is not known, release
252 PART II Patient Evaluation: Adult

of FFAs from abdominal adipocytes into the portal circula- creatinine, sex, age, and BMI. NASH is an independent risk
tion with subsequent induction of hepatic insulin resistance factor for renal dysfunction at any time after liver transplan-
and stimulation of glucose13a are likely to contribute. tation, with a higher proportion of NASH recipients devel-
In addition to the metabolic effects of obesity earlier, oping stage III chronic kidney injury compared to matched
liver transplantation alters circulating levels of leptin recipients for other indications (31% versus 8%; P = .009).19
(increased) and adiponectin (decreased), changes that
may contribute to posttransplant obesity and metabolic Histological Recurrence of NAFLD
syndrome.14,15 Tumor necrosis factor (TNF)-α, which
downregulates insulin-induced phosphorylation of insu-
and NASH
lin receptor substrate 1 and reduces the expression of the In a prospective histological analysis, at 1 year after trans-
insulin-dependent glucose-transport molecule Glut 4, plantation, 60% (9 of 15) of transplant recipients with
may also be involved in posttransplant NAFLD/NASH NASH, 5% (3 of 62) of transplant recipients with choles-
and associated insulin resistance. tatic diseases, 30% (12 of 40) of transplant recipients with
Susceptibility to steatosis in obese people has been alcoholic cirrhosis, and 15% (8 of 54) of transplant recipi-
recently found to genotype for adiponutrin or patatin- ents with HCV had steatosis of grade 2 or higher.20 Frank
like phospholipase domain containing 3 (PNPLA3),16 steatohepatitis occurred in approximately 60% of recipients
which normally regulates hydrolysis of triglycerides to with NASH by the second postoperative year. Recurrence
FFAs in the adipocytes. Polymorphisms of this gene are of NASH was nearly universal in patients who had under-
associated with NAFLD, NASH, and advanced fibrosis gone bariatric surgery before transplantation. Recurrence
with GG genotype at risk compared to CC genotype.17 of fibrosis is less frequent, with fibrosis stage 2 or higher
The impact of donor versus recipient genotype for seen in 33% of recipients undergoing liver transplantation
PNPLA3 on posttransplant NAFLD/NASH and meta- for NASH, versus 15% for cholestatic diseases, 13% for
bolic complications of transplantation is not known. alcoholic cirrhosis, and 46% for HCV. Five percent of
Although the link(s) between hepatic steatosis, inflamma- patients who underwent liver transplantation for NASH
tion, and fibrosis are not well established, increased oxida- developed cirrhosis in the follow-up period20 (Fig. 22-2). In
tive stress, a feature of both animal models of steatohepatitis another study, assessment of 1596 biopsy specimens in 599
and humans with NAFLD,10 and mitochondrial function patients performed at 1, 5, and 10 years after liver transplan-
derangement play an important role. Oxidative stress can tation showed presence of steatosis in 31%, NASH in 4%,
occur as a result of steatosis by lipid peroxidation by unsatu- and cirrhosis in 2.3%.21 In a more recent analysis a combi-
rated FFA–mediated induction of hepatic microsomal cyto- nation of normal ALT level (<40 International Units/L)
chromes CYP2E1 and CYP4A.17a When pro-oxidant and ultrasound examination for steatosis had 100% negative
pathways generate more reactive species than can be con- prediction for presence of NASH on liver biopsy.22 Based
sumed by antioxidant pathways (e.g., via protein disulfide on these data, we recommend liver biopsy in liver transplant
isomerase or reduced glutathione [GSH] peroxidase), oxida- recipients of NASH patients with presence of steatosis on
tive stress occurs, with resulting accumulation of reactive ultrasound examination and/or persistently abnormal ALT
oxygen species (chiefly superoxide and hydroxyl radicals levels that cannot be explained by any other cause.
plus hydrogen peroxide) and mitochondrial injury. Mito-
chondrial injury (as manifest by megamitochondrion) is a
hallmark of NAFLD.10 Increased oxidative stress usually TREATMENT OF NAFLD BEFORE AND
results in increased synthesis of protective antioxidant path- AFTER LIVER TRANSPLANTATION
ways and reactive oxygen species scavengers. Almost all liver
transplant recipients are maintained on a calcineurin inhibi- In lieu of a proven efficacious and safe pharmacotherapy
tor. Both cyclosporine and tacrolimus are associated with for NASH, treatment of NASH should focus on the asso-
resultant increased generation of reactive oxygen species, ciated conditions. In obese patients, who make up the
mitochondrial dysfunction, and lipid peroxidation.18 This majority of patients with NASH, treatment should be
may have important implications for the natural history of centered around weight loss and exercise programs, which
recurrence of NAFLD following liver transplantation. have been shown to be effective in treating NASH.23
Whether calcineurin inhibitor dosing should be minimized Attainment of an ideal body weight for height is not a
in patients with recurrence of NASH is not known, but prerequisite for improvement in aminotransferase levels
there exists a theoretical possibility for such an approach to and ultrasonographic evidence of steatosis.24-26 In a meta-
recurrence of NASH following liver transplantation. analysis of 15 studies on 766 patients undergoing bariatric
surgery, reduction of BMI (mean reduction of 19% to
42%) was associated with resolution of steatosis in 92%,
OUTCOMES FOLLOWING LIVER steatohepatitis in 81%, fibrosis in 65%, and NASH in
TRANSPLANTATION FOR NAFLD/NASH 70%.27 Rapid weight loss should be avoided because it can
exacerbate steatohepatitis and hepatic encephalopathy.
In an analysis of the SRTR patient survival at 1 and 3 years For many obese patients sustained weight loss and exer-
after liver transplantation for NASH was 84% and 78%, cise is, unfortunately, difficult to achieve, particularly in
respectively, and 87% and 78% for other indications for the setting of chronic liver disease. This has led to a prolif-
liver transplantation (P = .67).3 Patient and graft survival eration of empirical and semiempirical studies of pharma-
after liver transplantation for recipients with NASH was cotherapy of NASH. Most studies of pharmacotherapy of
similar to that for other indications after adjusting for NASH have been small, with only a few being randomized
 22 Transplantation for Nonalcoholic Steatohepatitis 253

80 Most data on the management of NAFLD/NASH

come from studies performed on patients outside the
70 transplant setting and can be applied to management of
NAFLD/NASH in post–liver transplantation patients.
60 Prescribing statins for the treatment of dyslipidemia in
patients with NAFLD and NASH is safe. Statins should
50 not be withheld from patients with NAFLD who meet
established statin treatment criteria.35,36
Percent

40 Based on our understanding of the pathogenesis of

NAFLD/NASH, insulin sensitization is an appealing
30 approach to treatment. A recent report suggested histo-
logical and biochemical improvement in patients with
20 NASH following therapy with a thiazolidinedione (piogli-
tazone).37 Unfortunately, although pioglitazone produces
10 histological and biochemical improvement in patients with
NASH, it can be associated with a significant increase in
0 BMI and possible idiosyncratic hepatotoxicity.38 Because
Stage 0 Stage 1 Stage 2 Stage 3 Stage 4 peroxisome proliferator-activated receptor (PPAR)-γ ago-
FIGURE 22-2 n The frequencies of stages of fibrosis on post–liver nists are adipogenic by nature, weight gain is likely to be a
transplantation (LT) biopsies among patients undergoing LT for class effect of thiazolidinediones and may well negate any
nonalcoholic steatohepatitis (NASH) at 5 years after LT are
shown. Although recurrence of steatosis is common, recurrence histological benefit in the long term. Combined PPAR-γ/α
of NASH with progressive fibrosis affects a small minority of agonists appear beneficial in animal models of steatohepa-
patients. titis.39 Preliminary results of selective PPAR-α agonism in
an animal model of NASH have been encouraging, with
with placebo controls. Histological follow-up is also lack- histological and biochemical improvement after short
ing in many studies of potential treatments of NASH. courses of PPAR-α agonism in methionine- and choline-
Improved glycemic control will lower lipid levels in deficient mice.40 The utility of PPAR-α agonism may be
patients with NASH who have type 2 diabetes mellitus limited by the excess morbidity and mortality associated
(approximately one third of NASH patients). Although gly- with PPAR-α agonists in large cohort studies and concerns
cemic control in the absence of weight loss will not improve regarding tumorigenic properties in animals.41,42
aminotransferase levels in this patient population, metfor-
min administration is associated with reversal of histologi- Choice of Immunosuppression
cal changes of steatohepatitis in a mouse model of NASH.28
Metronidazole has been reported to be effective in As discussed earlier, many patients with NAFLD have
improving steatosis in patients who develop NASH follow- the metabolic syndrome before transplantation. The
ing jejunoileal bypass surgery in a small uncontrolled study.29 prevalence of dyslipidemia, hypertension, and insulin
Very limited data are available for clofibrate, lipid-low- resistance all increase following liver transplantation
ering agents, N-acetylcysteine, and betaine in NASH. because of the effects of immunosuppression. Immuno-
There is no conclusive evidence for a beneficial effect for suppression is an important factor in the development
any of these agents. Ursodeoxycholic acid treatment was and exacerbation of posttransplant metabolic syndrome.
associated with biochemical improvement in NASH in a Corticosteroids are known to produce insulin resistance,
pilot study.30 In a subsequent randomized, placebo-con- truncal fat deposition, hypertension, and dyslipidemia.
trolled study, however, ursodeoxycholic acid treatment for Tacrolimus and cyclosporine may produce insulin resis-
2 years was associated with improvements in liver bio- tance.18 In addition to increasing oxidative stress and lipid
chemical and histological results but at a similar frequency peroxidation, calcineurin inhibitors in general cause
to that of the placebo group.31 In a recently reported ran- hypertension. Sirolimus is associated with dyslipidemia.
domized double-blind controlled study on 247 nondiabetic Mammalian target of rapamycin (mTOR) inhibition has
biopsy-proven NASH patients, 2 years of treatment with insulin-sensitizing effects in vitro, however, making the
vitamin E 800 International Units/day (n = 84) was better role of mTOR inhibitors of interest in patients with post-
than pioglitazone 30 mg/day (n = 80) or placebo (n = 83) in transplant metabolic syndrome and NASH. In lieu of
the improvement of NASH without worsening of fibrosis randomized studies to determine optimal immunosup-
(43% versus 34% versus 19%, respectively; P = .001).32 pression, steroid avoidance and minimization of calcineu-
Both drugs, however, were effective in reducing liver rin inhibition should be considered in recipients with
enzyme levels and improvement in steatosis and inflamma- NASH. Nuances of prescribing for the treatment of com-
tion on liver biopsy. There was no improvement in fibrosis ponents of the metabolic syndrome in liver transplant
with either agent. Vitamin E was safe, but pioglitazone was recipients is shown in Table 22-1.
associated with weight gain.32 Systematic reviews and
meta-analysis of use of antioxidants in NASH have neither Diet
refuted nor supported the use of these agents in the treat-
ment of NASH.33,34 Encouraging results of vitamin E in There is increasingly overwhelming evidence for a caus-
nondiabetic NASH patients need confirmation before rou- ative role for dietary cholesterol in the pathogenesis of
tinely recommending its use in routine clinical practice. NASH and fibrosing NASH. Cholesterol loading, in
254 PART II Patient Evaluation: Adult

TABLE 22-1 T
 reatment of Diabetes, in the animal models of fibrosing NASH.47-49 Cholesterol
Hypertension, and Dyslipidemia in should be minimized in patients with NASH and in liver
Liver Transplant Recipients transplant recipients with a history of NASH.

Agent Advantage/Disadvantage
THE ROLE OF POSTTRANSPLANTATION
Second-Generation Weight gain, hypoglycemia
Sulfonylureas LIVER BIOPSY
Glipizide May increase CNI level
Gliclazide The role of liver biopsy in the diagnosis and management
Glyburide Weak inhibitor CYP2C8, of posttransplant NAFLD/NASH is still evolving. Liver
CYP3A4 biopsies may be helpful in assessing disease stage and
Glimepiride determining effects of medical treatment or change in
Biguanides immunosuppression but are associated with morbidity
Metformin Lactic acidosis—rare, GI side and cost. The entire histological spectrum of NAFLD can
effects, metallic taste be seen in individuals with normal ALT values, and the
Meglitinides Weight gain, hypoglycemia histological spectrum is not significantly different among
Repaglinide Only with renal insufficiency patients with normal ALT levels from those with elevated
Nateglinide CNI—may increase repa- ALT levels.1 Because NASH can recur and be severe,
glinide level, cost there is always a question whether patients transplanted
Thiazolidinediones Weight gain, fluid retention for NASH should undergo annual protocol liver biopsies.
Rosiglitazone Cardiovascular risk (rosigli- Although the approach varies from center to center, in
tazone > pioglitazone)
our own analysis a combination of normal ultrasound
Pioglitazone Expensive, CNI may decrease
metabolism of TZD examination results and persistently normal ALT levels
α-Glucosidase Inhibitors GI side effects, less effective had 100% negative predictive value for NASH. Until
Acarbose Cost larger, prospective studies are reported, patients trans-
planted for NASH could be followed in the posttransplant
Antihypertensives
period with ultrasound examination and liver biochemical
Calcium Channel Blockers assessment with consideration of biopsy in those with
Nifedipine Leg edema, inhibits intestinal abnormality in one or both of these parameters.
CYP-450, will increase CNI
level
Amlodipine, isradipine, Very effective, minimal Pearls and Pitfalls
and felodipine edema, no effect on
CYP-450 • Making a pretransplant diagnosis of nonalcoholic steato-
β-Blockers May reduce portal blood flow hepatitis (NASH) as a cause of cirrhosis can be difficult
ACE Inhibitors/Receptor May exacerbate CNI-induced due to increased lipid oxidation in cirrhosis, resulting in
Blockers hyperkalemia, theoretical loss of steatosis.
antifibrotic properties • Although NASH commonly recurs following liver trans-
Diuretics Electrolyte abnormalities, plantation, cirrhosis and liver failure caused by recurrence
dehydration of NASH are unusual following liver transplantation.
Lipid-Lowering Agents • The most severe recurrence of NASH with rapidly pro-
gressive fibrosis is seen among patients with NASH asso-
HMG-CoA Inhibitors (Statins) ciated with hypopituitarism, who are also at risk for severe
Pravastatin Metabolism does not require hepatopulmonary syndrome.
CYP-450 • Remember the potential role of immunosuppression in
Atorvastatin, simvastatin, Effective, safe, may slightly posttransplant dyslipidemia. Cyclosporine, sirolimus,
lovastatin decrease CNI levels and, to a lesser extent, tacrolimus can all contribute.
Fish Oils Safe, no effect on CNIs • 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
reductase inhibitors are generally safe and free of drug-drug
ACE, Angiotensin-converting enzyme; CNI, calcineurin inhibitor; interactions in the posttransplant s­ etting.
CYP, cytochrome P; GI, gastrointestinal; HMG-CoA, 3-hydroxy-
3-methylglutaryl coenzyme A; TZD, thiazolidinedione.

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24. Vajro P, Fontanella A, Perna C, et al. Persistent hyperaminotrans- fibrosis, and high physiological fidelity to the human condition.
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J Pediatr. 1994;125(2):239-241. 48. Wouters K, van Gorp PJ, Bieghs V, et al. Dietary cholesterol,
25. Drenick EJ, Simmons F, Murphy JF. Effect on hepatic morphol- rather than liver steatosis, leads to hepatic inflammation in hyper-
ogy of treatment of obesity by fasting, reducing diets and small- lipidemic mouse models of nonalcoholic steatohepatitis. Hepatol-
bowel bypass. N Engl J Med. 1970;282(15):829-834. ogy. 2008;48(2):474-486.
26. Hickman IJ, Jonsson JR, Prins JB, et al. Modest weight loss and 49. Kristiaan W, Patrick JvG, Veerle B, et al. Dietary cholesterol,
physical activity in overweight patients with chronic liver disease rather than liver steatosis, leads to hepatic inflammation in hyper-
results in sustained improvements in alanine aminotransferase, lipidemic mouse models of nonalcoholic steatohepatitis. Hepatol-
fasting insulin, and quality of life. Gut. 2004;53(3):413-419. ogy. 2008;48(2):474-486.
 CHAPTER 23

Unusual Indications
for Transplantation
Francisco A. Durazo • Myron J. Tong

CHAPTER OUTLINE

INBORN ERRORS OF METABOLISM AND Acute Liver Failure from Non-A, Non-B, Non-C,
HERITABLE DISEASES Non-D, Non-E Hepatitis
Primary Hyperoxaluria Recurrent Bacterial Cholangitis
Familial Homozygous Hypercholesterolemia Chronic Fungal Infections of the Biliary Tract
Familial Amyloid Polyneuropathy Echinococcus granulosus/Hydatid Cyst
Protoporphyria Disease
Deficits in Fatty Acid Metabolism Polycystic Liver Disease
Urea Cycle Defects Sarcoidosis
Cystic Fibrosis Neuroendocrine Tumors
Diffuse Bile Duct Stenosis/Idiopathic Adult
VASCULAR DISORDERS Bile Ductopenia
Budd-Chiari Syndrome Hepatic Epithelioid Hemangioendothelioma
Giant Hemangioma with Kasabach-Merritt Benign Hepatic Tumors
Syndrome
Hepatic Adenoma
Hereditary Hemorrhagic Telangiectasia
Mesenchymal Hamartomas
Sinusoidal Obstruction Syndrome
Massive Hepatic Hemangiomas
MISCELLANEOUS DISORDERS Hepatic Lymphangiomatosis
Drugs Inflammatory Pseudotumor of the Liver
Infectious Agents Focal Nodular Hyperplasia
Bacterial Toxins and Fulminant Hepatic Failure Biliary Papillomatosis
Acute Liver Failure from Systemic Viruses Caroli’s Disease and Caroli’s Syndrome
Acute Liver Failure Caused by Hepatitis A or Total Parenteral Nutrition–Related End-Stage
Hepatitis E Liver Disease

Liver transplantation is a widely available and accepted specific reasons for liver transplantation in various
procedure for the treatment of advanced-stage liver dis- unusual conditions for which liver transplantation has
ease.1 The leading indications for liver transplantation in been shown to be effective therapy.
adults are chronic hepatitis C, nonalcoholic steatohepati-
tis, chronic hepatitis B, alcoholic liver disease, and the
cholestatic liver diseases primary biliary cirrhosis (PBC) INBORN ERRORS OF METABOLISM
and primary sclerosing cholangitis (PSC).2 In children
the leading indication for liver transplantation is biliary
AND HERITABLE DISEASES
atresia.3 Liver transplantation is also used as a lifesaving Primary Hyperoxaluria
procedure in adults and children with acute liver
failure.4,5 Type 1 primary hyperoxaluria (PH1) is a rare autosomal
In addition to these usual indications for liver trans- recessive disorder caused by a deficiency of the liver-­
plantation, a great number of unusual indications exist. specific enzyme alanine glyoxylate aminotransferase. As a
These conditions are rarely seen at any given transplant result of this deficiency, overproduction of oxalate from
center and, as a result, may not be recognized as an indi- glycine occurs in the liver and leads to progressive cal-
cation for liver transplantation. This chapter identifies cium oxalate formation, nephrocalcinosis, and eventually

256
 23 Unusual Indications for Transplantation 257

renal failure.6 Isolated kidney transplantation in patients severe coronary artery disease.19-21 In severe cases (less
with PH1 has failed universally because it does not cure than 2% of normal low-density lipoprotein [LDL] recep-
the metabolic defect and has been associated with a high tor activity), cardiovascular death is likely to occur within
rate of graft loss because of disease recurrence.7 Although the first decade of life. These abnormalities are due to an
the liver is histologically and biochemically normal in pri- intrinsic hepatocyte defect, specifically a reduction in
mary hyperoxaluria, the enzymatic defect within the liver LDL cholesterol (LDL-c) hepatocyte receptors with
results in systemic hyperoxalosis. Liver transplantation extraordinary elevation in serum LDL-c level.22 In
corrects the metabolic defect of PH1 and will also reverse patients with a less severe deficiency of the LDL receptor
growth retardation related to PH1.8 To prevent recur- (2% to 30% of normal activity), the disease is likely to
rent renal failure in cases of PH1, combined simultane- produce cardiovascular death within the second or third
ous or sequential liver transplantation followed by kidney decade of life.
transplantation is performed. In the past, end-to-side portocaval shunting and ileal
There is as yet no standard approach to transplanta- bypass were used to treat this condition in an effort to
tion of patients with PH1. Most would agree that a delay liver transplantation. Both these procedures have
patient with end-stage renal disease (ESRD) due to oxa- been discarded and replaced with the use of statin drugs
late nephropathy secondary to PH1, who shows no and inhibitors of cholesterol absorption, as well as
response to pyridoxine, with no potential living donor for mechanical removal of plasma LDL by means of aphere-
kidney transplantation, should receive a combined kidney sis.23 Aggressive use of these drugs and LDL-apheresis
and liver transplantation. Hyperdialysis and medical may delay the development of atherosclerosis and overt
therapy should be used in these patients to reduce serum cardiac disease in patients with FHH. Trials demonstrate
oxalate levels before and after combined kidney and liver that drugs that interfere with apolipoprotein B-100
transplantation. Ideally these measures should be initi- metabolism (mipomersen and lomitapide) can further
ated before kidney and liver transplantation. It is critical lower LDL-c by 25% to 55% in adult patients with FHH,
to minimize the time between the onset of ESRD and but with hepatic and gastrointestinal side effects.24,25
transplantation.9 After the combined liver-kidney trans- Long-term studies to assess the safety and efficacy of
plant, there is a prompt fall in plasma oxalate concentra- these medications are needed in patients with FHH.
tions. Nonetheless, urine oxalate levels remain markedly Because 75% of the LDL receptors are in the liver,
elevated for many months or even years after successful liver transplantation becomes the treatment of choice for
liver transplantation.10 The time required for resolution FHH for patients not responding to routine pharmaco-
of hyperoxaluria following liver transplantation varies logical treatments.19,20,26 Liver transplantation provides a
widely, occurring most rapidly in those who undergo source of normal LDL receptors that may clear choles-
transplantation within 6 months after reaching ESRD terol from plasma very effectively. Liver transplantation,
and who have undergone intensive dialysis.11 The use of before the onset of cardiovascular disease, offers the best
isolated liver transplant as a bridge to later kidney trans- chance for cure for patients with FHH, but it is not yet
plant (sequential transplantation) has been fraught with regarded as the treatment of choice and is generally con-
problems, because the liver transplant recipient with con- sidered only after the development of cardiovascular dis-
tinued renal failure and oxalosis is a special challenge.8 ease because of short- and long-term complications.
Preemptive isolated liver transplant as an intentional Preemptive liver transplantation has been done with nor-
strategy remains an option with good results for patients malization of LDL-c levels and resolution of skin lesions
with chronic kidney disease stage 3 with a continuous 2 years after transplantation.27
decrease of glomerular filtration rate, in spite of aggressive Living donor liver transplant from a parent is not an
medical therapy. Therefore there is only a narrow window option because the parent is invariably a carrier of one
in which isolated liver transplant may performed.12-15 copy of the defective gene(s).28 Patients with coronary
Domino liver transplant, in which a liver from a patient artery disease are considered a high-risk group for liver
with oxalosis is transplanted into another individual with transplantation.29 Coronary artery disease should be
hepatic disease, has been done. However, outcomes have addressed before liver transplantation by percutaneous
not been very successful. Results in a case report from transluminal coronary angioplasty or coronary artery
Europe on five patients were dismal. Within the first 4 bypass grafting.
weeks, all the domino recipients developed dialysis- The current approach to FHH with severe cardiovas-
dependent kidney failure despite good liver function. cular disease is to perform either simultaneous or
Four of the five patients died.16 Other reports have shown sequential heart-liver transplantation. Simultaneous
similar results.17,18 Domino liver transplant using donors transplantation is preferred if the heart graft functions
with PH1 results in early renal failure and cannot be rec- immediately. In cases in which such is not the case,
ommended for transplantation unless preventive strate- sequential transplantation can be accomplished. In both
gies have been identified. situations the heart relieves the cardiac disease (usually
advanced coronary artery disease with ischemic cardio-
Familial Homozygous myopathy), whereas the liver graft removes the underly-
ing defect, a hepatic deficiency of LDL receptors. In most
Hypercholesterolemia cases after liver transplantation, the serum cholesterol
Familial homozygous hypercholesterolemia (FHH) is an level declines markedly and in some cases can actually
autosomal recessive disease characterized by hypercho- normalize. In patients who continue to have moderate
lesterolemia and accelerated atherosclerosis leading to degrees of hypercholesterolemia, statin drugs can be used
258 PART II Patient Evaluation: Adult

to normalize the serum cholesterol level. There are two

published cases of domino liver transplantation using a
Protoporphyria
liver from a patient with FHH. Recipients developed The erythropoietic porphyrias include two disorders
hypercholesterolemia after liver transplant, but it was characterized by excess production of free protoporphy-
able to be controlled with diet and medication.30,31 rin from the bone marrow, due to either deficiency of the
enzyme ferrochelatase (erythropoietic protoporphyria)
Familial Amyloid Polyneuropathy or a gain-of-function mutation in the enzyme erythroid
aminolevulinic acid synthase (X-linked dominant proto-
Familial amyloid polyneuropathy is a dominantly inher- porphyria).38 The latter is less common but appears to
ited neuropathic form of amyloidosis caused by the carry a higher risk for liver disease.39
hepatic production of a mutant transthyretin (TTR).32-34 Classically the disease is described as an autosomal
Because TTR is produced almost exclusively by the liver, dominant trait with incomplete penetrance. However,
liver transplantation eliminates the underlying cause of most patients have severely reduced ferrochelatase lev-
the disease: production of an insoluble β-pleated mutant els, thus suggesting the presence of two rather than one
TTR that accumulates in peripheral and autonomic abnormal gene.40-42 Cases have been described in which
nerves. The disease is fatal with an expected survival of both parents of an affected patient have a different gene
12 to 15 years after the onset of clinical disease. The ini- defect with little or no clinical disease, but the combina-
tial symptom is usually a peripheral neuropathy, although tion of both abnormal genes in their offspring results in
autonomic neuropathy with gastrointestinal and cardio- the phenotypic expression of overt protoporphyria.
vascular symptoms is also common. The presence of Regardless of the specific method of inheritance,
clinical autonomic neuropathy has a negative impact on affected patients have a unique form of immediate
both morbidity and mortality before and after liver hypersensitivity to sun exposure characterized by a
transplantation. burning or stinging sensation coupled with erythema
Initially liver transplantation was performed in patients and edema. Photo-excitation of protoporphyrin in the
who were severely malnourished and those who had skin leads to the painful photosensitivity characteristic
advanced peripheral or autonomic neuropathy. Because of the disease. Increased biliary protoporphyrin excre-
the disease resolves very slowly, if at all, as the deposited tion exerts toxic effects on hepatobiliary structure and
amyloid material is resolubilized and removed, these function, although advanced, progressive liver disease
patients continue to experience their disease manifesta- manifests in only a small minority.43 It has been esti-
tions after transplantation. Thus the results are poor, and mated that 10% of patients with severe protoporphyria
some recipients actually die of posttransplant malnutri- experience clinically evident hepatic injury that pro-
tion, sepsis (usually urosepsis), or cardiac arrhythmias as a gresses to hepatic fibrosis and, ultimately, hepatic fail-
consequence of their persistent amyloid-induced disease ure. Once hepatic decompensation occurs, the disease
processes. progresses rapidly to death unless hepatic transplanta-
The current approach to patients with is to perform tion is accomplished.
transplantation early after the initial onset of clinical Hepatic accumulation of protoporphyrin can be
manifestations of familial amyloid polyneuropathy their reduced but not eliminated by the administration of oral
disease. Because the liver of these patients is normal charcoal, cholestyramine, or colestipol. Additional mea-
except for its production of a mutant TTR protein, the sures that have been used include frequent red blood cell
liver explant in such cases is often used as part of a dom- transfusions to suppress erythropoiesis, administration of
ino transplant despite the fact that the recipient of the hematin to suppress porphyrin synthesis, and plasma-
explant domino liver will, with sufficient time, acquire pheresis to remove free protoporphyrin in plasma. Liver
the disease process (amyloid polyneuropathy). The period transplantation is the only treatment with a long-lasting
before the onset of clinical disease is usually long, between effect for patients with protoporphyria that have advanced
10 and 50 years depending on variations in phenotypic liver disease.
expression of amyloid polyneuropathy in different When liver transplantation is used as a lifesaving pro-
endemic areas, so acceptance of a liver from a donor with cedure in individuals with protoporphyria, the patient
familial amyloid polyneuropathy can be expected to pro- needs to be prepared for surgery with aggressive plasma-
vide the recipient of the domino liver with 10- to 50-year pheresis to remove protoporphyrin from the blood, and
disease-free (polyneuropathy) posttransplant survival. the operating room must be modified to reduce light
For most transplant recipients in their mid-40s or 50s, exposure to exposed tissues during the transplant proce-
this extra risk represents a minimal addition to the inher- dure by using red lights, which do not activate the proto-
ent risks of liver transplantation. In light of the current porphyrin in light-exposed tissues. Biliary complications
treatment and its outcome, several therapeutic research after liver transplant are more common in this group of
projects will become the clinical tool for slowing down patients.44 Neuropathy, a well-documented manifesta-
the progress of familial amyloid polyneuropathy, includ- tion of acute hepatic porphyrias, was seen in 16% of pro-
ing reduction of variant TTR levels in plasma downregu- toporphyria patients after liver transplantation.45
lating TTR gene mRNA, inhibition of amyloid The ideal theoretical therapy for protoporphyria with
deposition, stabilization of the tetrameric TTR structure, developing liver failure is a combined bone marrow and
and replacement of the variant TTR gene with the nor- liver transplant procedure. Unfortunately, once the liver
mal TTR gene (which can be achieved by liver transplan- disease is sufficiently advanced to justify liver transplanta-
tation or by gene therapy).35-37 tion, there is insufficient time to perform a bone marrow
 23 Unusual Indications for Transplantation 259

transplant and allow the individual to recover normal diseases are evident on electron microscopy. Once initi-
hematological status before the liver transplant because ated, the disease process is rapidly progressive and leads
of rapid progression of the liver disease. Protoporphyrin- to death from liver failure or sepsis, or from both. These
induced liver disease recurs in the transplanted liver diseases are heterogeneous in terms of their extrahepatic
despite the reduction in hepatic protoporphyrin produc- manifestations. Most patients have severe neurological
tion as a result of the liver transplant. Persistent produc- involvement with weakness, hypotonia, poor cry and
tion of excess protoporphyrin by bone marrow results in suck responses, recurrent episodes of apnea, and
recurrent photosensitivity and hepatic disease. This fact myoclonic seizures. Patients with neurological signs
­
strongly supports sequential transplantation of the liver and symptoms are not candidates for liver transplanta-
followed by a bone marrow transplant in patients with tion because these findings do not revert but can con-
protoporphyria once early clinical hepatic involvement tinue and lead to severe neurological disease and death.
becomes manifest. Some patients, however, do not have neurological
findings, and these few can undergo successful liver
transplantation.
Deficits in Fatty Acid Metabolism
Congenital Mitochondrial DNA Depletion Syn-
Disorders of Fatty Acid Oxidation
drome. This disorder is manifested within the first week
Advances in our understanding of the structure and func- of life as hypotonia, hepatic failure, renal dysfunction,
tion of mitochondria have led to the recognition that and lactic acidosis. It is characterized by an increased
inherited and acquired mitochondrial dysfunction may be number of mitochondria with reduced mitochondrial
responsible for diseases affecting the liver and other organ DNA content. The diagnosis is established by document-
systems. Mitochondrial health may also determine hepa- ing a reduced mitochondrial DNA–to–nuclear DNA
tocyte survival in other hepatic disorders not directly ratio in affected tissues. Reduced activity of the respira-
related to the mitochondrion. Primary mitochondrial tory chain complexes I, III, and IV can be documented in
hepatopathies are conditions in which there are inherited patients, whereas the activity of complex II remains nor-
defects in structure or function of the mitochondria, most mal. In a few cases the disease appears to be liver specific
of which involve the respiratory chain and oxidative phos- and spares the muscle, brain, kidneys, and heart. In such
phorylation, fatty acid oxidation, the urea cycle, and other cases, liver transplantation is lifesaving.
pathways confined to mitochondria.46 Hepatic mitochon-
dria are responsible for the metabolism of fatty acids and Reye’s Syndrome. This acquired form of hepatic mito-
the production of ketone bodies (3-hydroxybutyrate and chondrial disease is due to an interaction between a viral
acetoacetate), which serve as alternative fuel for the cen- illness (influenza, varicella, enteroviruses, and other
tral nervous system during fasting.47-50 Disorders of oxi- viruses) and salicylate therapy and results in defective
dative phosphorylation are known causes of hepatic ureagenesis, ketogenesis, hyperammonemia, hypoglyce-
failure in neonates and infants. Two forms of liver disease mia, elevated free fatty acid levels, lactic acidosis, and
associated with mitochondrial respiratory chain disorders the production of various dicarboxylic acids. Most cases
have been described on the basis of clinical course and occur in the autumn and winter, when viral illnesses in
severity: a severe neonatal form with onset in the first children ages 5 to 15 years are most frequent. The
week of life with transient hypoglycemia, neurological symptoms of hepatic disease in children with Reye’s
involvement (severe hypotonia, myoclonus epilepsy, psy- syndrome develop after the clinical onset of the viral ill-
chomotor retardation), early liver failure, and a rapidly ness, often after the child appears to be recovering from
fatal course; and a delayed form with onset after age 2 the prodromal viral illness. After several hours of vomit-
months, with hepatic failure occurring later in the course ing, which can be severe and lead to dehydration,
of the disease.51 Liver transplantation has been suggested encephalopathy develops. Serum alanine and aspartate
as a therapeutic option in patients with the delayed type aminotransferase levels increase, as does the blood
in the hope there would not be any further extrahepatic ammonia level. Mild to moderate prolongation of the
involvement.52 prothrombin time and hypoglycemia also occur. It is
important to note that despite the potentially lethal dis-
Neonatal Liver Failure Caused by Deficiencies in the ease, the serum bilirubin level remains normal. Liver
Respiratory Chain of Mitochondria. These diseases biopsy samples show microvesicular steatosis in the
can occur in the first few months of life and are charac- absence of hepatic inflammation or necrosis. Electron
terized by lactic acidosis, jaundice, conjugated hyperbili- microscopy can demonstrate abnormal mitochondria.
rubinemia, abnormal serum alanine aminotransferase In patients with suggested Reye’s syndrome and overt
levels, coagulopathy, ketotic hypoglycemia, and hyper- liver failure, it may be that Reye’s syndrome is in actual-
ammonemia. Early clinical symptoms are lethargy, ity a consequence of a defect in fatty acid oxidation
hypotonia, and vomiting. Liver biopsy specimens from rather than true Reye’s syndrome. In these latter cases,
affected patients show microvesicular steatosis, canalicu- liver transplantation is indicated as a lifesaving
lar cholestasis, and bile duct proliferation. The peripor- procedure.
tal and centrilobular fibrosis in these cases can progress
to overt micronodular cirrhosis. Glycogen depletion and Long-Chain 3-Hydroxyacyl-Coenzyme A Dehydro-
iron deposition within the liver are common in these genase Deficiency. Women who are heterozygotes for
disease processes. The abnormal mitochondria in these this enzyme deficiency are at risk for third-trimester
260 PART II Patient Evaluation: Adult

life-threatening complications of pregnancy, including Cystic Fibrosis

acute fatty liver of pregnancy and the HELLP syndrome
(hemolysis, elevated liver enzymes, low platelets). In Cystic fibrosis is an autosomal recessive multisystem dis-
addition, they are at risk for preeclampsia/eclampsia. ease, primarily affecting the lungs, pancreas, gastrointes-
These disorders are associated with variable degrees of tinal tract, and liver.58 Because of improvement in
hepatic steatosis, hyperammonemia, an elevated lactate- managing respiratory complications, liver disease has
to-pyruvate ratio, lactic acidosis, ketosis, and hepatic dis- emerged as a significant medical issue.59 Focal biliary cir-
ease that occurs suddenly and progresses rapidly to coma rhosis is the pathognomonic hepatic manifestation and
and death in the absence of hyperbilirubinemia. In these results from biliary obstruction and progressive peripor-
more advanced cases, liver transplantation is lifesaving tal fibrosis over time. Focal biliary cirrhosis can progress
and may have to be performed either before or after to multilobular cirrhosis with clinically significant portal
delivery. Other defects in fatty acid oxidation that can hypertension and related complications.60
occur rarely and cause liver failure in pregnant women Severe liver disease affects 4.5% to 10% of individuals
include trifunctional protein deficiency, carnitine palmi- with cystic fibrosis and is the third most common cause
toyltransferase deficiency, and short-chain acyl-CoA of death.61 Liver transplantation alone or combined liver
dehydrogenase deficiency. and lung transplantation is an established treatment for
patients with cystic fibrosis–related liver disease. Prefer-
ably, patients should undergo isolated liver transplanta-
Urea Cycle Defects tion before their lung function declines to a critical stage
Urea cycle disorders are inborn errors of ammonia because combined liver-lung transplantation carries a
detoxification/arginine synthesis resulting from defects worse prognosis. The overall survival rates after sole
affecting the catalysts of the Krebs-Henseleit cycle (five liver transplantation in adults and children were 85%
core enzymes, one activating enzyme, and one mito- and 90% at 1 year and 65% and 85% at 5 years, respec-
chondrial ornithine/citrulline antiporter) with an esti- tively.62 It has been suggested that patients with nutri-
mated incidence of 1 in 8000.53 These disorders are tional deterioration should undergo early and elective
inherited as autosomal recessive disorders except for liver transplant because of association with worse out-
ornithine transcarbamylase deficiency,54,55 which is come after liver transplant.63
inherited as an X-linked recessive disorder. No single
mutation in any of these disorders has been shown to
define the disease. Rather, a large number of different VASCULAR DISORDERS
mutations have been identified for each disorder. Thus
the diagnosis of a urea cycle defect relies on enzymatic Budd-Chiari Syndrome
assays of blood and urine for the metabolites that char-
acterize each disorder. Patients present with hyperam- Budd-Chiari syndrome encompasses a number of condi-
monemia either shortly after birth (approximately 50%) tions that cause obstruction of the hepatic outflow tract
or later at any age, leading to death or to severe neuro- from the small hepatic veins to the junction of the infe-
logical handicap in many survivors. Despite the exis- rior vena cava (IVC) and right atrium.64,65 This process
tence of effective therapy with alternative pathway can occur as a consequence of a congenital web in the
therapy and liver transplantation, outcomes remain IVC between the right atrium and the entry site of the
poor. This may be related to underrecognition and hepatic veins and has been observed most often in Asian
delayed diagnosis due to the nonspecific clinical presen- Indians and Japanese women.
tation and insufficient awareness of health care profes- The IVC web leads to stasis and hepatic venous vascu-
sionals because of disease rarity. lar injury, which can progress to vascular thrombosis
Liver transplantation for a urea cycle deficiency is within the hepatic veins and the subdiaphragmatic IVC
essentially curative. Episodes of hyperammonemia no caudal to the web. It can also develop as a consequence of
longer occur, dietary restriction is no longer necessary, a congenital defect in either coagulation or fibrinolysis, as
and alternative pathway medications can be discontinued. occurs in patients with factor V Leiden mutation or a
It is important to note that liver transplantation does not prothrombin mutation or in those homozygous for meth-
correct the low levels of plasma arginine and citrulline ylenetetrahydrofolate reductase (MTHFR), antithrom-
present in individuals with carbamoyl phosphate synthe- bin III, protein C, or protein S deficiency. Often the use
tase deficiency or ornithine transcarbamylase deficiency of oral contraceptives, estrogen replacement therapy, or
because most of the citrulline in plasma is a product of pregnancy is responsible for precipitating the venous
intestinal rather than hepatic synthesis. Thus individuals thrombosis in such cases. Yet another cause of Budd-­
with either of these two disorders, even after successful Chiari syndrome is the presence of a myeloproliferative
liver transplantation, continue to require supplements of disorder (usually with a mutation in the Janus tyrosine
either citrulline or arginine. Because the preexisting neu- kinase-2) such as polycythemia rubra vera, essential
rological damage appears not to reverse,56,57 it is essential thrombocytosis, or paroxysmal nocturnal hemoglobin-
to prevent endogenous catabolism and hyperammonemia uria.66 Finally, Behçet’s syndrome, antiphospholipid or
before and during liver transplantation. Liver transplanta- anticardiolipin autoantibodies (or both), sarcoidosis,
tion offers severely affected patients with urea cycle disor- α1-antitrypsin deficiency, ulcerative colitis, and celiac dis-
ders a better alternative in terms of quality of life than ease have also been reported as a cause of Budd-Chiari
medical treatment. syndrome.67
 23 Unusual Indications for Transplantation 261

Liver transplantation for the treatment of Budd-Chiari

syndrome is accomplished at two chronological ends of
Sinusoidal Obstruction Syndrome
the natural history of the disease process. Specifically, in Sinusoidal obstruction syndrome (SOS) is a clinical syn-
acute cases of Budd-Chiari syndrome associated with drome characterized by hepatomegaly, ascites, weight
acute or subacute hepatic failure, liver transplantation can gain, and jaundice. SOS is described with alkaloids, alco-
be lifesaving. In patients with end-stage Budd-Chiari dis- hol, oral contraceptives, toxic oil, drugs such as terbin-
ease and cirrhosis secondary to chronic venous outlet afine, or radiation injury. Hematopoietic stem cell
obstruction, liver transplantation is also lifesaving. In these transplantation has become the most important and fre-
latter cases, previous mesocaval portal shunts, side-to-side quent cause of SOS.74 SOS is also reported after kidney
portal shunts, or portal-atrial vascular shunts may have transplantation, mainly related to azathioprine toxicity,
been created earlier in the natural history of the disease and after liver transplantation as a process of cellular
and are complicating the recipient hepatectomy. Five-year rejection.75 Liver transplantation has been performed as a
survival after undergoing liver transplantation for Budd- rescue therapy in patients with SOS after stem cell trans-
Chiari syndrome is 83%.67 plantation not responding to medical therapy. When
With resection of the initiating IVC web and throm- SOS develops after liver transplantation itself, retrans-
bosis as part of the recipient hepatectomy or replacement plantation can be performed as a rescue therapy because
of the diseased liver with a liver that does not have a the liver is the only damaged organ.68 Graft-versus-host
mutant process such as factor V Leiden, a prothrombin disease can also be an indication for liver transplantation
mutation, MTHFR homozygosity, or antithrombin III, in patients with a previous bone marrow transplant.76-80
protein C, or protein S deficiency, the vasculopathy is
resolved. Although almost all genetic thrombophilic dis-
orders are cured by transplantation, thrombosis still
occurs and routine anticoagulation therapy is necessary.68
MISCELLANEOUS DISORDERS
In patients in whom the primary disease process exists
outside the liver, as for example with polycythemia rubra
Drugs
vera and other myeloproliferative diseases, Behçet’s dis- Idiosyncratic drug-induced liver injury (DILI), though
ease, and other rare vasculopathies, lifelong anticoagula- uncommon, has become a major concern over the last
tion is also necessary after liver transplantation. decade. Acute liver failure (ALF) resulting from DILI
shows infrequent spontaneous recovery with 75% mortal-
Giant Hemangioma with Kasabach-Merritt ity without a liver transplant. Liver transplantation affords
Syndrome excellent survival. More than 1100 drugs, herbal reme-
dies, natural products, vitamins, minerals, dietary supple-
Patients with giant hemangiomas and coagulopathy con- ments, and recreational and illicit compounds have been
sisting of thrombocytopenia, prolongation of the pro- reported to cause DILI. Isoniazid, as monotherapy or in
thrombin and activated partial thromboplastin time, and combination, commonly causes hepatotoxicity leading to
laboratory evidence of disseminated intravascular coagu- liver transplantation,81 followed by propylthiouracil, phe-
lopathy (Kasabach-Merritt syndrome) have occasionally nytoin, and valproate.81 Among the complementary and
been treated by liver transplantation, including living alternative medications, anabolic steroids are the most
donor liver transplant and emergency liver transplanta- common, followed by weight loss supplements.82 The
tion for ruptured giant hemangioma.69-71 outcome of DILI ALF is predicted by the degree of liver
dysfunction (as judged by the severity of coma, hyperbili-
Hereditary Hemorrhagic Telangiectasia rubinemia, and coagulopathy) but not by the class of
drugs, drug injury pattern, age, sex, obesity, or timing of
Hereditary hemorrhagic telangiectasia, or Rendu-Osler- cessation of drug use. When transplant-free recovery
Weber syndrome, is an inherited autosomal dominant from DILI ALF is combined with the excellent results of
disease characterized by arteriovenous malformations liver transplantation, overall survival approaches 70%.
that occur in multiple organs.52,53 Hepatic involvement
is uncommon but can be complicated by portal hyper-
tension, hepatic encephalopathy, high-output conges- Infectious Agents
tive heart failure, and, rarely, hemobilia. When these
Bacterial Toxins and Fulminant Hepatic Failure
complications occur, liver transplantation is one of sev-
eral therapeutic options, which also include vascular Cereulide, the emetic toxin of Bacillus cereus, has been
embolization and partial hepatic resection, depending shown to inhibit the respiratory chain and lead to hepatic
on the extent of disease within the liver. Treatment with steatosis and a picture of fulminant hepatic failure (FHF)
antivascular endothelial growth factor treatments such that can be treated by liver transplantation and antibiotics
as bevacizumab was associated with a decrease in cardiac directed at the responsible bacterial infection.83
output and reduced duration and number of episodes of
epistaxis.72 This therapy has the potential to be used as a
Acute Liver Failure from Systemic Viruses
bridge to liver transplantation. However, the only treat-
ment available to restore normal cardiac output in The classic hepatotropic viruses, hepatitis A to E, are not
patients with hereditary hemorrhagic telangiectasia and the only viral agents able to infect the liver. Other sys-
cardiac failure is liver transplant.73 temic viruses may cause hepatic injury that can range
262 PART II Patient Evaluation: Adult

from mild and transient elevation of aminotransferase onset but a similar clinical course to other forms of FHF
levels to acute hepatitis and occasionally acute liver fail- and appears to preferentially affect women. It can also
ure and fulminant hepatitis. The clinical presentation occur in young adults, especially if the individual is either
may be indistinguishable from that associated with classic pregnant or malnourished.91-93 Liver transplantation is
hepatotropic viruses. These agents include cytomegalovi- lifesaving in these cases. Unfortunately, in 15% of such
rus; Epstein-Barr virus; herpes simplex virus; varicella- cases the FHF recurs after transplantation and thus
zoster virus; human herpesvirus 6, 7, and 8; human necessitates a second liver transplant procedure within
parvovirus B19; and adenoviruses, among others. Wide days to weeks. Moreover, aplastic anemia is a late compli-
spectrums of clinical syndromes are associated with cyto- cation of the disease process.
megalovirus disease. Unique clinical syndromes may
present in neonates, young adults, and immunocompro- Recurrent Bacterial Cholangitis
mised hosts infected with cytomegalovirus. Cases of ful-
minant hepatitis have been reported in both Patients with structural biliary disease carry a high risk for
immunocompromised and immunocompetent hosts recurrent bacterial cholangitis and septicemia and have a
infected with Epstein-Barr virus. Occasionally these high incidence of morbidity. The most common disease
patients with acute hepatic failure may need liver trans- leading to structural damage to the biliary tree is PSC.
plantation. Herpes simplex viruses may involve the liver Complications of septicemia have been reported, includ-
in neonatal infections, pregnancy, immunocompromised ing endocarditis, osteomyelitis, and hepatic abscess.94
hosts and, occasionally, immunocompetent adults. Vari- Caroli’s syndrome can present with bouts of recurrent
cella-zoster virus has also been associated with severe cholangitis in its end stages and can be associated with the
acute hepatitis and fulminant hepatitis in adults. The development of cholangiocarcinoma. Patients with second-
drug of choice for these conditions is intravenous acyclo- ary sclerosing cholangitis resulting from bile duct injury
vir. These may also need liver transplantation in the more during surgery can also have repeated episodes of bacterial
severe forms of clinical presentation. Typical liver biopsy cholangitis. Finally, ischemic cholangiopathy after liver
findings can be useful in determining the diagnosis of transplantation presents as strictures, biliary casts, sludge,
these viral infections. Human herpesviruses 6, 7, and 8; and recurrent cholangitis. Liver transplantation remains an
human parvovirus B19; and adenoviruses can also be excellent treatment for patients with structural biliary dis-
present with features of acute liver injury and occasion- ease who have recurrent bouts of cholangitis.95,96
ally as fulminant hepatitis. The clinical syndromes are
less well delineated than those associated with herpesvi- Chronic Fungal Infections of the Biliary Tract
ruses. It is important to consider these viruses as possible
etiological agents in patients who have acute liver injury Rarely, chronic biliary candidiasis or cryptococcal infec-
and their serological markers for the classic hepatotropic tion can be mistaken for PSC.97 When such a patient is
viruses are not indicative of an active infection.84-86 correctly identified, antifungal therapy should be admin-
istered and liver transplantation may be avoided. In rare
cases the diagnosis of fungal cholangiopathy is not made
Acute Liver Failure Caused by Hepatitis A or
preoperatively, and an incorrect diagnosis of either PSC
Hepatitis E
or idiopathic bile duct paucity (a form of the idiopathic
These two forms of viral hepatitis rarely cause FHF except vanishing bile duct syndrome seen in adults) is made, and
in older individuals (>40 years of age) in the case of hepa- hepatic transplantation is performed. These patients
titis A and pregnant malnourished women in the case of require prolonged antifungal therapy after transplanta-
hepatitis E.87,88 Hepatitis E genotypes 1 and 2 have been tion for a minimum of 4 to 6 weeks and possibly longer
identified as causing epidemic hepatitis. Genotypes 3 and (3 months to a year), depending on the presence or
4 are swine viruses and appear to infect humans as an acci- absence of recurrent fungal disease in the allograft.
dental host (zoonoses). The association of acute liver fail-
ure with pregnancy is common with genotype 1 infection.89 Echinococcus granulosus/Hydatid Cyst
Both conditions can result in severe hepatic failure in Disease
individuals with underlying chronic hepatitis B or C or
other forms of chronic parenchymal liver disease. Liver This parasitic disease is common in parts of France, Ger-
transplantation for such cases of acute on chronic liver many, Poland, and extensive areas of the former Soviet
failure occurring in an individual with preexisting chronic Union.98,99 The natural host for this infection is the fox.
hepatitis B or C is the only available successful therapy. Once acquired by humans as a result of the ingestion of
cysts, the disease can progress to liver failure as a result of
vascular disease (Budd-Chiari syndrome), hepatobiliary
Acute Liver Failure from Non-A, Non-B,
disease (pseudosclerosing cholangitis), or secondary biliary
Non-C, Non-D, Non-E Hepatitis
cirrhosis. With any of these manifestations of the disease,
Acute liver failure (FHF) in the absence of serum markers liver transplantation may be an appropriate therapeutic
of hepatitis A (HAV) or B (HBV) infection or another option. The main conditions to qualify a patient with Echi-
cause is called non-A, non-B (NANB) FHF. The patho- nococcus multilocularis for liver transplantation are absence
genetic role of viral infection in NANB FHF remains of extrahepatic sites of disease, severe liver insufficiency,
controversial.90 NANB FHF is not associated with hepa- and inability to perform radical liver resection, which is the
titis A, B, C, D, E, or G in plasma.91 It has a later age of treatment of choice.100 Postoperative complications in
 23 Unusual Indications for Transplantation 263

patients who receive transplants for echinococcal infection In the United States the Surveillance, Epidemiology, and
are common and can be catastrophic if the hepatic tumor End Results (SEER) database showed an increase in
is violated and cysts contaminate the operative field. reported incidence from 1 in 100,000 in 1973 to 5 in
100,000 in 2004.105 About 85% of NETs originate from
the gastrointestinal tract, and the majority of patients
Polycystic Liver Disease present at diagnosis with metastasis. The liver is the most
Polycystic liver disease can progress to massive hepato- common organ involved.106,107 Liver transplantation has
megaly resulting in severe physical and social disabil- a selected role in unresectable NETs and is proposed for
ity.101 Liver transplantation can reverse the malnutrition, certain candidates, with 5-year survival up to 70% and
cachexia, and quality-of-life dysfunction associated with 5-year recurrence-free survival up to 50%.106 Patients
this disease. Simultaneous renal transplantation is not with metastatic carcinoid/neuroendocrine tumors and
required unless renal failure is present, and it can often be severe symptoms unresponsive to octreotide therapy or
delayed for many years. those with massive hepatic tumor and no evidence of
extrahepatic disease can be treated by liver transplanta-
tion.108,109 In such cases the primary lesion should have
Sarcoidosis been either resected previously or removed at the time of
Sarcoidosis is a multisystem disease characterized by the the liver transplant procedure.
presence of noncaseating granuloma and fibrosis.102,103
Most deaths attributable to sarcoidosis are a result of car- Diffuse Bile Duct Stenosis/Idiopathic Adult
diac disease (50%), with pulmonary disease accounting
for most of the remaining deaths (43%). Noncardiac,
Bile Ductopenia
nonpulmonary disease is responsible for less than 7% of Diffuse bile duct stenosis consists of a homogeneous and
the total deaths from sarcoidosis. Thus advanced liver diffuse obliteration of the biliary system combined with
disease as a result of sarcoidosis is an extremely unusual the presence of an intrahepatic gallbladder and pancreas
indication for liver transplantation. When hepatic sar- divisum, suggesting a congenital or developmental cause.
coidosis does progress, the damage is similar to that found The biliary tree and the ventral pouch of the pancreas
in other organs. Granulomas lead to chronic intrahepatic derive from a common outpouching in the ventral surface
cholestasis with loss of interlobular bile ducts. Periportal of the primitive gastrointestinal tract.110 Idiopathic adult-
fibrosis is followed by micronodular cirrhosis. It leads to hood ductopenia is a chronic cholestatic liver disease
severe liver-related complications such as jaundice, pruri- associated with loss of intrahepatic bile ducts of unknown
tus, portal hypertension, and liver failure.104 Liver trans- cause with clinical onset in adulthood.111 Both diseases
plantation for sarcoidosis is generally performed when can be severe and progress to cirrhosis and portal hyper-
the sarcoidosis complicates cases of chronic hepatitis C or tension. Liver transplantation has been a curative proce-
other disease processes involving the liver. Liver trans- dure for both diseases.
plantation has also been performed for cases of hepatic
sarcoidosis in which the sarcoidosis has severely affected Hepatic Epithelioid
the individual’s quality of life in a negative manner such
that movement, self-care, and eating are made difficult, as
Hemangioendothelioma
occurs in patients with polycystic liver disease. Primary hepatic epithelioid hemangioendothelioma
In a study characterizing the outcomes for a large, ret- (HEH) is a rare soft tissue vascular tumor with an inter-
rospective, multicenter cohort, patients undergoing liver mediate clinical course between benign hemangioma and
transplant for hepatic sarcoidosis had significantly poorer malignant angiosarcoma, first described in 1984 by Ishak
outcomes than a case-matched cohort with cholestatic et al.112 No definitive cause has been confirmed, although
liver diseases (PSC and PBC). Recurrent sarcoidosis or an several factors have been correlated to HEH, such as vinyl
exacerbation of preexisting sarcoidosis in the lung can be chloride, asbestos, and thorotrast.113 Mortality is more
difficult to differentiate from tuberculosis or lymphoma than 50% without treatment, although a few patients have
(or both) after liver transplantation in a patient who been reported to survive without any therapy. Systemic or
received a transplant for sarcoidosis. The incidence of locoregional chemotherapy, as well as radiotherapy, have
disease recurrence in the liver is unknown but appears to been reported without significant success.113,114 Liver
have minimal impact on the long-term outcomes for both transplantation has been the most frequent therapeutic
patients and grafts. The systemic nature of sarcoidosis, option (44.8% of patients).113 Fludeoxyglucose F 18 posi-
which includes end-organ damage in other organs, and tron emission tomography (FDG-PET) scan can be use-
the need for high-dose corticosteroid therapy may be the ful in the staging of the disease, particularly before
two biggest contributors to the worse outcomes of orthotopic liver transplantation (OLT).115 Long-term
patients with sarcoidosis versus patients with other chole- results were satisfying with 5- and 10-year overall survival
static liver diseases.104 rates of 83% and 74%. About a quarter of the patients
developed recurrence after a median time of 49 months,
but aggressive treatment using antiangiogenic therapies
Neuroendocrine Tumors or rapamycin-based immunosuppression significantly
Neuroendocrine tumors (NETs) are a variety of neo- prolonged survival.113,116 Studies confirm that lymph
plasm characterized by slow growth rate and potential to node invasion and minimal extrahepatic disease are not a
secrete a variety of hormones and vasoactive substances. contraindication to OLT. Only the presence of
264 PART II Patient Evaluation: Adult

macrovascular invasion significantly affected long-term sequential hepatic resection is the treatment of choice
outcome.113,116-118 OLT should be proposed earlier in the unless the lesion has recurred after a previous attempt at
disease course of HEH and, because of the incidence of resection, is centrally located with involvement of the
extrahepatic disease and graft recurrence, antiangiogenic hilar structures, or is of such size that resection without
adjuvant treatment using antivascular endothelial growth transplantation is not possible.
factor should be introduced routinely.119
Inflammatory Pseudotumor of the Liver
Benign Hepatic Tumors This “tumor” can occur in many different tissues. In rare
Hepatic Adenoma cases it involves the liver.125 When it is located in a hilar
location, it can lead to secondary biliary cirrhosis as a
Hepatic adenoma can occur as an isolated lesion (most result of recurrent episodes of cholangitis. The presence
often) or as multiple adenomas (unusual).120,121 The more of this lesion along with hepatic failure, portal hyperten-
typical case consists of a single adenoma and is seen in sion with bleeding, or a combination of these two prob-
individuals with glycogen storage disease (type I), women lems can be a rare indication for liver transplantation.
who use oral contraceptive agents, or men and women
who have used sex steroids for any of a number of legiti- Focal Nodular Hyperplasia
mate clinical or illicit indications. These tumors, although
benign, can undergo central necrosis or hemorrhage and As with the other benign lesions, focal nodular hyperpla-
cause pain, or they can be strategically located and cause sia can be treated by liver transplantation if the lesion is
biliary or vascular injury to the rest of the liver, thus centrally located (which is often the case) and is causing
necessitating their removal. In centrally located lesions or hilar strictures with resultant portal hypertension, biliary
lesions that involve such a large fraction of the liver that obstruction with recurrent cholangitis, or hepatic failure
hepatic resection is precluded, liver transplantation is as a result of hilar vascular involvement.126,127 This dis-
indicated. ease is often associated with vascular abnormalities
Multiple hepatic adenomas can occur as an isolated involving the liver or collagen vascular disease processes.
disease process or as part of a familial disorder. Repetitive Rarely, nodular hyperplasia is a diffuse phenomenon in
segmental hepatic resection of these lesions is unlikely to the liver. This too can be an indication for transplanta-
remove all the lesions safely and may enhance the growth tion and is often mistaken preoperatively for cryptogenic
of residual tumors in the liver. In some of these patients, cirrhosis.
especially those with adenomas that are growing or caus-
ing symptoms or with increased serum α-fetoprotein
Biliary Papillomatosis
level with concern about malignant transformation, liver
transplantation is an appropriate therapy.119 Biliary papillomatosis is a rare entity associated with
recurrent episodes of cholangitis and the development of
secondary biliary cirrhosis; it can be complicated by
Mesenchymal Hamartomas
recurrent episodes of sepsis or portal hypertension, or
These lesions can be of such size that they incapacitate both.128 In very rare cases, cholangiolar carcinoma can
the patient or cause recurrent abdominal pain and, rarely, arise from the chronically inflamed epithelium that exists
hepatic failure.122 If these lesions either cannot be in these cases. Liver transplantation with a Roux-en-Y
resected with a standard surgical procedure or recur after choledochojejunostomy can be a treatment option and
such surgery, liver transplantation is an appropriate should be performed before malignant transformation of
course of action. the adenomatous biliary epithelium.

Massive Hepatic Hemangiomas Caroli’s Disease and Caroli’s Syndrome

Occasionally, hepatic hemangiomas are of sufficient size Caroli’s disease is a rare congenital disease characterized
or centrally located in the hilar area of the liver that resec- by gross segmental dilatation of the intrahepatic bile
tion without liver transplantation is not possible.123 In ducts causing a macroscopic appearance of intrahepatic
general, these lesions do not require surgical intervention multiple cysts; it is included in type IVa and V of Toda-
unless they are causing pain, enlarging progressively, or ni’s classification for choledochal cysts and combined
consuming platelets and clotting factors and resulting in with polycystic renal disease in a few cases. It can be asso-
thrombocytopenia and disseminated intravascular coagu- ciated with hepatic fibrosis, which is a different entity,
lation (Kasabach-Merritt syndrome). named Caroli’s syndrome.129 Clinically it is dominated by
episodes of cholangitis that might become frequent with
a dismal long-term outcome. Liver resection is the treat-
Hepatic Lymphangiomatosis ment of choice in the case of monolobar forms and
This extremely rare condition has caused hepatic dys- absence of congenital hepatic fibrosis; conservative man-
function, as well as intractable dyspnea, fatigue, and mal- agement with percutaneous or endoscopic drainage and
nutrition as a result of the inability of affected individuals stent or hepaticojejunostomy have failed in the definitive
to eat; it can also be associated with debilitating chronic solution of symptoms and are considered palliative treat-
abdominal pain.124 As with other benign tumors, ments. Chronic episodes of cholangitis with formation of
 23 Unusual Indications for Transplantation 265

liver abscesses can be complicated by the occurrence of 14. Lorenzo V, et al. Presentation and role of transplantation in adult
cholangiocarcinoma in 7% up to 14% of patients.130,131 patients with type 1 primary hyperoxaluria and the I244T AGXT
mutation: Single-center experience. Kidney Int. 2006;70(6):
The diagnosis of cholangiocarcinoma in these cases is 1115-1119.
quite difficult, and no clear clinical or biochemical param- 15. Galanti M, Contreras A. Excellent renal function and reversal of
eters seem to allow an early diagnosis. Liver transplanta- nephrocalcinosis 8 years after isolated liver transplantation in an
tion is the treatment of choice even in patients with infant with primary hyperoxaluria type 1. Pediatr Nephrol.
2010;25(11):2359-2362.
Caroli’s syndrome when the association with congenital 16. Saner F, et al. Early renal failure after domino liver transplanta-
hepatic fibrosis can lead to development of signs of portal tion using organs from donors with primary hyperoxaluria type 1.
hypertension with esophageal varices. In patients with Transplantation. 2010;15(7):782-785.
concomitant end-stage renal disease resulting from a 17. Popescu I, Dima S. Domino liver transplantation: how far can we
polycystic kidney, combined liver-kidney transplantation push the paradigm? Liver Transpl. 2012;18(1):22-28.
18. Franchello A, et al. Severe course of primary hyperoxaluria and
is advisable.130,132 renal failure after domino hepatic transplantation. Am J Trans-
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Total Parenteral Nutrition–Related 19. Bilheimer D, Goldstein J, Grundy S. Liver transplantation to pro-
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60. Davis P. Cystic fibrosis since 1938. Am J Respir Crit Care Med. 85. Chauveau E, et al. Fatal fulminating hepatitis due to herpes sim-
2006;173:475-482. plex virus type 2 in a young immunocompetent female. Med Trop.
61. Miller M, et al. Pulmonary function in individuals who underwent 1999;59:58-60.
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try. Liver Transpl. 2012;18:585-593. always what it seems to be. Rev Med Chil. 2010;138:1302-1311.
62. Nash K, et al. Cystic fibrosis liver disease: to transplant or not to 87. Kyrlagkitsis I, et al. Acute hepatitis A virus infection: A review of
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63. Colombo C, Costantini D, Rocchi A. Effects of Liver transplanta- center. Hepatogastroenterology. 2002;49:524-528.
tion on the nutritional status of patients with Cystic Fibrosis. 88. Nicoluzzi J, et al. Hepatitis E-associated subacute liver failure: A
Transpl Int. 2005;18:246-255. rare indication for liver transplantation. Am J Gastroenterol.
64. Plessier A, Valla D. Budd-Chiari syndrome. Semin Liver Dis. 2001;96:2278-2279.
2008;28:259-269. 89. Hoofnagle J, Nelson K, Purcell R. Hepatitis E. N Engl J Med.
65. Zimmerman M, Cameron A, Ghobrial R. Budd-Chiari syndrome. 2012;367(13):1237-1244.
Clin Liver Dis. 2006;10:259-273. 90. Ferraz M, et al. Fulminant hepatitis in patients undergoing liver
66. James C, et al. A unique clonal JAK2 mutation leading constitutive transplantation: evidence for a non-A, non-B, non-C, non-D, and
signaling causes polycythemia vera. Nature. 2005;434:1144-1148. non-E syndrome. Liver Transpl Surg. 1996;2(1):60-66.
67. Mackiewicz A, et al. Results of liver transplantation in the treat- 91. Ben-Ari Z, et al. Fulminant non-A-G viral hepatitis leading to
ment of Budd-Chiari syndrome. Ann Transplant. 2012;17: liver transplantation. Arch Intern Med. 2000;160:388-392.
5-10. 92. Mutimer D, et al. Failure to incriminate hepatitis B, hepatitis C,
68. Senzolo M, Riggio O, Primignani M. Vascular disorders of the and hepatitis E viruses in the aetiology of fulminant non-A, non-B
liver: recommendations from the Italian Association for the Study hepatitis. Gut. 1995;36:433-436.
of the Liver (AISF) ad hoc committee. Dig Liver Dis.
2011;43(7):503-514.
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93. Ellis A, et al. Late-onset hepatic failure: Clinical features, serology 114. Bioulac-Sage P, et al. Benign and malignant vascular tumors of
and outcome following transplantation. J Hepatol. 1995;23: the liver in adults. Semin Liver Dis. 2008;28:302-314.
363-372. 115. Nguyen B. Epithelioid haemangioendothelioma of the liver with
94. Wiesner R, LaRusso N. Clinicopathologic features of the syn- 18 F-FDG PET imaging. Clin Nucl Med. 2004;29:828-830.
drome of primary sclerosing cholangitis. Gastroenterology. 116. Lerut J, et al. The place of liver transplantation in the treatment
1980;79:200-206. of hepatic epithelioid hemangioendothelioma. Report of the
95. Brandsaeter B, et al. Liver transplantation for primary sclerosing European Liver Transplant Registry. Ann Surg. 2007;246:
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nancy. J Hepatol. 2004;40:815-822. 117. Lauffer J, et al. Epithelioid haemangioendothelioma of the liver.
96. Gores G, et al. Model for End-Stage Liver Disease (MELD) excep- A rare hepatic tumor. Cancer. 1996;78:2318-2327.
tion for bacterial cholangitis. Liver Transpl. 2006;12:S91-S92. 118. Maklouf H, Iashak K, Goodman Z. Epithelioid haemangioendo-
97. Noack K, et al. Successful orthotopic liver transplantation in a thelioma of the liver: a clinicopathologic study of 137 cases. Can-
patient with refractory biliary candidiasis. Gastroenterology. cer. 1999;85:562-582.
1991;101:1728-1730. 119. Ercolani G, Grazi G, Pinna A. Liver transplantation for benign
98. Moreno-Gonzalez E, et al. Liver transplantation for Echinococ- hepatic tumors: a systematic review. Dig Surg. 2010;27(1):
cus granulosus hydatid disease. Transplantation. 1994;58:797-800. 68-75.
99. Loinaz C, et al. Liver transplantation in liver disease: Echinococ- 120. Marino I, et al. Total hepatectomy and liver transplantations for
cus granulosus. Transplant Proc. 1998;30:328-329. hepatocellular adenomatosis and focal nodular hyperplasia.
100. Chomicz L, et al. Human cystic and alveolar echinococcoses as Transpl Int. 1992;5(suppl 1):201-205.
indication to liver transplantation. Transplant Proc. 2003;35(6): 121. Yunta P, et al. A new case of hepatic adenomatosis treated with
2260-2261. orthotopic liver transplantation. Ann Chir. 2001;126:672-674.
101. Pirenne J, et al. Liver transplantation for polycystic liver disease. 122. Kim H, et al. Orthotopic liver transplantation for inflammatory
Liver Transpl. 2001;7:238-245. myofibroblastic tumor of the liver hilum. J Pediatr Surg.
102. Casavilla F, et al. Clinical course after liver transplantation in 1996;31:840-842.
patients with sarcoidosis. Ann Intern Med. 1993;118:865-866. 123. Belli L, et al. Surgical treatment of symptomatic giant hemangio-
103. Barbers R. Role of transplantation (lung, liver, and heart) in sar- mas of the liver. Surg Gynecol Obstet. 1992;174:474-478.
coidosis. Clin Chest Med. 1997;18:865-873. 124. Miller C, et al. Orthotopic liver transplantation for massive
104. Vanatta J, et al. Outcomes of orthotopic liver transplantation for hepatic lymphangiomatosis. Surgery. 1988;103:490-495.
hepatic sarcoidosis: an analysis of the United Network for Organ 125. Hemeghan M, et al. Inflammatory pseudotumor of the liver: A
Sharing/Organ Procurement and Transplantation Network data rare cause of obstructive jaundice and portal hypertension in a
files for a comparative study with cholestatic liver diseases. Liver child. Pediatr Radiol. 1984;14:433-435.
Transpl. 2011;17:1027-1034. 126. Radomski J, et al. Results of liver transplantation for nodular
105. Yao J, et al. One hundred years after “carcinoid”: epidemiology of regenerative hyperplasia. Am Surg. 2000;66:1067-1070.
and prognostic factors for neuroendocrine tumors in 35,825 cases 127. Elariny H, et al. Nodular regenerative hyperplasia: A controver-
in the United States. J Clin Oncol. 2008;26:3063-3072. sial indication for orthotopic liver transplantation. Transpl Int.
106. Mazzaferro V, Pulvirenti A, Coppa J. Neuroendocrine tumors 1994;7:309-313.
metastatic to the liver: how to select patients for liver transplanta- 128. Beavers K, et al. Orthotopic liver transplantation for biliary papil-
tion? J Hepatol. 2007;47:460-466. lomatosis. Liver Transpl. 2001;7:264-266.
107. Oberg K, Eriksson B. Endocrine tumours of the pancreas. Best 129. Todani T, et al. Congenital bile ducts cysts: classification, opera-
Pract Res Clin Gastroenterol. 2005;19:753-781. tive procedures and review of 37 cases, including cancer arising
108. Ramage J, Catnach S, Williams R. Overview: The management of from choledochal cyst. Am J Surg. 1977;134:263-269.
metastatic carcinoid tumors. Liver Transpl Surg. 1995;1:107-110. 130. De Kerckhove L, et al. The place of liver transplantation in Car-
109. Routley D, et al. Orthotopic liver transplantation in the treatment oli’s disease and syndrome. Transpl Int. 2006;19:381-388.
of metastatic neuroendocrine tumors of the liver. Liver Transpl 131. Chapman R. Risk factors for biliary tract carcinogenesis. Ann
Surg. 1995;1:118-121. Oncol. 1999;10(suppl4):308.
110. Camargo Jr C, et al. Adult Presentation of Diffuse Bile Duct Ste- 132. Habib S, et al. Caroli’s disease and orthotopic liver transplanta-
nosis: Therapy With Liver Transplantation. Liver Transpl Surg. tion. Liver Transpl. 2006;12:416-421.
1996;l2:235-237. 133. Kelly D. Intestinal failure-associated liver disease: what do we
111. Rios R, et al. Idiopathic adulthood ductopenia: long-term follow- know today. Gastroenterology. 2006;130(2 suppl 1):S70-S77.
up after liver transplantation. Dig Dis Sci. 2001;46:1420-1423. 134. Kelly D. Liver complications of pediatric parenteral nutrition–
112. Ishak K, et al. Epithelioid haemangioendothelioma of the liver. epidemiology. Nutrition. 1998;14(1):153-157.
A rare hepatic tumor. Hum Pathol. 1984;15:839-853. 135. Nathan J, et al. Isolated liver and multivisceral transplantation for
113. Mehrabi A, et al. Primary malignant hepatic epithelioid heman- total parenteral nutrition-related end-stage liver disease. J Pediatr
gioendothelioma. A comprehensive review of the literature with Surg. 2007;42(1):143-147.
emphasis on the surgical therapy. Cancer. 2006;107:2108-2121. 136. Guglielmi F, et al. Total parenteral nutrition-related gastroen-
terological complications. Dig Liver Dis. 2006;38(9):623-642.
 CHAPTER 24

General Criteria for

Transplantation in Children
Henry C. Lin • Estella M. Alonso • Riccardo A. Superina • Peter F. Whitington

CHAPTER OUTLINE

GENERAL INDICATIONS FOR LIVER Acute Liver Failure

TRANSPLANTATION IN CHILDREN Metabolic Liver Disease
Primary Liver Disease That Leads to Hepatic REFERRAL TO A TRANSPLANT CENTER
Insufficiency
Acute Liver Failure EVALUATING THE PEDIATRIC TRANSPLANT
Liver Transplantation as Primary Therapy for CANDIDATE
Inborn Errors of Metabolism ISSUES UNIQUE TO PEDIATRIC LIVER
Secondary Liver Disease TRANSPLANTATION
Primary Hepatic Malignancy Nutritional Consequences of Chronic
GENERAL CONTRAINDICATIONS TO LIVER Liver Disease and Their Effect on
Transplantation
TRANSPLANTATION
Surgical Innovations Affecting Pediatric Liver
MANAGEMENT OF SOME SPECIFIC DISEASES Transplantation
LEADING TO LIVER TRANSPLANTATION IN
LIVER TRANSPLANTATION IN NEONATES
CHILDREN
Decompensated Cirrhosis

Liver transplantation provides lifesaving treatment for discerning about whom we transplant. Comorbidities
children with liver disease. Current challenges include such as hepatopulmonary syndrome and impaired cardiac
identifying those ready for a liver transplantation and the function, rather than size and age, are now the limiting
optimal timing for listing a patient for transplantation. factors to successful transplantation. With improved
Condition at the time of transplantation affects survival, knowledge of candidate selection, the 1-year graft sur-
and consequently time spent on the waiting list can be vival following pediatric liver transplantation exceeds
paramount to overall prognosis. Within a span of 3 90%, and 5-year survival rates are 85%.1,2
decades, pediatric liver transplantation has matured as a In North America this ongoing process of recognizing
clinical therapy into one that is practiced worldwide in appropriate candidate selection and application of trans-
innumerable medical institutions. This transformation plantation has been aided by the creation in 1995 of Studies
can be traced to a few critical developments, including of Pediatric Liver Transplantation (SPLIT), a nationwide
improvements in immunosuppression, application of database comprising the experience of 38 centers in the
technical variant allografts, and selection of potential United States.1,3,4 As of 2006 a total of 2445 patients and
candidates and organ allocation. Progress in the manage- 2738 liver transplants have been reported to the registry.5
ment of immunosuppressive therapy suitable for children Initial analysis demonstrates that 5-year survivors of liver
has been of key importance in improving survival after transplantation have good graft function. However, post-
transplantation. The application of technical variant transplantation complications and chronic medical condi-
allografts overcame the shortage of suitable donors for tions can affect extrahepatic organs, reflecting the need for
children and permitted many more children to be trans- more comprehensive management to further optimize
planted and reduced waiting list mortality. Finally, there long-term outcomes.2 As the data from SPLIT continue to
has been improved understanding of where, when, and be analyzed and disseminated, further improvements
how to use transplant therapy in children. As we continue should be realized. For European experiences in pediatric
to make strides in defining proper patient selection and in liver transplantation, the European Liver Transplant Reg-
organ allocation methodology, we are becoming more istry provides a similar observational repository.

270
 24 General Criteria for Transplantation in Children 271

Several factors about liver transplantation must be TABLE 24-1 A

 pproximate Frequencies of the
kept in mind if it is to be used in a manner that is consis- Specific Indications for 2445
tent with the best medical interests of a pediatric patient. Pediatric Liver Transplant Recipients
First, it must be remembered that it is a high-risk proce- Enrolled in Studies of Pediatric Liver
dure, carrying a significant risk for mortality under the Transplantation (SPLIT)
best of circumstances. Second, there is potential for
chronic disability and requirement for long-term drug Indication Frequency
administration. Some transplant critics believe that hav-
Chronic Cholestatic Disease 54.3%
ing a liver transplant represents trading one disease for
Biliary atresia 41.1%
another. Although a long-term, high-quality life is possi-
Alagille syndrome 2.9%
ble,6 recent studies indicate that children with liver trans-
Primary sclerosing cholangitis 2.7%
plantations have lower health-related quality of life levels
TPN-induced cholestasis 1.8%
than healthy individuals. Children with liver transplanta-
Progressive intrahepatic cholestasis 1.5%
tion report impairments across both physical and psycho-
Idiopathic cholestasis 1.1%
logical dimensions and have health-related quality of life
Neonatal hepatitis 1.0%
levels comparable to those of children with other chronic
Biliary cirrhosis, other cholestatic diseases 2.2%
health conditions such as cancer in remission or renal
Acute Liver Failure 13.8%
transplantation.7,8 Assessment of children 10 years after
Cirrhosis 6.7%
transplant shows that roughly one quarter of children
Autoimmune hepatitis with cirrhosis 2.9%
have continued impairment of linear growth. Further-
Neonatal hepatitis cirrhosis 0.5%
more, at 10 years after transplant only 32% of children
Metabolic Disease 14.4%
achieve the ideal triad of normal growth, stable allograft
α1-Antitrypsin deficiency 3.0%
function on single-agent immunosuppression, and an
Urea cycle defects 2.4%
absence of immunosuppression-related complications.8 A
Cystic fibrosis 1.6%
third consideration is that liver transplantation is
Wilson’s disease 1.2%
extremely expensive. In an age of managed care in the
Tyrosinemia 1.0%
private sector and budget deficits in the public sector,
Primary hyperoxaluria 0.7%
every effort is being made to reduce the cost of transplant
Crigler-Najjar syndrome 0.7%
therapy and to seek alternatives therapies.
Glycogen storage disease 0.7%
The goal of this chapter is to review liver transplanta-
Neonatal hemochromatosis 0.5%
tion as it is practiced now, with particular focus on the
Inborn error in bile acid metabolism 0.1%
indications for liver transplantation in children. We
Primary Hepatic Malignancy 6.2%
provide a general overview, a discussion of some specific
Hepatoblastoma 4.2%
indications in children, and an overview of aspects of
Other 2%
liver transplantation that are unique to the pediatric
Other 4.7%
population.
Congenital hepatic fibrosis 1%
Budd-Chiari syndrome 0.4%
GENERAL INDICATIONS FOR LIVER Toxicity 0.7%

TRANSPLANTATION IN CHILDREN TPN, Total parenteral nutrition.

The indications for liver transplantation in children can

be categorized within the following framework: (1) pri- functional implications, and its diagnosis has poor prog-
mary liver disease that is expected to progress to hepatic nostic implications. However, in certain circumstances,
failure, (2) acute liver failure (ALF), (3) primary therapy transplantation may not improve the 5-year survival of
for liver-based metabolic diseases, (4) liver disease as part some children with cirrhosis. For example, the develop-
of a systemic illness, and (5) primary hepatic malignancy ment of portal hypertension and gastrointestinal bleeding
(Table 24-1). in children with biliary atresia and successful portoenter-
ostomy does not always correlate with survival.9 Directly
Primary Liver Disease That Leads addressing the complications of cirrhosis, such as by per-
to Hepatic Insufficiency forming distal splenorenal shunts for bleeding varices or
hypersplenism, may be more appropriate treatment
Hepatic failure, whether acute or the result of end-stage options than transplantation.10 Cirrhosis should not be
liver disease, is the major indication for liver transplanta- considered an indication for liver transplantation unless
tion in infants and children. Progressive biliary cirrhosis there is evidence of functional hepatic decompensation.
due to biliary atresia is the most frequent single disease An important factor in determining when hepatic
indication in all series. Alagille syndrome, primary scle- insufficiency will develop is the natural history of the
rosing cholangitis, and parenchymal liver diseases, patient's liver disease. Biliary atresia, for example, has a
including autoimmune and chronic viral hepatitis, are clearly defined natural history in patients either who did
also common indications. not receive a portoenterostomy or in whom surgery failed
Cirrhosis is neither a specific disease entity nor a gen- to produce effective biliary drainage. These patients will
eral indication. It is an anatomical diagnosis with typically reach end-stage disease sometime between 9 and
272 PART III Patient Evaluation: Pediatric

18 months of age and thus present with a clear indication (types III and IV), Wilson's disease, and neonatal hemo-
for liver transplantation in infancy.11,12 Unfortunately, chromatosis, cause structural liver injury (including cir-
few other chronic liver diseases in children have such a rhosis) and constitute routine indications for liver
clearly defined natural history. transplantation in pediatric and adult patients. Trans-
The natural history of several chronic cholestatic disor- plantation is required for acute or chronic liver failure or
ders of childhood can include severe symptoms but infre- to eliminate the potential for malignancy, a frequent
quently results in the development of end-stage liver complication of several metabolic disorders.19-21 Replace-
failure. Alagille syndrome represents the prototype of this ment of the liver also results in correction of the meta-
indication. When estimating the value of liver transplanta- bolic defect.
tion in treating these diseases, the clinician must carefully Liver transplantation can benefit children with inborn
weigh the morbidity of the liver disease against the mor- errors of metabolism that do not injure the liver, the prin-
tality associated with liver transplantation. Pruritus that cipal goal of treatment being to correct the metabolic
results in cutaneous mutilation and poor school perfor- error. Examples of disorders that have been treated in
mance and is refractory to medical therapy can be a valid this way include urea cycle defects, Crigler-Najjar syn-
indication for liver transplantation. Other morbid effects drome, homozygous familial hypercholesterolemia, and
of chronic cholestatic liver disease that merit consider- primary hyperoxaluria. The decision of whether to per-
ation for transplantation include severe growth failure and form liver transplantation depends on knowing that it
malnutrition, refractory bone disease, hypercholesterol- will correct the metabolic defect, that there is no effective
emia, and xanthomatosis. In these cases, all other avenues alternative therapy, and that the patient has not experi-
of therapy should be exhausted before transplantation is enced irreversible complications. Crigler-Najjar syn-
considered. For example, partial cutaneous biliary diver- drome represents the prototype for this decision-making
sion can alleviate severe pruritus, hypercholesterolemia, process.22-25 The severe deficiency of bilirubin uridine
and xanthomatosis in children with Alagille syndrome,13 diphosphate–glucuronyl transferase results in the sys-
which is clearly preferable to transplantation. temic accumulation of bilirubin, which, if untreated,
leads to neurological injury. These patients can be effec-
tively treated for a time with phototherapy and enteric
Acute Liver Failure administration of bilirubin-binding agents.24 However,
Liver transplantation holds the greatest potential for sur- medical therapy is cumbersome and inevitably fails to
vival in children with ALF.14,15 Although there are several maintain safe levels of bilirubin in teenagers. As a result,
scoring systems designed to predict mortality in non- these patients are usually managed medically until age 10
transplanted ALF, there is a lack of adequately powered to 12 years, at which time liver transplantation is
studies to inform diagnostic algorithms and guide liver performed.
transplant decisions. Currently it is not possible to reli- The decision-making process is different for urea cycle
ably determine which children will recover spontaneously defects, which result in hyperammonemia and brain dam-
without transplantation. Continued study should improve age. Despite advances in medical management, severe
our ability to estimate the probabilities of recovery based defects such as ornithine transcarbamylase (OTC) defi-
on cause and other factors and enhance our decision-mak- ciency in males still have a very poor outcome.26 OTC
ing process regarding transplantation. Challenging issues deficiency is an X-linked disease. Boys with OTC defi-
for clinicians to consider before transplantation include ciency should be considered for transplantation immedi-
the risk for a patient developing multisystem organ failure ately upon making the diagnosis. Even taking an
during the course of recovery, estimation of which causes aggressive approach, neurological outcome is poor if the
are treatable with transplantation, and expectations for child has experienced very high serum ammonia levels or
full recovery without transplantation.16,17 significant brain injury.27 Successful transplantation cor-
The ongoing National Institutes of Health–funded rects the metabolic defect but cannot undo preexisting
pediatric ALF study has described the course of 653 chil- brain damage. Girls who are heterozygous for the condi-
dren with ALF enrolled in the registry, demonstrating that tion have a spectrum of illness, from none to quite
causes of ALF are different in children compared to adults severe.28,29 More severely affected girls should be consid-
and that short-term outcome also varies depending on the ered for transplantation if medical therapy fails to prevent
diagnosis.6,18 Common causes of ALF in children can be episodes of hyperammonemia. In contrast, obligate het-
broadly categorized as infectious, metabolic, immunologi- erozygous mothers have provided living donor allografts
cal, and drug related, but a specific diagnosis is not estab- for affected sons.21,30 Diseases with variable expressions
lished in over 50% of children.6,17,18 At present every child and responses to medical therapy, such as the glycogen
with ALF and associated hepatic encephalopathy should storage disease type I and familial hypercholesterolemia,
be evaluated as a candidate for emergency transplantation. must be considered individually.
Complete replacement of the liver may not be neces-
Liver Transplantation as Primary Therapy sary when considering treatment of metabolic diseases in
which there is deficient enzyme activity. The quantity of
for Inborn Errors of Metabolism functioning liver mass needed to carry out critical meta-
Many human diseases result from inborn errors of critical bolic functions may allow for the effective use of auxiliary
metabolic or synthetic processes that principally involve transplants or hepatocyte transplants. Orthotopic
the liver. Some of these, including α1-antitrypsin defi- replacement of the left lobe of the liver has been used to
ciency, hereditary tyrosinemia, glycogen storage disease treat OTC deficiency and Crigler-Najjar syndrome with
 24 General Criteria for Transplantation in Children 273

some success.31,32 Liver-directed gene therapy in the neoadjuvant chemotherapy do not constitute a contrain-
form of hepatocyte transplantation has shown some dication to transplantation.
promise for inherited metabolic diseases, although main- Limited experience in a few centers has also suggested
taining function over time has proven difficult.6,23,33,34 that “rescue transplants” carry a much worse prognosis
Primary hyperoxaluria is a metabolic liver disease than tumors treated by primary transplantation. Liver
that uniquely results from an abnormal metabolic path- transplants that are done after a tumor has recurred in the
way that produces excess metabolite. Overproduced liver carry a nonrecurrence rate of 20% to 30% in com-
oxalate is filtered by the kidney, crystallizes, and causes parison to rates of greater than 90% for primary trans-
micro-obstructive renal failure.35 Transplanted kidneys plants. Posttransplant adjuvant chemotherapy has also
suffer the same fate if the liver is not replaced as well, been associated with improved tumor-free survival.
whereas preemptive liver transplantation can prevent Transplantation for centrally placed Pretreatment extent
renal damage.36-38 of disease (PRETEXT) III and PRETEXT IV tumors is
controversial. Some authors favor transplantation,
Secondary Liver Disease although results with aggressive resection have been
shown to be very effective in one series.49 All cases of
Many children and young adults with cystic fibrosis and hepatoblastoma should be managed in centers with sub-
biliary cirrhosis have undergone liver transplantation.39-43 stantial experience in pediatric hepatobiliary surgery,
Despite initial concern that the associated use of immu- transplantation, and oncology so that treatment may be
nosuppressives might lead to more severe infectious com- optimally selected.50-57
plications in these patients, many patients actually have The prognosis after liver transplantation for adults
improved pulmonary function, probably as the result of with hepatocellular carcinoma on a background of
improved strength and general health. Successful liver chronic hepatitis has improved dramatically.50,52 After
transplantation has also been performed in children with application of the Milan criteria, hepatocellular carci-
sclerosing cholangitis secondary to Langerhans cell his- noma is now a frequent indication for transplantation,
tiocytosis.44-47 It is imperative to gain control of the sys- whereas it was a near-absolute contraindication in the
temic disease before undertaking liver transplantation past because of extremely high rates of tumor recurrence
while understanding that the liver disease is irreversible. (see Chapter 16).
Thus the appropriate use of chemotherapy should not be Hepatocellular carcinoma is extremely rare in children
curtailed because of concerns about causing liver damage. outside the context of metabolic liver disease. The experi-
This disease is notable for a significantly increased risk ence in metabolic liver disease suggests that large and
for posttransplant lymphoproliferative disease46 and per- slow-growing lesions do not reduce survival after trans-
haps recurrence.48 When dealing with secondary liver plantation, and thus the relevance of applying the Milan
disease, each patient and set of circumstances must be criteria to children with hepatocellular carcinoma on a
weighed on an individual basis to determine whether this background of an otherwise normal liver or even with
approach is justified. some forms of metabolic disease such as tyrosinemia is
questionable. The prognosis in children with rapidly
growing multifocal carcinomas is bleak, particularly
Primary Hepatic Malignancy because the efficacy of neoadjuvant chemotherapy is very
Hepatoblastoma is the most common malignancy in chil- limited in comparison to that for hepatoblastoma. In
dren leading to transplantation, which has become an some instances, such as for tyrosinemia, the incidence of
increasingly used modality in children whose malignancy hepatocellular carcinoma is so great that liver transplan-
cannot be removed by conventional surgery. The most tation has been performed as preemptive therapy.58-60
important tenet of hepatoblastoma treatment is the com- However, with improved metabolic control it is reason-
plete removal of the primary tumor by surgical means. able to use prolonged medical therapy while monitoring
Neoadjuvant chemotherapy has been extremely effective closely for the development of cancer, which is done by
in converting what are initially judged as unresectable frequent measurement of the α-fetoprotein level.61 Dis-
tumors into tumors that can be resected safely without eases associated with very little risk for malignancy dur-
compromising the vascularity of the remaining liver. ing the early stages of disease need not be monitored. For
However, clear indications for transplantation include example, carcinoma can develop in patients with glyco-
centrally positioned tumors that encroach on all three gen storage disease, but only after adenomas are present;
hepatic veins, involvement of both branches of the portal thus the development of adenomas marks the time when
vein bifurcation, and tumor present in all four sectors of frequent monitoring of the α-fetoprotein level should be
the liver. initiated and transplantation considered.
Important steps in increasing the likely success of The experience with liver transplantation in hepato-
transplantation include complete control of the primary blastoma is limited.50-55 This malignancy often presents
tumor at the time of transplantation, as exemplified by an symptomatically with abdominal distension due to a large
α-fetoprotein level that is declining and is ideally less tumor. Hepatoblastomas are often quite sensitive to che-
than 1% of its original value at presentation. Also, ideally motherapy, which should be used initially to shrink the
there must be no evidence of noncontiguous spread of tumor mass before resection is attempted.50,56 Transplan-
disease in the abdomen and no evidence of metastatic dis- tation should be considered only if complete resection is
ease in the chest and elsewhere. Lung metastases that not possible. However, liver transplantation for recurrent
have been removed surgically or that resolve after hepatoblastoma following previous resection is associated
274 PART III Patient Evaluation: Pediatric

with a poor survival outcome and should be considered a in patients with biliary atresia than in the general popula-
relative contraindication.55 Transplantation in the pres- tion.71,72 Examples of involvement of other systems
ence of metastatic disease remains a complex issue. With include severe congenital hepatic fibrosis and polycystic
chemosensitive tumors, resection of lung lesions followed kidney disease presenting at an early age, and nephropa-
by transplantation and posttransplant chemotherapy has thy with α1-antitrypsin deficiency and Alagille syndrome.
met with reasonable success.50,53 Such cases should prob- In these situations the strategy may include multiorgan
ably be managed in centers with substantial experience in transplantation or a decision not to offer the patient a
dealing with this cancer. liver transplant. The current challenge is to improve our
Hepatic hemangioendothelioma is the most common understanding of organ system limitations to transplanta-
hepatic vascular tumor of infancy. In instances where tion in hopes of developing management algorithms that
hepatic hemangioendothelioma presents with ALF, liver support optimal outcomes following transplantation.
transplantation can be a lifesaving option to consider if Secondary organ failure can have a negative effect on
medical therapy is ineffective.62-65 However, early neona- outcome after liver transplantation, and in some instances
tal liver transplantation can be associated with other risk these systemic effects of liver disease must be addressed
factors, so alternative treatment options should be con- before liver transplantation can be considered.
sidered first. Hepatopulmonary syndrome is an important example
of secondary organ injury that affects liver transplant out-
comes.73 In hepatopulmonary syndrome, hypoxemia
GENERAL CONTRAINDICATIONS results from intrapulmonary arteriovenous dilation that
TO LIVER TRANSPLANTATION leads to intrapulmonary shunting and ventilation-perfu-
sion mismatch. Consequently, increasing oxygen delivery
Many patients referred for liver transplantation are found does not improve oxygenation. The development of these
to be candidates for beneficial alternative therapies. The intrapulmonary shunts, with or without pulmonary
experienced personnel at referral centers are frequently hypertension, can result in advanced respiratory failure
better prepared to judge the relative risks and benefits of that may not recover. However, recent experience with
transplantation versus alternative therapies than referring focused intraoperative management suggests that indi-
physicians in the community, so consultation in this viduals with hepatopulmonary syndrome can tolerate a
regard should be a primary role of referral centers. liver transplantation with good outcome if transplant
Because liver transplantation carries a significant risk, any occurs before irreversible injury.74,75 Therefore patients
potentially effective therapy should be pursued. How- presenting with chronic liver disease and chronic hemo-
ever, there is also risk involved with pursuing another globin desaturation, as evidenced by cyanosis, digital
therapy that turns out to be ineffective. In some cases it clubbing, and other symptoms, should undergo careful
makes sense to place the patient on the active transplant pulmonary function study and possible cardiac catheter-
waiting list while closely observing the effects of other ization before transplantation to evaluate the degree of
therapeutic interventions. shunting and screen for pulmonary hypertension.76
Long-term survival following liver transplantation is Although gas exchange abnormalities generally correlate
the rule rather than the exception, but if a poor quality of with the severity of liver disease, liver transplantation is
life is expected following transplantation, consideration not always indicated in hepatopulmonary syndrome,
should be given to withholding therapy. This particu- because clinical resolution can occur after medical or sur-
larly applies to diseases that injure the central nervous gical treatments other than transplantation and careful
system. Many infants with advanced liver disease have review of the underlying pathophysiological and clinical
poor psychomotor development, especially of gross status should direct treatment decisions.77
motor skills, but these deficits seem to recover, although Other pulmonary complications that may complicate
possibly not fully, after liver transplantation.66-69 Most or contraindicate transplantation include severe pulmo-
infants with severe motor delay before transplantation nary hypertension and acute respiratory distress syn-
will test within the normal range a year after transplanta- drome. Severe progressive pulmonary disease requiring
tion.66 Social development is not impaired to as great a escalating ventilator support, such as acute respiratory
degree as physical development, and recovery is faster. distress syndrome, is a contraindication to transplanta-
Neither physical nor social disabilities are reasons to tion. Patients requiring oscillating ventilation to support
deny transplantation. oxygenation are not transplantation candidates due to
It may not be possible to make any predictions about poor pulmonary reserve. Elevated pulmonary artery pres-
neurological outcome in some cases, such as the previ- sures and pulmonary vascular resistance, as can be seen in
ously healthy child who presents with ALF and deep severe portopulmonary hypertension, is associated with
hepatic coma. Liver transplantation almost always increased mortality and would exclude a candidate from
reverses encephalopathy, but the recovery of the patient transplantation.
with cerebral edema is often incomplete, and sometimes Portopulmonary hypertension is defined as a resting
brain death follows successful transplantation.70 mean pulmonary artery pressure greater than 25 mm
Chronic liver disease and hepatic insufficiency have Hg.78-82 For severe portopulmonary hypertension, in
profound effects on the function of other organ systems. which the mean pulmonary artery pressure is greater than
Impairment of other organ systems can preclude liver 50 mm Hg, the cardiopulmonary mortality rate
transplantation. Complex congenital heart disease often approaches 100%.78 In addition, elevated right-sided
accompanies Alagille syndrome and is severalfold higher heart pressures to over half systemic pressure raises
 24 General Criteria for Transplantation in Children 275

concern of adequate allograft perfusion following trans- avoided. For example, one of the complications encoun-
plantation, as well as overall cardiac tolerance of and tered in the patient with biliary atresia is ascending chol-
recovery following the surgery.83-88 The challenge angitis, which can be refractory to all medical management.
remains to identify the specific limitations of pulmonary Continued antibiotic therapy is likely to be ineffective,
function necessary for an individual to successfully toler- and liver function can deteriorate, rendering the patient a
ate a liver transplant.89 less favorable candidate. Although the risk for postopera-
Cardiac function is another important pretransplant tive infectious complications is high in this group, it is
consideration. Currently there is no consensus on how appropriate to proceed with liver transplantation when a
cardiac disease affects transplant candidacy in pediatrics, donor becomes available. Likewise, patients with end-
making it difficult to determine the cardiac exclusion stage liver disease frequently develop systemic infections,
parameters for transplantation. In adults, end-stage liver including spontaneous bacterial peritonitis (SBP) and
disease is associated with an increased risk for several car- sepsis. If these infections result in rapid hepatic decom-
diac complications. Severe pulmonary hypertension, pensation, a combined medical/surgical approach is usu-
symptomatic coronary artery disease, severe ventricular ally justified. For SBP there is no clear consensus on the
dysfunction, aortic stenosis with poor ventricular func- timing of transplantation following treatment, but a sin-
tion, severe valvular heart disease, and advanced cardio- gle episode of SBP does not seem to affect the outcome of
myopathy are contraindications to liver transplantation, liver transplantation in adults.99,100 Specifically, liver
and these same parameters can be extended to children. transplantation performed within 30 days of an episode of
As previously mentioned, severe pulmonary hypertension SBP is not associated with higher rates of posttransplant
can preclude survival in the early posttransplant period. sepsis.99 Liver transplantation should be deferred until
Many children with advanced cirrhosis secondary to bili- any viral infection, no matter how trivial, is resolved. Pos-
ary atresia develop cardiomegaly, which appears to be sible exceptions to this involve infections with the herpes-
secondary to a mild dilated cardiomyopathy, which may viruses, other than Epstein-Barr virus (EBV), which often
be related to chronic malnutrition. These patients occa- can be controlled even in the face of immunosuppression
sionally exhibit heart failure and require therapy but usu- (e.g., cytomegalovirus [CMV], varicella, herpes simplex
ally recover normal cardiac function after transplantation. virus [HSV]-1).
However, the degree of abnormality of pretransplant Finally, one of the most important contraindications
echocardiogram findings in infants with cirrhotic cardio- to liver transplantation is the presence of disease that is
myopathy predicts length of hospital stay.90 In general, expected to recur after therapy. Metastatic carcinoma and
for children with specific cardiac anomalies that compro- some other cancers that involve the liver (such as sarco-
mise heart function, corrective surgery is indicated before mas) also have a dismal long-term outcome after trans-
transplantation.88,91 Obesity is another consideration plantation. Chronic viral infections, including hepatitis B
with cardiovascular implications, especially in teenagers and C viruses (HBV and HCV) and human immunodefi-
and older children. Patients with morbid obesity, defined ciency virus, can persist or recur after liver transplanta-
as body mass index greater than 40, have an increased risk tion but can be effectively controlled. The management
for posttransplant mortality because of associated cardio- of these conditions in adult patients has improved and is
vascular morbidity.92 discussed in Chapters 9 and 11. Data in children are lim-
Renal involvement should be another consideration ited, and treatment of children with these infections gen-
before liver transplantation, because acute kidney injury erally follows the paradigms established in adult
at the time of transplantation can be associated with populations. Despite a high recurrence rate after trans-
increased morbidity. For example, the patient with func- plantation, children with autoimmune hepatitis are not
tional renal insufficiency (hepatorenal syndrome, urinary denied transplant therapy if needed.101-104
sodium < 20 mEq/L, normal sediment) is managed by
establishing an access for renal dialysis before or during
the liver transplant procedure. Renal function typically
recovers after liver replacement,93-95 but some studies in
MANAGEMENT OF SOME SPECIFIC
patients with hepatorenal syndrome report conflicting DISEASES LEADING TO LIVER
results, and some advocate for simultaneous liver-kidney TRANSPLANTATION IN CHILDREN
transplantation.96 However, multivariate analysis sug-
gests that acute tubular necrosis at the time of transplan- The diseases that result in a need for liver transplantation
tation is only variable with a higher 1-year posttransplant in children can be classified under the general indications
mortality.97 Major intra-abdominal vascular anomalies as previously discussed. Table 24-1 presents an overall
associated with biliary atresia were once considered abso- list of the indications for transplantation in over 2400
lute contraindications to liver transplantation, but surgi- children based on the experiences of SPLIT. The follow-
cal advances allow for successful liver transplantation ing discussion highlights some of the questions regarding
even in the child with congenital absence of the portal application of this therapeutic modality in children with
vein.98 In these instances, thorough preoperative evalua- the more important specific diseases.
tion of the vascular anatomy of the abdomen is required
to plan the operative approach.
Any major acute systemic infection is a relative contra-
Decompensated Cirrhosis
indication to liver transplantation, but sometimes trans- Biliary atresia is by far the most common specific indica-
plantation in the setting of active infection cannot be tion for liver transplantation in children. Recent SPLIT
276 PART III Patient Evaluation: Pediatric

data indicate that this single disease results in 41% of portoenterostomy should be performed just as Kasai
pediatric transplants performed and 65% performed in described, using a relatively short biliary limb entering the
children under the age of 1 year.1,3,5 Given the incidence intestinal mainstream as close as possible to the ligament
of this disease, 400 to 600 new cases are seen in the United of Treitz.118
States annually. Without a Kasai portoenterostomy, Hypoplastic portal veins, often only 1 to 2 mm in
patients with biliary atresia will progress to chronic liver diameter, are seen in patients with failed portoenterosto-
failure with portal hypertension, cirrhosis, and malnutri- mies and can complicate transplantation. Patients with
tion. Approximately one third of children will have a suc- successful portoenterostomies who continue to grow and
cessful outcome from a Kasai portoenterostomy that will come to transplantation years later have normal portal
delay the need for transplant until they are older.105-107 veins, which supports performing the procedure. Hypo-
Patients with biliary atresia and failed portoenterostomy plastic portal veins are also observed in small children
will typically reach end stage sometime between 9 and 18 undergoing liver transplantation without prior portoen-
months of age, which results in 250 to 400 infants with terostomy. The hypoplasia appears to be a consequence
biliary atresia who require transplant each year. of cirrhosis early in life. Portal hypertension does not dis-
The general strategy in managing a patient with bili- tend the portal vein under these conditions because of its
ary atresia should be one that maximizes overall outcome. intrinsic small radius and the effect of Laplace's law on
Successful portoenterostomy prolongs survival out of the wall tension. Also, collateral circulation might develop
infancy, and performing this procedure does not seem to relatively more easily in early life, limiting the magnitude
imperil the patient at the time of transplantation. Survival of the portal pressure. No matter what the reason for the
statistics following a portoenterostomy show that this portal vein hypoplasia, it should not be a reason against
approach is as good as early transplantation.11,12,108,109 An performing a portoenterostomy.
elevated bilirubin level 30 days following portoenteros- The infant with a failed portoenterostomy should be
tomy is a main predictive prognostic factor for the need referred as early as possible for evaluation because there
for liver transplantation, and some studies suggest that is a significant lag time for obtaining a donor, and there is
transplant evaluation should occur as the Pediatric End- little risk of early transplantation in these children. In the
Stage Liver Disease (PELD) score approaches 10.110,111 patient with a successful portoenterostomy, the matter of
Survival following liver transplant for infants under 1 timing becomes more difficult. Indications for liver trans-
year of age for biliary atresia is improving,112,113 and plantation in jaundice-free biliary atresia include compli-
weight alone is not a contraindication to liver transplan- cated portal hypertension refractory to therapy,
tation.114 However, any patient who can benefit from a intractable cholangitis, declining liver synthetic dysfunc-
portoenterostomy, based on age at diagnosis and other tion, and hepatopulmonary syndrome or portopulmo-
clinical factors, should have that procedure as initial nary hypertension. Portal hypertension, which results
therapy. from progressive hepatic fibrosis, occurs regardless of the
Occasionally surgeons may perform the Kasai proce- status of the portoenterostomy and is part of the natural
dure again when it has not worked previously. Some course of disease. Splenomegaly is the predominant early
common sense must be applied in this regard, although clinical indicator of portal hypertension, with ascites
there is no evidence upon which to base recommenda- being a late finding. Management of portal hypertension
tions. If the portoenterostomy results in only a brief in biliary atresia consists of supportive care aimed at pre-
period of bile drainage and the histological examination vention of variceal bleeding. Strategies for treating
of the ductal remnants indicates little chance for effective esophageal varices remain a challenge. Management
drainage to begin with, there should be no attempt to options including serial endoscopic variceal ligation via
repeat the procedure. If there has been long-term effec- sclerotherapy or banding and portosystemic shunts are
tive drainage that has abruptly stopped, suggesting local considered in select cases.119 Splenectomy is not typically
cicatrix formation, an experienced surgeon may attempt considered an effective treatment option for portal
to remove the scar and reestablish bile flow. However, hypertension.72,120-122
repeated attempts to redo portoenterostomies in hopeless Most older children with biliary atresia will experience
situations should be avoided because the repeated surger- progressive cirrhosis because it is not a failure of surgery
ies can make transplantation much more difficult. that brings the patient to transplant after 5 to 10 years.
In the evolution of the portoenterostomy a number of Good medical management and prudent surgery can be
variants have been introduced with the purported advan- used to overcome the complications of cirrhosis and
tage of reducing the frequency of ascending cholangitis. extend life without transplantation in some cases. How-
Unfortunately, no data have emerged supporting their ever, the development of end-stage liver disease should
use, and ascending cholangitis remains an important factor be considered as an indication to proceed with
in the long-term survival of patients who have undergone transplantation.72,120
successful portoenterostomy procedures.115,116 Intestinal Chronic intrahepatic cholestasis syndromes represent
complications after transplantation are more common in a complex group of disorders in which liver transplanta-
patients with complex bowel surgery. Both long loops and tion has a variable role because symptoms are usually
externalization of bile drainage interfere with nutrition severe, but the diseases often are not life threatening.
before transplantation, and long loops are associated with Patients with progressive familial intrahepatic cholestasis
posttransplant malabsorption.117 Exteriorization of enter- (e.g., gene defects in FIC-1 and BSEP [bile salt export
ostomy loops is associated with bleeding from the stoma pump]) develop cirrhosis early in life,123-125 but there are
and infection at the time of transplantation. Therefore the effective alternative therapies available that have much
 24 General Criteria for Transplantation in Children 277

lower risk than transplantation.126-128 However, once cir- children with hepatitis A, certain hepatotoxicity (partic-
rhosis has developed, there is little reason to avoid trans- ularly when caused by acetaminophen poisoning), and
plantation because these patients will progress to severe autoimmune hepatitis may make a complete
end-stage disease. It is better to perform transplantation recovery with medical therapy. Thus careful monitoring
early and improve the quality of life. for poor prognostic factors is required before selection.
Patients with Alagille syndrome, another chronic Degree of encephalopathy is the best predictor of out-
intrahepatic cholestasis syndrome, may have debilitating come for children with ALF; children with peak encepha-
pruritus and hypercholesterolemia with xanthomatosis lopathy of stage II or III have a 6-month posttransplant
but infrequently develop end-stage liver disease.71 The survival rate of over 75%, compared to only 48% for
issue arises as to whether liver transplantation should be those with Stage IV.136 Rigorous assessment for hepatic
used to treat symptoms only, its risks weighed only encephalopathy should be incorporated into the manage-
against the degree of incapacitation from symptoms, ment algorithm for patients with severe acute liver injury.
which can in some cases result in social invalidism. Alter- Our center’s experience is that abnormalities on continu-
nate forms of therapy, including administration of urso- ous digital electroencephalographic assessment, includ-
deoxycholic acid and partial cutaneous biliary ing slowing and epileptiform discharges, are an early
diversion,13,126 may provide relief from pruritus in some indicator of neurological deterioration. Neuroimaging
patients. Many of the complications can be treated by may also play a role in predicting prognosis, but imaging
specific administration of vitamins and other nutrients. is frequently normal until late in the course of neurologi-
However, in some instances the cholestasis is refractory cal injury. The development of cerebral edema on imag-
to all therapy, and liver transplantation should be consid- ing is associated with a grave prognosis.
ered.129 Review of the SPLIT database reveals that com- Children with ALF require an aggressive, empirical
mon indications for liver transplantation in Alagille approach to management. It is appropriate to list for
syndrome include refractory pruritus, bone fractures, dis- emergency liver transplantation all children who have
figuring xanthomas, signs of end-stage liver disease, and reached stage III hepatic coma, and liver transplantation
severe growth failure. Growth failure as an indication for should be performed as soon as a donor is available.14,137
transplant in Alagille syndrome merits further comment. A patient showing signs of stabilization (lack of progres-
Poor growth is likely a result of chronic malnutrition and sive deterioration) or evidence of recovering function
alterations in the growth hormone axis and is seen in 50% (improved coagulation parameters) while awaiting graft
to 90% of children with Alagille syndrome. This failure availability has an outlook for spontaneous recovery that
to thrive is characterized by low muscle and bone mass in is comparable with liver transplantation, so the decision
addition to poor linear growth and weight gain. Liver to transplant is reversed. However, most children with
transplantation can improve growth velocity, with longi- ALF have a rapid downhill course and require maximum
tudinal studies demonstrating improvement in mean medical therapy until a donor becomes available.
height, weight, and z-scores.129 For the occasional Ala- Survival after liver transplantation performed for
gille patient with cirrhosis, transplantation should also be ALF is somewhat reduced when compared to general
considered, even before decompensation of function, transplantation survival rates in children.* The causes
because these patients are usually refractory to other of decreased survival are not entirely known. The
management measures. However, following liver trans- development of irreversible brain damage is a major
plantation, renal, vascular, and neurological complica- cause of reduced survival,139 and it is essential to be cer-
tions are noted at a higher rate compared to children with tain that brain damage has not occurred before the
biliary atresia, reflecting the multisystem nature of Ala- operation. Current assessment techniques remain sub-
gille syndrome.129-134 optimal but include monitoring intracranial pressure,
identifying cerebral infarction or intracranial hemor-
rhage by cerebral computed tomography or magnetic
Acute Liver Failure resonance imaging, and looking for evidence of mid-
Liver transplantation holds the greatest lifesaving poten- brain coning, such as fixed, dilated pupils. Children
tial for children with ALF, but the decision to use it in with ALF can develop hepatic coma, and irreversible
this situation is complex.14,135 Determining the cause of brain damage would be a contraindication to perform-
hepatic failure is an important factor in determining ing transplantation.
whether transplantation is appropriate. Analysis of data The shortage of donors also affects survival because
collected by the National Institutes of Health–sponsored the limited availability of deceased donor organs remains
multicenter collaborative Pediatric Acute Liver Failure a major factor in poor outcome. Not only do children die
Study Group revealed two peak incidences of ALF, with without transplantation, but less-than-ideal donor organs
the first peak occurring in infancy and the second peak are often accepted because of the urgency of the situa-
observed between 13 and 16 years of age.18 The highest tion. Living donor and split-liver transplants are viable
mortality is seen in children with indeterminate hepati- transplant options with comparable outcomes.140-142 The
tis, acute Wilson's disease, some hepatotoxicity such as use of auxiliary liver transplants and hepatocyte trans-
mushroom poisoning, and some idiosyncratic drug- plantation shows promise and may be useful as a support
induced hepatitis. Patients with these disorders who measure, with some patients recovering without the need
present with a rapid onset and progression to stage III or for full liver replacement.143,144
IV hepatic encephalopathy and coagulopathy should be
considered for immediate transplantation. In contrast, *References 14, 16, 70, 136, 138.
278 PART III Patient Evaluation: Pediatric

in patients presenting with acute or chronic tyrosin-

Metabolic Liver Disease emia. However, many patients will have chronic liver
α1-Antitrypsin deficiency is the most common inborn disease such as postnecrotic cirrhosis due to toxic injury
error of metabolism that results in the need for liver suffered before instituting therapy.153 Untreated
transplantation.145 The liver phenotype is highly variable, patients have an extremely high risk for hepatic malig-
and most individuals have no liver disease. Approximately nancy.58,59,154 The current approach is to treat these
10% will have neonatal cholestasis, which usually resolves patients with NTBC and a low-tyrosine diet. If the
after a few months, while a small proportion of these patient cannot be completely stabilized by medical
patients will develop macronodular cirrhosis before 20 means, transplantation must be performed. If the patient
years of age. Rarely, the disease causes rapidly progressive responds to therapy, transplantation can be delayed
cirrhosis and liver failure in infancy and is associated with while monitoring the clinical course and serum
an increased incidence of hepatocellular carcinoma in α-fetoprotein levels. Failure to maintain normal levels
children and adults.146 Although newer therapies target- indicates incomplete metabolic control or irreversible
ing cellular accumulation of the defective peptides show genetic changes in the liver,155 either of which predicts
promise,147 there is currently no medical therapy that a high risk for developing hepatocellular carcinoma. In
effectively prevents the progression of liver disease. Liver these cases, liver transplantation should be performed
transplantation has a role only in the patient with hepatic by 2 to 3 years of age because of the risk for malignancy.
insufficiency or early malignancy and cannot be justified Liver transplantation reverses the clinical syndrome,
for the treatment or prevention of lung or kidney dis- but some patients continue to excrete succinylacetone
ease.148,149 It should be considered for the infant with into the urine, indicating that a renal tubular defect
progressive liver failure. Patients with neonatal cholesta- remains.156,157
sis that resolves should simply be observed for the onset Maple syrup urine disease (MSUD) is an autosomal
of cirrhosis with yearly physical and biochemical evalua- recessive disorder caused by the deficiency of branched-
tions. If cirrhosis develops, the patient will probably chain α-keto acid dehydrogenase activity. It results in the
develop hepatic insufficiency, but usually after several accumulation of the branched-chain amino acids valine,
years. All older patients with cirrhosis should have regu- leucine, and isoleucine, which can lead to severe neuro-
lar screening for hepatocellular carcinoma. Liver trans- logical disability. Therapy is directed at strict dietary
plantation should be performed only when needed for control of protein intake, but despite progress in nutri-
liver failure or malignancy. Transplantation results in the tional and medical management, neurological sequelae
recipient assuming the α1-antitrypsin phenotype of the such as developmental delay and neurocognitive deficits
donor but cannot be justified to simply correct the meta- still occur. Liver transplantation provides an effective
bolic error. long-term treatment option that can stabilize and prevent
Liver transplantation plays a significant role in the ongoing neurological damage but does not reverse exist-
management of specific urea cycle defects, such as ing impairments.158-160
OTC deficiency. Medical management primarily con- One fascinating consequence of liver transplantation
sists of protein-restricted diets and medications in MSUD is the opportunity for domino liver trans-
designed to prevent hyperammonemic coma and subse- plantation, an innovative strategy in which certain
quent neurological damage.150,151 Given the close mon- transplant recipients can donate their explanted native
itoring necessary, as well as the effect on quality of life, livers for use as a liver allograft in other patients. Dom-
liver transplantation is an accepted therapy. More ino liver transplantation has been successfully reported
recently, isolated hepatocyte transplantation has been in select metabolic diseases, including familial hyper-
reported as an effective therapy for OTC deficiency cholesterolemia, familial amyloid polyneuropathy, and
and other metabolic inborn errors of metabolism, MSUD. Although there are no long-term follow-up
including glycogen storage disease type Ia, Crigler- studies of MSUD domino graft recipients, initial reports
Najjar syndrome, and tyrosinemia.6,152 As our under- indicate that these recipients are asymptomatic with
standing of this therapy continues to improve, none to mild impairment of branched-chain amino acid
hepatocyte transplantation may be considered when metabolism.161-164
liver transplantation is not indicated or to serve as a Liver transplantation may not be indicated in the
bridge to liver transplantation. management of liver structure. Congenital hepatic
Tyrosinemia results from deficient fumarylacetoace- fibrosis is such a condition.165,166 In this disease there is
tate hydrolase activity in several tissues. Sometimes the dense fibrous scarring of the portal triads. Patients who
defect results in rapidly progressive liver disease or ALF have severe portal hypertension with hypersplenism
in infancy, with subsequent need for emergency liver and portosystemic collaterals may have little if any
transplantation. Rapid diagnosis by measurement of uri- parenchymal dysfunction. In contrast to the patient
nary succinylacetone is important because medical ther- with cirrhosis, other measures such as endoscopic
apy can prevent progression of disease to liver failure. sclerotherapy of varices and portosystemic shunts (e.g.,
Administration of an inhibitor of tyrosine catabolism, distal splenorenal shunt) should be used to treat these
2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexane- patients. Rarely, these patients have hepatic insuffi-
dione (NTBC), disrupts the metabolic pathway before ciency, in which case liver transplantation is indicated.
the production of toxic substances.61 NTBC therapy Because they also have associated cystic disease of
is effective if instituted before the onset of disease (in the kidney, combined liver-kidney transplant can be
siblings of affected patients diagnosed prenatally) and considered.
 24 General Criteria for Transplantation in Children 279

REFERRAL TO A TRANSPLANT CENTER disease or in the early stages of progressive liver disease,
when the prognosis without transplantation is excellent.
The best time for referral is as soon as the patient is iden- Although patients with end-stage disease sometimes
tified as having a condition that will require transplanta- undergo transplantation without a specific diagnosis, the
tion. Examples of who should be referred are infants with team should make every effort to confirm the diagnosis.
biliary atresia who remain jaundiced after portoenteros- Reasons for doing so include avoiding transplantation for
tomy, all children with acute hepatic failure, and patients disorders that will recur or when it is not indicated, and
with cirrhosis for any reason. An individual may not need providing appropriate genetic counseling to the family.
transplantation immediately, but it is in most patients' In addition, better alternative therapies can be found for
best interest not to wait until the complications of many patients. Primary or secondary disease of other
advanced liver disease have been encountered before organ systems should result in consultation with other
referring them to a transplant center. specialists.
Early referral allows the transplant center to have The transplant surgeon should be involved in evaluat-
maximal input into the management strategy. Transplant ing the patient for surgery, as well as participating in the
centers have extensive experience with children with general evaluation and becoming familiar to the child and
advanced liver disease and can help the referring physi- family. The most important anatomical variables to be
cian in the management of complications before trans- evaluated are the portal vein and other intra-abdominal
plantation, improving diagnosis, and suggesting vasculature and in the case of a patient with biliary atresia,
alternative therapies. In addition, a close working rela- the type of portoenterostomy performed. Advance
tionship between the transplant center and the family/ knowledge of the anatomy is essential for proper plan-
referring physician can develop before the procedure ning. Thorough preoperative evaluation of the vascular
takes place, which leads to improved ability to coordinate anatomy of the abdomen is required to plan the operative
postoperative care. approach. Some children with biliary atresia have associ-
ated congenital absence or thrombosis of the portal vein,
hypoplastic portal veins, or other major vascular anoma-
EVALUATING THE PEDIATRIC lies. Children may also have variants of the Kasai porto-
TRANSPLANT CANDIDATE enterostomy that involve long biliary limbs of the
Roux-en-Y or the creation of cutaneous stomas, and
The Centers for Medicare and Medicaid Services have advance knowledge of this anatomy is needed to plan the
specific requirements for approval of liver transplant pro- approach to choledochoenterostomy. Long limbs may
grams, which include applicable laws, regulations, and need to be returned to the intestinal mainstream to avoid
compliance information. All pediatric liver transplant postoperative malabsorption. Cutaneous stomas should
programs should meet these criteria, and pretransplant be taken down before transplantation to avoid postopera-
evaluation should be performed at a certified program. tive infections, improve growth, and avoid hemorrhage
The basic pretransplant evaluation involves the elements from stomal varices.
presented in Table 24-2. This evaluation can be per- Transplantation should be delayed until the point at
formed in approximately half a day in an outpatient set- which the likelihood of short-term survival is less than
ting, except in unusual or complex cases. A routine should that expected with transplantation, but it should occur
be established, and a checklist created for each patient before the opportunity for maximal posttransplant sur-
evaluated. A multidisciplinary approach is preferred vival and outcome has been lost. The level of illness at the
because it provides maximum input and balance to the time of transplantation directly influences posttransplant
evaluation. survival. Patients requiring intensive care, especially
Confirming the diagnosis and determining the urgency those requiring mechanical ventilation or dialysis, have a
for transplantation are essential in the effort to avoid per- significantly diminished 1-year survival. Likewise,
forming transplantation in a child with benign liver patients who develop multiple medical complications
before transplantation may sustain injury to other organ
systems that may have long-term health implica-
TABLE 24-2 B
 asics of the Pretransplant tions.167-169 Therefore quantifying illness at the time of
Evaluation transplant referral is invaluable in planning the appropri-
ate timing of transplantation.
• Confirm the diagnosis and need for transplantation. Liver allocation is a complex process that currently
• Determine the urgency for transplantation. uses a numerical system to calculate mortality risk, which
• Look for possible contraindications to transplantation. is used to stage chronic liver disease in children to allo-
• Look for processes that might present a problem after cate livers to the sickest patients. The PELD score was
transplantation. developed in 2002 to prioritize patients for transplanta-
• Establishing a relationship with parents and primary care tion.170 This system stages liver disease based on 3-month
providers.
waiting list mortality risk in children who have been
• Arrange for finances.
accepted as transplant candidates.171,172 Mathematical
• Arrange a mechanism for contacting parents and
providing transport. modeling was used to identify and weigh the effect of
• Establish a plan for interim management. readily available clinical variables on 3-month survival.
• Meet members of the interdisciplinary care team. These variables were chosen from existing data submitted
through the SPLIT project. The model was developed to
280 PART III Patient Evaluation: Pediatric

predict two possible end points—requirement for inten- score, the total number of liver transplants performed
sive care support and death—and has been validated as a annually in children has remain constant around 600,
tool to predict the probability of waiting list mortality in and the number of new children on the waiting list has
children with chronic liver disease.170,173,174 The result- also remained fairly constant with between 670 to 770
ing model for liver allocation to children was adopted by active children added annually. However, the overall
the United Network for Organ Sharing (UNOS): number of transplants per 100 waiting-list years is
increasing, specifically for status 1 patients, with a con-
PELD Score = (0.4336 [age]) − 0.687 loge [albumin g/dL] current decrease in mortality.175,176 These results might
+ 0.480 loge [total bilirubin mg/dL] + 1.857 suggest that despite long waiting list times, children—
loge [INR] + 0.667 [growth failure] especially infants and children under 5 years old—are
receiving adequate priority with the PELD scoring sys-
where age < 1 year, score = 1; age > 1 year, score = 0; tem. However, review of UNOS data demonstrates that
growth failure: 2 standard deviations below the mean for only two thirds of children had received a liver trans-
age, score = 1; ≤2 standard deviations below the mean for plantation at 36 months following initial listing. Of the
age, score = 0. INR, International normalized ratio. remainder, 7.5% of children were still awaiting trans-
The PELD score is used for children younger than 12 plant, 12.5% had died awaiting transplant, and 12.8%
years old, and the Model for End-Stage Liver Disease were removed from the list. In addition, the PELD
(MELD) score is used for children 12 years and older. score does not accurately predict pretransplant and
However, many children develop complications that posttransplant mortality.175
increase their mortality risk that are not captured by the Pretransplant mortality rates for pediatric liver trans-
scoring system. Examples include gastrointestinal bleed- plantation have improved slightly over time but remain
ing refractory to medical intervention, hepatopulmonary high, with an overall mortality rate of 8.2 deaths per 100
syndrome, recurring cholangitis, and hepatic malignan- waiting-list years in 2012 as compared to 9.9 deaths per
cies. Patients who develop such complications may be 100 waiting-list years in 2008 (Fig. 24-1). Waiting-list
granted additional priority on the waiting list by determi- mortality is highest for children under 6 years of age.175
nation of regional review boards. Such applications for Multivariate analyses of pretransplant factors affecting
review sidestep the philosophy of the allocation system, outcomes of liver transplantation indicate that intensive
which is to be objective and standardized, but may be care stay or ventilator requirement at the time of trans-
necessary to avoid waiting list mortality for individual plantation carries the highest relative risk for death or
patients. In addition, pediatric transplant candidates have graft loss. It would follow that providing transplantation
priority in receiving livers from pediatric donors (<18 before patients become critically ill would reduce both
years old), and although the same PELD and MELD pretransplant and posttransplant mortality. Other factors
score indicates a greater mortality risk for adults, this that contribute to increased posttransplant mortality
score is not adjusted and therefore benefits children.169 include the use of technical variant grafts and intraopera-
With the ongoing challenge of donor-organ short- tive blood loss. The most significant posttransplant fac-
age, children are spending longer periods of time on the tors for patient mortality and graft loss are posttransplant
waiting list. Since the implementation of the PELD surgical complications and reoperations.177

PRETRANSPLANT WAITING LIST MORTALITY RATE

20.0

18.0
Deaths per 100 Waiting List Years

16.0

14.0

12.0

10.0

8.0

6.0

4.0

2.0

0.0
2002 2004 2008 2012
Year
<6 years 6-10 years 11-17 years Overall
FIGURE 24-1 n Pretransplant waiting list mortality rate. (Data from United Network for Organ Sharing Annual Report, 2011.)
 24 General Criteria for Transplantation in Children 281

The current system is clearly an imperfect solution to

a serious problem because most children on the trans- ISSUES UNIQUE TO PEDIATRIC LIVER
plant waiting list have relatively low PELD scores. The TRANSPLANTATION
pretransplant mortality rate remains unacceptably
high,168,175 and the PELD score is an unreliable indicator Nutritional Consequences of Chronic Liver
of posttransplant events. Similar challenges exist with the Disease and Their Effect on
MELD scoring system, which is also a poor predictor of
posttransplant survival.178 Thus planning for liver trans-
Transplantation
plantation should include when a patient may have access Children with chronic liver disease almost invariably
to a living donor or split-liver graft. All aspects must be develop evidence of malnutrition—which is important to
considered and weighed before proceeding with trans- patient well-being—during the course of illness, and there
plantation, especially in cases of a low PELD or MELD is limited understanding of the basis of liver-related nutri-
score. Overall, ongoing development is necessary to tional disturbances. It is commonly believed that malab-
address these issues. sorption is the major cause of malnutrition in these
Growth is an important feature of childhood that patients. Assessment of malnutrition can be difficult in
reflects the functional status of the liver. A child with chronic liver disease because ascites, peripheral edema, and
growth failure secondary to liver disease cannot improve organomegaly confound the interpretation of anthropo-
as a transplant candidate, and growth failure is included metric measures. Midarm circumference and triceps skin-
in the current PELD allocation scheme. The inability fold are the most accurate measures of malnutrition.184
of the liver to support a child's growth and nutritional Most infants with cholestatic liver disease have malab-
status is as good a measure as any for the need to pro- sorption of fats and fat-soluble vitamins because of disrup-
ceed with transplantation. When it becomes evident tion of bile flow into the intestine. Fat-soluble vitamin
that no further growth is possible despite maximal deficiencies can lead to a range of complications, including
nutritional support, transplantation should be per- rickets, fractures, coagulopathy, and visual impairments.
formed as soon as possible. Catch-up growth following Oral supplementation is usually delivered in the form of a
liver transplantation is influenced by the age at trans- liquid preparation that contains multiple fat-soluble vita-
plantation, overall liver function pretransplantation mins. Although these combination supplementations are
and posttransplantation, pretransplantation growth safe, studies in children with biliary atresia suggest that
retardation, and steroid use. Corticosteroids are known fat-soluble vitamin deficiencies still exist despite these
to affect multiple growth parameters, including general combination supplements and that individual fat-soluble
anthropometrics as well as osteoporosis; therefore vitamin supplementation should be considered.185,186
medication use before transplantation should also be Clinical malnutrition remains a significant problem
considered. Certain childhood liver diseases such as that becomes evident only when the liver disease has
autoimmune hepatitis and biliary atresia may initially progressed to a more advanced stage. For example,
be treated with corticosteroids. In biliary atresia, ste- patients with biliary atresia often demonstrate normal
roids may be initiated following a portoenterostomy, rates of growth for up to 6 months with support pro-
which has been reported to be associated with a shorter vided by enteral diets and supplemental fat-soluble vita-
postoperative length of stay. However, the effect of ste- mins. Once clinical malnutrition is evident, it may be
roid use on delaying liver transplantation remains to be difficult to determine whether the cause of malnutrition
determined.72,179-181 is from inadequate caloric intake due to loss of appetite,
The candidate must also be evaluated with regard to caloric restriction resulting from ascites, or advancing
the potential for developing infections after transplanta- liver synthetic dysfunction in the face of adequate
tion. Serological CMV status determines the risk for caloric intake. Recent studies suggest a potential role of
serious infection after transplantation. EBV is also parenteral nutrition in improving the nutritional status
important because of its association with posttransplant of malnourished children with biliary atresia. Specifi-
lymphoproliferative disease, and EBV-naive patients cally, use of parenteral nutrition improved triceps skin-
seem to be at much higher risk.182,183 Varicella serologi- fold thickness and midarm circumference z scores in
cal status should be known so that proper care can be patients awaiting liver transplantation. In addition, use
provided in case of exposure. Potential recipients should of parenteral nutrition was not associated with any dif-
be provided immunizations before transplantation if at ference in graft survival, rates of pretransplantation
all possible. These should include rubella, rubeola, bacteremia, or posttransplantation days in the intensive
mumps, HBV, hepatitis A virus, polio, varicella, diph- care unit.184
theria and tetanus toxoids and pertussis (DTP), Hae- However, the nutrition status of some patients will not
mophilus influenzae type b, and Streptococcus pneumoniae improve despite initiation of parenteral nutrition. This
vaccines. suggests that erosion of parenchymal function is the criti-
Psychosocial assessment is also an essential aspect of cal phenomenon leading to disturbed nutrition. Simi-
the evaluation. Dedicated social workers provide impor- larly, wasting is characteristic of parenchymal liver disease
tant insight into the family's resources and resourceful- as seen in neonatal hepatitis. The transplant center should
ness and can identify problems that deserve focused input. do the following:
Travel arrangements and accommodations for the family • Routinely monitor the nutritional state of potential
at the time of transplant should be established with the candidates by performing regular anthropometric
help of the center staff. examinations
282 PART III Patient Evaluation: Pediatric

• Provide advice and support to the primary physi- donors larger than that. No formula can be used to deter-
cian with regard to nutritional support mine the volume of the hepatic fossa from the recipient's
Despite every effort, the majority of infants are size and weight. Left lateral lobe grafts are generally used
severely malnourished at the time of transplantation. when the donor-to-recipient weight ratio exceeds 4 and
Therefore restoration of nutrition is a focus for medical the left lobe graft is used when the ratio is between 2 and
postoperative care in most infants with biliary atresia. 4. Right lobe grafts have been used in teenagers as in
adult-to-adult procedures.
Surgical Innovations Affecting Pediatric There are several clear advantages to living donor liver
transplantation for infants and young children.195,196
Liver Transplantation First, the earlier and more elective transplantation of
Organ size is of utmost importance in pediatric trans- small infants provides a major advantage in that these
plantation. The majority of children reach end-stage dis- children are not malnourished and have not encountered
ease before 2 years of age, whereas relatively few do so major complications of liver disease at the time of trans-
between the ages of 2 and 10 years. There is a second plantation.197,198 The quality of the graft is uniformly
mortality peak after age 10 that extends into adult- outstanding. Although the overall frequency of allograft
hood.187,188 The pattern of mortality from liver disease is rejection and graft survival is similar to that of recipients
in contrast to the epidemiological factors of accidents, of deceased donor allografts, the frequency of rejection
which involve mainly preschool and school-age children. episodes 1 year after transplant and severity of rejection is
Consequently, most pediatric liver donors are too large less.15,199
for the typical pediatric recipient, creating a donor-to-
recipient mismatch that causes excessively long waiting
times and high pretransplant mortality among small chil- LIVER TRANSPLANTATION
dren. To overcome the inadequacy of donors for young IN NEONATES
children, techniques for using larger donors were devel-
oped. Technical variant allograft surgery is discussed in Infants younger than 3 months of age, defined as neo-
detail in Chapters 48 and 52. Developed in the late 1980s nates, present unique medical and technical challenges in
and early 1990s, this surgery is now used in all major transplantation.200-207 Their small size coupled with their
pediatric transplant centers. extremely critical condition at presentation results in
Reduced-size liver transplantation is the technique by high rates of operative and postoperative complications,
which a donor liver is reduced to provide a hepatic leading to reduced survival of those who undergo trans-
allograft for a recipient who is smaller than the donor.189 plantation. Liver transplantation of neonates is uncom-
It was the most common approach to pediatric transplan- mon, with 8 to 14 cases performed nationally per year out
tation for several years, until the shortage of deceased of approximately 600 pediatric liver transplants. Data
donors became critical. The techniques of technical vari- from SPLIT suggest that patient and graft survival is
ant allograft transplantation were further expanded to similar to that in older cohorts of liver transplant
split-liver transplantation and transplantation using liv- recipients.206
ing related donors.190,191 Split-liver transplantation is a All neonatal liver transplants are performed for ALF.
technique in which a donor liver is divided to provide The most commonly reported indications are idiopathic
grafts for two recipients. Despite its complexity, use of or neonatal giant cell hepatitis and neonatal hemochro-
split-liver transplantation is expanding because it offers matosis (NH), which account for more than half of liver
an effective way to increase the donor pool and reduce transplants in this age-group. Giant cell hepatitis can be
pediatric waiting list mortality.192,193 Living donor liver used to classify cases of neonatal liver failure of unknown
transplantation, where a healthy donor undergoes partial etiology, most likely due to an unidentified inborn error
hepatectomy for the purpose of providing a graft for of metabolism, or intrauterine or postnatal infection. It is
transplantation was developed for application in young a nonspecific response to hepatocellular injury character-
children. Although there is a higher possibility of vascular ized by multinucleated giant syncytial cells. Most cases of
complications, it remains an important option that reduces giant cell hepatitis do not produce ALF. Additional indi-
waiting list mortality and is associated with a high survival cations for transplantation in neonates include HBV,
ratio.194,195 Yet, despite these technical improvements, echovirus or other enterovirus infection, and hepatic
living donors accounted for only 9% of total pediatric hemangioendotheliomatosis.200,201,206,207
liver transplants in 2009, down from 20% in 2000.175 Neonatal hemochromatosis is the most frequently rec-
In pediatric transplantation it is necessary to compute ognized cause of ALF in newborns. NH is characterized
the size of the graft needed and therefore select the resec- by fetal liver injury accompanied by siderosis of extrahe-
tion required for the creation of an appropriate-sized patic tissues. Gestational alloimmune disease is the cause
graft. The crux of the issue is matching the graft to the of most cases of NH, and improvements in the under-
size of the space where it is to reside, and this must be standing of this mechanism of disease can help guide
done by visual inspection of the donor organ and the medical therapy. Current management includes high-
recipient's hepatic fossa. The anatomy of the liver is not dose intravenous immunoglobulin and plasmapheresis or
uniform; some donors will have relatively large or small double-volume exchange transfusion. Plasmapheresis
livers, and some livers will have relatively large or small aims to remove antibodies that may cause alloimmune-
lobes. Grafts can routinely be obtained from a donor up mediated liver injury in gestational alloimmune disease.
to 10 times the weight of the recipient and at times from Experience at our institution with this directed immune
 24 General Criteria for Transplantation in Children 283

therapy suggests that full recovery from liver injury is systematically studied, but review of data from SPLIT
likely with no residual clinical liver disease at 1-year fol- suggests that they are similar to those of older chil-
low-up. Unsuccessful medical management typically is dren.206 As additional longitudinal data become avail-
due to multiorgan failure, intercurrent infection, or intra- able, there is a clear need for careful outcomes analysis
cranial hemorrhage.208-213 to determine the value of neonatal liver transplantation
In select cases where liver failure is not quickly improv- and to identify areas in which improvements can be
ing, liver transplantation may be considered but should made.
be used with caution. Challenges with transplantation in
newborns with NH include prematurity, small size for
gestational age, and multisystem organ failure. Overall Pearls and Pitfalls
survival of infants with NH following transplantation is
around 35%.211 Management goals of NH are directed at • Delaying transplantation in patients with metabolic dis-
supportive care to avoid liver transplantation if at all eases that cause elevated ammonia levels (e.g., ornithine
possible.211,213 transcarbamylase deficiency) risks irreversible neuro-
The special considerations of neonatal transplantation logical injury. Patients with intact neurological function
relate to the specific physiological characteristics of the should receive a transplant before significant crises occur.
neonate in liver failure and the small size of neonates. A • Systemic diseases such as Langerhans cell histiocytosis or
malignant disease should be treated primarily (i.e., with
neonate in ALF is in a tenuous medical condition. chemotherapy) before liver transplantation.
Impaired respiratory function, severe coagulopathy, mal- • The most important contraindication to liver transplan-
nutrition, and ascites frequently complicate the picture in tation is effective alternative therapy.
these patients. Depressed cardiac and renal function are • Example 1: Biliary atresia with good synthetic function
also common, and patients frequently require hemodialy- but portal hypertension may respond to distal spleno-
sis or hemofiltration, both of which are difficult to per- renal shunt.
form in very small patients. • Example 2: Progressive familial intrahepatic cholestasis
The small size of these patients makes graft selection or Alagille syndrome may respond to biliary diversion
difficult and uniquely important. The typical body weight before requiring liver transplantation.
of neonatal recipients ranges from 3.5 to 4.5 kg. Full- • Systemic infections are usually contraindications for liver
transplantation, except in cases such as recalcitrant chol-
sized grafts from donors weighing less than 6 kg are asso- angitis and spontaneous bacterial peritonitis, which may
ciated with high rates of graft failure. Therefore all require aggressive medical therapy and liver transplanta-
neonatal liver transplants are performed with technical tion for resolution.
variant grafts, from either deceased or living donors. The • Growth failure in patients with biliary atresia can be an
use of oversized allografts should be avoided because it early and important indicator of liver synthetic insuffi-
commonly results in delayed abdominal closure and ciency.
increased intra-abdominal pressure with subsequent • One of the strongest predictors of outcome in children
impairment of respiratory function and decreased graft with acute liver failure is the cause of the liver injury.
perfusion. The effect of these complications should not • Progression to stage III encephalopathy in a patient with
be underestimated; an oversized graft often triggers a fulminant hepatic failure is an indication for emergency
liver transplantation.
series of events that ultimately leads to graft failure and • Early referral to a transplant center allows a transplant
patient mortality. hepatologist to assess and modify risk factors for morbid-
Other challenges in neonatal liver transplantation are ity and mortality in patients who will ultimately require
that technical variant grafts have a higher risk for both    liver transplantation.

primary nonfunction and poor early function. It is also

associated with an increased risk for postoperative bleed-
ing and bile leak. The incidence of vascular thrombosis is
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72. Balistreri WF, Bezerra JA, Ryckman FC. Biliary atresia and other 99. Van Thiel DH, et al. Liver transplantation after an acute episode
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286 PART III Patient Evaluation: Pediatric

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123. Whitington PF, et al. Clinical and biochemical findings in pro- treatment of urea cycle disorders: a review of the worldwide Eng-
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135. Squires RH, Alonso EM. Acute Liver Failure in Children. In: niques, and outcomes. Transplant Rev (Orlando). 2011;25(4):
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Cambridge: Cambridge University Press; 2007:71-98. 162. Popescu I, Dima SO. Domino liver transplantation: how far can
136. Baliga P, et al. Posttransplant survival in pediatric fulminant we push the paradigm? Liver Transpl. 2012;18(1):22-28.
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137. Emond JC, et al. Liver transplantation in the management of ful- 164. Khanna A, et al. Domino liver transplantation in maple syrup
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165. Rogers J, et al. Results of simultaneous and sequential pediatric 189. Broelsch CE, et al. Liver transplantation with reduced-size donor
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8(9):851-858. 199. Toyoki Y, et al. Allograft rejection in pediatric liver transplanta-
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175. Organ Procurement and Transplantation Network (OPTN) and Scien- 200. Woodle ES, et al. Liver transplantation in the first three months
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176. Davies DB. The impact of PELD on OPTN liver allocation: pre- 202. Noujaim HM, et al. Techniques for and outcome of liver trans-
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 CHAPTER 25

Transplantation for Cholestatic

Liver Disease in Children
Samar H. Ibrahim • Jorge A. Bezerra • William F. Balistreri

CHAPTER OUTLINE

DIFFERENTIAL DIAGNOSIS North American Indian Cholestasis

SPECIFIC CLINICAL CONDITIONS Fatal Familial Cholestasis Syndrome in
Greenland Eskimo Children
Neonatal Cholestasis
Benign Recurrent Intrahepatic Cholestasis
Alagille Syndrome
Hereditary Cholestasis with Lymphedema
Progressive Familial Intrahepatic Cholestasis (Aagenaes Syndrome)
Progressive Familial Intrahepatic Cholestasis, Inborn Errors of Bile Acid Biosynthesis
Type 1 (Byler’s Disease)
Infectious Hepatitis
Progressive Familial Intrahepatic Cholestasis,
Type 2 Total Parenteral Nutrition–Associated
Cholestasis
Progressive Familial Intrahepatic Cholestasis,
Type 3 CONCLUSIONS

Cholestasis, a potentially serious condition that indicates conditions that directly or indirectly affect the liver and
hepatobiliary dysfunction, is defined as a serum conju- biliary tract; however, no identifiable cause is detected in
gated bilirubin fraction greater than 1.0 mg/dL if the total up to 15% of cases of neonatal cholestasis. Biliary atresia
serum bilirubin level is less than 5 mg/dL, or a value of is the most common cause of neonatal cholestasis,
conjugated bilirubin more than 20% of the total bilirubin accounting for up to 25% of the cases; genetic forms of
if the total bilirubin level is 5 mg/dL or higher,1 or ele- intrahepatic cholestasis account for 25%, α1-antitrypsin
vated total serum bile acid level. Cholestasis is a relatively deficiency accounts for 10%, other metabolic diseases
common pediatric disorder, especially in neonates, affect- account for 20%, and viral infections account for 5% of
ing approximately 1 in every 2,500 live births.2 Disorders neonatal cholestasis.3 Table 25-1 lists the recognizable
associated with cholestasis are diverse, although the clini- disease entities associated with cholestasis and elevated
cal presentation is similar, reflecting a common underly- liver enzyme levels.6 In view of the extensive differential
ing defect in bile flow or formation. Patients with diagnoses, the evaluation of the infant with cholestasis
cholestasis frequently progress to end-stage liver disease, should be undertaken in a stepwise fashion. The goal is
often despite initial palliative treatment. The outcome of prompt identification of treatable disorders such as sepsis,
pediatric patients with cholestasis has improved dramati- endocrinopathies (including panhypopituitarism and
cally with progress in understanding the pathogenesis of congenital hypothyroidism), and specific metabolic dis-
cholestasis and the development of therapy targeted to orders (such as galactosemia, tyrosinemia type I, and
the molecular defect.3 Another important factor is the inborn errors of bile acid metabolism) to allow initiation
broader application of liver transplantation, with the use of appropriate treatment and to prevent progression of
of segmental liver transplantation4 and new immunosup- liver damage. Cholestasis associated with severe hepatic
pressive regimens.5 In this chapter we review the clinical synthetic dysfunction points to life-threatening meta-
aspects of different forms of diseases associated with pro- bolic disorders, such as tyrosinemia type 1 or neonatal
longed cholestasis in the pediatric patient and the impact iron storage disease. In infants without evidence of
of liver transplantation. infection and with normal synthetic function, early eval-
uation of the patency of the biliary system is a high priority
to recognize biliary atresia.7 Portoenterostomy per-
DIFFERENTIAL DIAGNOSIS formed before 2 months of age improves the outcome of
patients with biliary atresia.1,4,8 In the past, neonatal cho-
Cholestasis in the pediatric patient can be associated lestasis was separated into extrahepatic and intrahepatic
with infectious, toxic, anatomical, metabolic, or genetic forms—this is too simplistic. For example, biliary atresia

288
 25 Transplantation for Cholestatic Liver Disease in Children 289

mainly affects the extrahepatic bile ducts, yet it shares

TABLE 25-1 D
 iseases Causing Jaundice/
many characteristics with neonatal hepatitis, a primary
Elevated Liver Enzymes in the
parenchymal disease.9-11 Likewise, progression of histo-
Pediatric Patient6
logical features of intrahepatic cholestasis (IHC) and
Infants
portal inflammation to paucity or absence of bile ducts
occurs in patients with Alagille syndrome (syndromic pau-
Infections city of interlobular bile ducts).12,13
Bacterial: sepsis/UTI (Escherichia coli), syphilis, tuberculosis This chapter focuses on descriptions of the clinical char-
Parasitic: toxoplasmosis acteristics and potential treatment modalities, including the
Viral: cytomegalovirus, rubella, coxsackievirus, echovirus, use of liver transplantation, for conditions associated with
herpesvirus, adenovirus, enterovirus, parvovirus B19,
Epstein-Barr virus cholestasis in the pediatric patient. It does not contain
discussions of biliary atresia or metabolic and genetic/chro-
Metabolic Disorders mosomal disorders, which are covered elsewhere in this book.
Inherited
α1-antitrypsin deficiency
Cystic fibrosis
SPECIFIC CLINICAL CONDITIONS
Disorders of peroxisomal function (Zellweger syndrome)
Disorders of bile acid synthesis
IHC represents a unique class of disorders characterized
Disorders of urea cycle
by marked cholestasis, often with specific phenotypic and
Disorders of amino acid metabolism (tyrosinemia)
epidemiological features. The heterogeneous subsets of
Disorders of lipid metabolism (Niemann-Pick type
C/Gaucher/Wolman)
cholestatic diseases, which are characterized by IHC with
Disorders of carbohydrate metabolism (galactosemia,
or without bile duct paucity, represent specific syndromes
fructosemia, type IV glycogen storage disease) with different prognostic implications. The multiple forms
Progressive familial intrahepatic cholestasis (e.g., Byler’s of IHC have varying clinical features with a high degree of
disease) variability in presentation and prognosis. Certain progres-
Benign recurrent intrahepatic cholestasis sive, familial forms, such as progressive familial intrahe-
Acquired patic cholestasis (PFIC), are often fatal; however, in
Cholestasis and liver disease associated with hypothyroidism, patients with syndromic paucity of the ducts (Alagille
panhypopituitarism syndrome), the prognosis is much more favorable.
Idiopathic Disorders Some patients have paucity of interlobular bile ducts on
Neonatal hepatitis liver biopsy. These patients may be grouped into “paucity
Neonatal iron storage disease syndromes,” which may have different underlying patho-
logical mechanisms, including congenital absence, partial
Malformation of the Bile Ducts/Obstruction
failure to form, atrophy secondary to diminished bile flow,
Atresia/paucity: biliary atresia, Alagille syndrome
or progressive injury (secondary to immune, viral, or isch-
Cystic malformations: choledochal cysts, cystic dilatation of
the intrahepatic bile ducts (Caroli’s disease), congenital emic cause) with secondary disappearance. The histopath-
hepatic fibrosis ological changes may relate to presumed physiological
Inspissated bile alterations; the ductular abnormalities associated with
Cholelithiasis IHC may represent a primary functional or enzymatic
defect or a change secondary to the toxic effects of retained
Toxic/Pharmacological Injury (Acetaminophen, Total
Parenteral Nutrition, Hypervitaminosis A) compounds, such as bile acids. The pathogenesis of bile
duct paucity is unknown. However, the progressive nature
Tumors (Intrahepatic and Extrahepatic) (segmental destructive changes or a progressive decrease
Children and Adolescents in the number of bile ducts per portal tract seen in serial
Acute viral hepatitis sectioning of biopsy specimens), from the early features of
Chronic viral hepatitis bile duct inflammation to the later observation of paucity,
Autoimmune hepatitis suggests immunological injury to existing ducts (similar to
Inherited disorders: Wilson’s disease, cystic fibrosis, hepatic other syndromes of disappearing intrahepatic bile ducts)
porphyrias, Dubin-Johnson syndrome, Rotor’s syndrome rather than failure of ducts to develop.13 Other postulated
Malignancies: leukemia, lymphoma, liver tumors mechanisms include alterations in bile acid metabolism,
Chemicals: hepatotoxic agents, toxins (insecticides, hydro- chromosomal abnormalities, and intrauterine or postnatal
carbons, alcohol, organophosphate, hypervitaminosis A,
mushrooms, acetaminophen)
infection.14 Table 25-2 lists the disorders in which bile
Parasitic infections: schistosomiasis, leptospirosis, visceral
duct paucity has been reported.15
larva migrans
Liver disease associated with inflammatory bowel disease
(sclerosing cholangitis) and rheumatoid arthritis
Neonatal Cholestasis
Occlusion of the hepatic veins Neonatal cholestasis is a descriptive term for patients with
Fatty liver of obesity (nonalcoholic steatohepatitis) prolonged IHC of neonatal onset.11 There are at least
Hypotension/ischemia/cardiac failure three subgroups:
1. Viral hepatitis in the neonate
UTI, Urinary tract infection. 2. Metabolic liver disease mimicking viral hepatitis
3. Idiopathic neonatal cholestasis
290 PART III Patient Evaluation: Pediatric

only diagnosis that can be made in up to 15% of infants

TABLE 25-2 D
 isorders in Which Bile Duct
with prolonged neonatal cholestasis.3
Paucity Has Been Reported
Idiopathic neonatal cholestasis has traditionally been
Infectious Diseases categorized into familial and nonfamilial (sporadic)
forms. The familial form (which probably represents a
Cytomegalovirus
heterogeneous collection of undiagnosed or unrecog-
Herpes simplex virus
nized genetic or metabolic causes) is more likely to be
Rubella
progressive or recurrent, whereas the nonfamilial forms
Syphilis
have a more favorable outcome. The idiopathic category
Metabolic or Endocrine Diseases will continue to shrink with the discovery of new meta-
α1-Antitrypsin deficiency bolic or genetic causes of liver disease presenting in the
Cystic fibrosis neonatal period.16 The overall prognosis in idiopathic
Inborn errors of bile acid synthesis neonatal cholestasis is difficult to estimate because of the
Peroxisomal disorders (Zellweger syndrome) constant changes with new entities identified. In a large
Panhypopituitarism series of infants in whom no cause could be found, the
Chromosomal Disorders cholestasis was found to be transient and recovery was
Trisomy syndromes 17, 18, and 21 observed with long-term follow-up. Transient neonatal
Turner’s syndrome cholestasis was defined as a form of spontaneously resolv-
ing cholestasis that results from the association of several
Immunological Disorders
factors, including immaturity of bile secretion and peri-
Graft-versus-host disease
natal disease leading to hepatic ischemia or hypoxia.17 In
Vanishing bile duct syndrome (chronic rejection after liver
transplant) 10% of the children with transient neonatal cholestasis
Sclerosing cholangitis no remarkable event was identified.17 In contrast, some
children with perinatal hypoxia or ischemia do not
Genetic Disorders develop transient neonatal cholestasis. This predisposi-
Alagille syndrome
tion is attributed to a heterozygous genetic defect in any
Byler’s disease
hepatocellular canalicular adenosine triphosphate (ATP)-
Others dependent transport system, such as familial intrahepatic
Nonsyndromic bile duct paucity cholestasis 1 (FIC1), bile salt export pump (BSEP), or
Aagenaes syndrome multidrug resistance 3 (MDR3). Defects in these trans-
Toxin Exposure porters involved in bile formation are known to be
Data from Balistreri WF: Interrelationship between the infantile
responsible for different types of autosomal recessive
cholangiopathies and paucity of the intrahepatic bile ducts. In forms of familial intrahepatic cholestasis, which may have
Balistreri WF, Stocker JT, editors. Pediatric hepatology. New a benign course or a more progressive form that leads to
York: Hemisphere; 1990:1-18. end-stage cirrhosis.18
The clinical course of patients with idiopathic neona-
tal cholestasis is highly variable, and the treatment is pri-
Viral hepatitis in the neonate and metabolic liver marily supportive. Emphasis is given to optimizing
disease differ from idiopathic neonatal cholestasis by nutrition to maintain growth and prevent the conse-
the presence of an identifiable offending agent. Idio- quences of vitamin deficiency by supplementation with
pathic neonatal cholestasis implies the existence of an fat-soluble vitamins. In both sporadic and familial forms
unidentified pathophysiological process associated with the severe, progressive course of liver disease has been
inflammatory changes in the liver without evidence of altered by liver transplantation. Before liver transplanta-
mechanical obstruction. The presence of histological tion, however, patients with idiopathic neonatal cholesta-
changes of pronounced giant cell transformation of sis must be thoroughly evaluated so that specific infectious
hepatocytes with variable levels of inflammation of and metabolic disorders, such as α1-antitrypsin deficiency
unknown etiology in this group of patients resulted in and inborn errors of bile acid metabolism, are ruled out.
the use of idiopathic neonatal hepatitis to describe this A close follow-up individualized to each patient is needed
group of patients. Despite the common use, the term to establish the pace of the disease. Liver transplantation
implies some type of viral etiology and is best used is indicated for these patients when they develop growth
when a specific agent is identified (e.g., neonatal cyto- failure or end-stage liver disease. The frequency of neo-
megalovirus [CMV] hepatitis). Here, we will use the natal cholestasis as an indication for liver transplantation
term idiopathic neonatal cholestasis to refer to the rela- varies (Table 25-3).
tively common group of neonates with persistent cho- In summary, patients with idiopathic neonatal cho-
lestasis; giant cell transformation and lobular or portal lestasis require a care plan that includes the following:
inflammation; as a nonspecific response of the neonatal • Thorough evaluation to exclude specific infectious,
liver to injury. For example, cholestasis associated with genetic, or metabolic disorders
α1-antitrypsin deficiency, cholestasis associated with • Nutritional support and vitamin supplementation
inborn errors of bile acid biosynthesis, and PFIC were • Close follow-up to understand the pace of the disease
included in this idiopathic category but are now specific • Evaluation for liver transplantation when there is
identifiable metabolic liver diseases. In the absence of a growth failure, portal hypertension, or other com-
specific cause, idiopathic neonatal cholestasis is the plications of end-stage liver disease
 25 Transplantation for Cholestatic Liver Disease in Children 291

TABLE 25-3 Indications for Pediatric Liver Transplant at Children’s Hospital Medical Center,
Cincinnati, Ohio (July 1986 to December 2011)
Evaluated Listed for OLT Transplant Reduced Whole Died Waiting
Diagnosis (n = 699) (n = 562) (n = 468) (n = 238) (n = 230) (n = 30)
Cholestatic conditions 236
Biliary atresia 280 211 193 78 115 14
Alagille syndrome 22 22 15 10 5 0
Primary sclerosing cholangitis 18 16 12 10 2 0
Idiopathic cholestasis 14 11 8 5 3 2
TPN cholestasis/short gut* 12 10 8 2 6 2
PFIC 5 2 1 0 1 0
Metabolic disease 77
α1-antitrypsin deficiency 46 42 31 20 11 1
Urea cycle defects 12 10 10 5 5 0
Tyrosinemia 12 12 11 5 6 0
Cystic fibrosis 10 4 3 2 1 1
Glycogen storage disease 9 7 5 2 3 0
Citrullinemia 8 7 7 4 3 0
Wilson’s disease 8 7 4 4 0 0
Primary hyperoxaluria 6 5 4 4 0 0
Neonatal hemochromatosis 4 4 2 2 0 1
Acute and chronic hepatitis 91
Acute liver failure 91 86 72 36 36 2
Autoimmune hepatitis 32 20 13 12 1 0
Neonatal cholestasis 7 7 5 1 4 0
Hepatitis C 2 2 1 1 0 1
Hepatitis A 1 0 0 0 0 0
Neoplastic disease 35
Hepatoblastoma 31 28 25 13 12 1
Hemangioendothelioma 8 5 3 2 1 2
Hepatocellular carcinoma 6 4 3 2 1 1
Other tumor 4 4 4 2 2 0
Cryptogenic cirrhosis 33 25 19 12 7 1
Congenital hepatic fibrosis 5 2 1 0 1 1
Other 13 9 8 4 4 0

*Multivisceral transplant.
OLT, Orthotopic liver transplantation; PFIC, progressive familial intrahepatic cholestasis; TPN, total parenteral nutrition.

Alagille Syndrome levels of alkaline phosphatase (ALP), γ-glutamyl trans-

peptidase (γ-GTP), and bile acids are increased, reflect-
Alagille et al described syndromic paucity of interlobular ing the defect in biliary excretion.
bile duct (arteriohepatic dysplasia) associated with a con- Cholestasis manifests in the neonatal period, and pru-
stellation of features, including (1) peculiar facial features ritus and xanthomas become prominent during early
(broad forehead; deeply set eyes; long, straight nose; and childhood.26 The liver biopsy specimens obtained during
underdeveloped mandible) (95%), (2) chronic cholestasis early infancy may resemble those of any other form of
(91%), (3) posterior embryotoxon (88%), (4) butterfly- neonatal cholestasis; the evolution to classic findings of
like vertebral arch defects (87%), and (5) peripheral pul- paucity may occur over time. Paucity is defined as an
monary artery hypoplasia or stenosis, either isolated or absence or marked reduction in the number of bile ducts
associated with complex cardiovascular abnormalities in the portal triads (<0.5 interlobular bile ducts per triad)
(85%). Other less frequent features observed include in the presence of normal-sized branches of the portal
growth retardation (50%), renal abnormalities (68%), vein and hepatic artery.26,27
bone abnormalities (<10%), high-pitched voice (<10%), Alagille syndrome exhibits a complex phenotype and
delayed puberty (<10%), along with long bone fractures19 inheritance pattern. It has been reported in successive
and other vascular malformations.20,21 A broader spec- generations of single kindreds, strongly supporting an
trum of clinical manifestations can be compiled from sub- autosomal dominant mode of inheritance, with decreased
sequent reports by several authors; some of these features penetrance and variable expressivity.20 Siblings and par-
may actually represent concomitant nutrient deficiencies ents of probands often have mild expression of the disease
secondary to chronic cholestasis (Table 25-4).20-25 Serum gene, with only one or two abnormalities. A segregation
292 PART III Patient Evaluation: Pediatric

develop cirrhosis; of the 80 patients in the initial Alagille

TABLE 25-4 C
 linical, Laboratory, and
series, 4 died of liver complications (2 each with liver fail-
Radiographic Findings in Patients
ure and portal hypertension).20 The outcome and survival
With Alagille Syndrome
of Alagille syndrome is influenced by multiple factors.
Organ or System Findings Cardiac disease, hepatic disease, and intracranial bleeding
account for the majority of the cases of mortality in Ala-
Hepatic Neonatal cholestasis
Hypercholesterolemia, often of
gille syndrome.20,31 Although early jaundice and higher
extreme degree bilirubin levels suggested a worse prognosis, the association
Paucity of intrahepatic bile ducts between high bilirubin and poor outcome was no longer
Attenuated extrahepatic bile ducts significant when patients with complex congenital heart
Heart Peripheral pulmonic stenosis disease were excluded.32
Pulmonic valvular stenosis The 20-year predicted life expectancy is 75% for all
Ventricular septal defect
Tetralogy of Fallot patients, 80% for those not requiring liver transplantation,
Central nervous Absent reflexes (vitamin E deficiency) and 60% for those who required liver transplantation.31
system Poor school performance Lykavieris et al33 reviewed the outcome of 163 children
Renal Tubulointerstitial nephropathy with Alagille syndrome and liver involvement and reported
Decreased creatinine clearance that survival rates with native liver were 51% and 38% at
Increased uric acid, increased blood 10 and 20 years, respectively. The prognosis of liver dis-
urea nitrogen levels
ease is worse in children who present with neonatal chole-
Eyes Posterior embryotoxon
Abnormal iris strands (Axenfeld’s
static jaundice. However, severe liver complications are
anomaly) possible even after late onset of liver disease.33 Hepatocel-
Retinal pigmentary changes lular carcinoma is a rare complication that has been
High myopia reported in patients with the Alagille syndrome.34,35
Posterior subcapsular cataracts Treatment of patients with the Alagille syndrome is
Strabismus
aimed at improved nutrition, fat-soluble vitamin supple-
Bones Abnormal vertebrae (butterfly
compression, mentation, and support of associated nonhepatic (cardiac,
pointed anterior process C1) renal) complications. Therapy is often ineffective. In our
Short distal phalanges experience, the use of ursodeoxycholic acid (UDCA; 15
Short ulnae mg/kg/day in divided doses) may help to decrease the
Recurrent bone fracture
severity of the pruritus, lower the cholesterol levels,
Lumbar spine Decreased interpedicular distance
Abnormal progression of interpedicular
reduce xanthomas, and improve biochemical parameters.
distance In cases of extreme, intractable pruritus, biliary diversion
Endocrine Decreased thyroxine level is a successful therapeutic option.36
Increased testosterone level It is important to establish a precise diagnosis and
Skin Porphyria cutanea tarda–like blistering avoid unnecessary procedures; hepatoportoenterostomy
Scarring of light-exposed skin in patients with Alagille syndrome is associated with a
poor clinical course.37 The use of liver transplantation
Modified from Balistreri WF. Interrelationship between the infantile
cholangiopathies and paucity of the intrahepatic bile ducts. In for patients with Alagille syndrome is rarely required.
Balistreri WF, Stocker JT, editors. Pediatric hepatology. New Liver transplantation is indicated in patients with refrac-
York: Hemisphere; 1990:1-18. tory debilitating pruritus and poor quality of life or when
the patient develops end-stage liver disease or portal
hypertension. In our experience severe osteopenia and
analysis of 33 families collected through 43 probands cor- recurrent long bone fractures was the indication for liver
roborated the theory of autosomal dominant inheritance; transplantation in a 6-year-old with Alagille syndrome.
penetrance was 94%, and 15% of the cases were spo- Ganschow et al reported 23 children with Alagille syn-
radic.28 In another study 6 parents of 14 probands had drome, 14 of whom underwent liver transplantation.
features of Alagille, suggesting an autosomal dominant Patient and graft survival rate was 85.7%. Three of the
inheritance in 43% of the probands, and new mutation in 14 patients who underwent transplantation showed
57% of the probands.29 The candidate region for the Ala- unexpected extrahepatic complications, such as severe
gille gene was narrowed to a 250-kb segment on chromo- bleeding (caused by intrathoracic arterial malformation)
some 20p12; within this region the JAG1 gene (Jagged-1) and hypoplastic aorta.38 Liver transplantation may result
was identified.30 Mutations in human JAG1, which in an increased risk for vascular complications in patients
encodes a ligand for the Notch receptor, have thus been with Alagille syndrome.39 The timing of liver transplan-
linked to Alagille syndrome. Members of the Notch gene tation should be considered carefully because the risk for
family encode evolutionarily conserved transmembrane death associated with transplantation may not be justi-
receptors that are involved in cell fate specification during fied to treat morbid cholestasis. Emerick et al have
embryonic development. The Notch locus encodes a reported that liver transplantation for hepatic decom-
receptor that mediates cell-cell interactions.30 The prog- pensation was necessary in 21% (19 of 92) of patients.
nosis for prolonged survival is good, but patients with The factors that contributed significantly to mortality
Alagille syndrome are at high risk for growth failure and were complex congenital heart disease (15%), intracra-
morbidity because of pruritus, xanthomas, and complica- nial bleeding (25%), and hepatic disease or hepatic trans-
tions of vitamin deficiency. Young patients usually do not plantation (25%).31
 25 Transplantation for Cholestatic Liver Disease in Children 293

In summary, the primary goal in the management of evaluate for liver transplantation if end-stage liver disease
patients with the Alagille syndrome is do no harm. The supervenes.
diagnosis must be established to avoid surgical procedures The evolution of molecular diagnostic testing for inher-
that will worsen the clinical course.37 A well-delineated ited cholestatic liver disease has provided confirmation of
care plan should therefore include the following: the diagnosis in patients with intrahepatic cholestasis,
• Thorough evaluation opportunity for counseling, and detection of asymptomatic
• Nutritional support and vitamin supplementation siblings. At our institution the Jaundice Chip analysis is
• Treatment of associated pruritus with UDCA or employed for the molecular diagnosis of the five most
partial external biliary diversion common genes associated with heritable liver disease in
• Close follow-up and treatment of nonhepatic childhood.41,42 The genes tested are SERPINA1 (α1-
complications antitrypsin deficiency), JAG1 (Alagille syndrome), ATP8B1
• Evaluation for liver transplantation when there is (PFIC1), ABCB11 (PFIC2), and ABCB4 (PFIC3). The
growth failure, portal hypertension, other complica- analytical sensitivity of this method varies by gene (>99%
tions of end-stage liver disease, or poor quality of life for SERPINA1, 47% for JAG1, 82% for ATP8B1, 82% for
ABCB11, and 82% for ABCB4).
Progressive Familial Intrahepatic
Cholestasis Progressive Familial Intrahepatic Cholestasis,
Type 1 (Byler’s Disease)
Severe forms of intrahepatic cholestasis with progressive
hepatocellular damage may occur sporadically or on a Byler’s disease, PFIC type 1 (PFIC-1), is a severe form of
familial basis. The clinical and pathological features and familial intrahepatic cholestasis, most commonly mani-
natural progression vary, implying significant heteroge- fested as neonatal cholestasis and characterized by pro-
neity. Table 25-5 reflects a proposed classification gressive hepatocellular damage. The first detailed
scheme.7 The term progressive familial intrahepatic cholestasis description of PFIC-1 involved members of Amish kindred
(PFIC) is used to refer to a group of disorders with descended from Jacob Byler; therefore the eponym Byler’s
chronic, unremitting hepatocellular cholestasis when disease was used to describe this variant.43 Patients usually
identifiable metabolic or anatomical disorders have been present with jaundice, hepatomegaly, pruritus, chronic
excluded. The occurrence pattern is consistent with auto- watery diarrhea, and failure to thrive in the first several
somal recessive inheritance. A characteristic combination months. Some patients may have delayed clinical findings
of clinical, biochemical, and histological features is often not noted until later in the first year of life. Disabling
present.3,7,40 PFIC typically presents in the first 6 months pruritus nonresponding to medical therapy is the domi-
of life as cholestasis, hepatomegaly, pruritus, growth failure, nant presentation in some of these patients.40 Cholestasis
or fat-soluble vitamin deficiency. In view of the progres- and pruritus may initially wax and wane but may eventually
sive course of patients with PFIC, it is important to ascertain persist. Patients develop progressive and persistent cho-
a precise diagnosis, provide nutritional support and vita- lestasis with the development of cirrhosis and end-stage
min supplementation, treat the associated pruritus, and liver disease during the first decade of life.40 Neuromus-
cular manifestations and rickets may develop because of
vitamin deficiencies secondary to chronic cholestasis.
TABLE 25-5 P
 roposed Classification of Affected patients may also develop gallstones and hepato-
Disorders Associated with Chronic cellular carcinoma.44-46 Patients with PFIC-1 may have
Intrahepatic Cholestasis extrahepatic disease with diarrhea, pancreatic disease,
pneumonia, abnormal sweat test results, hearing impair-
I. Persistent ment, and poor growth.47 Laboratory evaluation shows
A. Idiopathic neonatal cholestasis elevation of serum aminotransferase and ALP levels.
B. With intrahepatic bile duct paucity Although there is a marked elevation of serum bile acids
1. Alagille syndrome and bilirubin levels, serum cholesterol levels are normal
2. Nonsyndromic paucity or only mildly elevated. Serum γ-GTP levels may also be
C. Progressive familial intrahepatic cholestasis (PFIC) normal or low; this may be a relatively specific feature of
1. Disorders of canalicular transport PFIC-1.48 The biliary bile acid concentration is decreased
a. Bile acid with a predominance of cholic acid; however, chenode-
1) Byler’s disease (PFIC-1; FIC1 deficiency) oxycholic acid may be the predominant species in the
2) PFIC-2 (BSEP deficiency) serum and in the urine.49
b. Phospholipids (PFIC-3, MDR3 deficiency) The FIC1 (ATP8B1) gene, located on chromosome
2. Disorders of bile acid biosynthesis 18q21-22, has been identified as the gene involved in
II. Recurrent PFIC-1 and benign recurrent intrahepatic cholestasis-1
A. Benign recurrent intrahepatic cholestasis (BRIC-1, (BRIC-1). PFIC-1 and BRIC-1 are considered as two
BRIC-2) ends of a continum.50,51 ATP8B1 (FIC1) is a canalicular
B. Hereditary cholestasis with lymphedema (Aagenaes P-type adenosine triphosphatase (ATPase) that partici-
syndrome) pates in maintaining the distribution of aminophospho-
BSEP, Bile salt export pump; MDR3, multidrug resistance protein-3. lipids between the inner and outer leaflets of the plasma
Modified from Balistreri WF. Intrahepatic cholestasis. J Pediatr membrane.50-52 The FIC1 gene is expressed in several
Gastroenterol Nutr. 2002:35(Suppl 1):S17-S23. epithelial tissues and, surprisingly, more strongly in the
294 PART III Patient Evaluation: Pediatric

pancreas and the small intestine than in the liver.51 Chen of bile acids similar to PEBD, and results from a few
et al53 determined the interactions among the apical patients were promising.58 PEBD was shown to be more
sodium-dependent bile acid transporter, the farnesoid X effective than IB for the long-term improvement of
receptor (FXR), and FIC1 in the ileum of children who symptoms of PFIC because IB becomes less effective,
have PFIC-1. Loss of FIC1 leads to diminished nuclear probably because of intestinal reabsorption of bile acids
translocation of the FXR, with the subsequent potential increasing over time.59 IB is usually reserved for patients
for pathological alterations in intestinal and hepatic bile who have had a prior cholecystectomy. Therapy with
acid transporter expression. The authors speculate that UDCA and PEBD may prevent evolution toward cirrho-
hypercholanemia and cholestasis develop because of sis and therefore avoid, at least in the short term, the need
enhanced ileal uptake of bile acids through the increased for liver transplantation in some children.60 In patients
expression of the apical sodium-dependent bile acid who have not progressed to liver cirrhosis, PEBD should
transporter and diminished canalicular secretion of bile be the first choice of treatment. Patients presenting with
acids secondary to downregulation of the bile acids excre- cirrhosis or after ineffective PEBD qualify for liver trans-
tory pump.54 plantation.60,61 Severe allograft steatosis progressing to
The liver histological examination may show a variety steatohepatitis and cirrhosis has been described in patients
of findings, including early features of giant cell transfor- with PFIC-1 after liver transplantation, especially when
mation and slight proliferation or paucity of bile ducts. using living related donors. Steatosis was associated with
Later biopsy specimen findings demonstrate periportal diarrhea and attributed to altered bile acid enterohepatic
fibrosis or progression to biliary cirrhosis.43,55 Hepatoca- circulation. Resin therapy was useful in controlling the
nalicular cholestasis and disruption of the liver cell plate diarrhea and delaying the progression of the graft
arrangement were early, uniform findings. Duct loss was steatosis.62
a prominent finding. Proliferating ductules at the margins
of portal tracts increased as fibrosis progressed and were
Progressive Familial Intrahepatic Cholestasis,
especially prominent histologically in end-stage disease.
Type 2
The constellation of histological findings in PFIC-1
forms a recognizable pattern, and the liver histological A second distinct form of PFIC (PFIC-2) is caused by a
findings appear to have a predictable progression.56 Light defective function of the canalicular BSEP. Affected chil-
microscopy findings on liver biopsy specimens in infancy dren present with cholestasis, high serum bile acid levels,
are indistinguishable in PFIC-1 and BRIC, but portal and low serum γ-GTP activity. PFIC-2 patients have a
tract fibrosis and bridging are seen with advancing age in phenotype consistent with an isolated defect in ATP-
patients with PFIC-1. Electron microscopy of the liver of dependent bile acid transport at the canalicular mem-
patients with PFIC-1 shows dilatation of the canalicular brane level. In contrast to patients with PFIC-1 (who
lumen, which is filled with coarse, particulate, amorphous, have a number of extrahepatic features that may continue
granular material; a decreased number of microvilli; and to manifest after liver transplantation, including pancre-
focal interruption of the canalicular membrane. The atitis, diarrhea, and malabsorption), infants with PFIC-2
coarsely granular bile found in canaliculi with transmis- appear to have a defect restricted to the liver, which is
sion electron microscopy in PFIC-1 has not been identified readily corrected by liver transplantation.63 Jaundice
in BRIC or in other forms of PFIC.57 appears during the first 3 weeks of life, and serum γ-GTP
The treatment is primarily supportive, with aggressive levels are normal. At presentation in infancy, liver biopsy
nutritional and vitamin supplementation. Symptomatic findings uniformly show canalicular cholestasis with giant
treatment of pruritus is important because it is a frequent, cell change rather than the bland intracanalicular cho-
debilitating symptom. lestasis of PFIC-1. In hepatectomy and autopsy specimens,
Because FIC1 protein expression is higher in the intes- chronic hepatitis with lobular inflammation and portal-
tine than in the liver, defects in intestinal absorption may portal bridging fibrosis has been found. The phenotype
be involved in the pathogenesis of these diseases and may suggests an isolated transport defect in bile acid excretion
explain the success of partial external biliary diversion because chenodeoxycholic acid concentrations in bile are
(PEBD) in the treatment. In PEBD the gallbladder is decreased, as in patients with PFIC-1; the coarse granular
externalized through a stoma using a loop of small intes- bile seen by transmission electron microscopy in PFIC-1
tine. PEBD diverts bile salts from the enterohepatic is not present.
circulation, arrests the progression of disease, and relieves The gene responsible for this form of PFIC has been
pruritus in the majority of patients. Following diversion, mapped to chromosome 2q24. The ATP-dependent bile
the coarse granular bile changes to the normal amor- acid transporter, BSEP, is responsible for active transport
phous state; this was associated with conversion of the of bile acids across the hepatocyte canalicular membrane
bile salt pool to predominantly chenodeoxycholic acid into bile. It is now recognized that mutations in the gene
and resolution of hepatic morphological and biochemical ABCB11, which encodes the liver-specific BSEP containing
abnormalities. Rare patients develop “watery” bile output ATP-binding cassettes, are responsible for infants and
after PEBD with electrolyte losses that need to be moni- children with PFIC-2.64-66 PFIC-2 is compatible with a
tored and replaced.36,49 Hollands et al58 used ileal bypass loss of the ability to excrete bile acids efficiently into the
(IB) in the treatment of pruritus; IB offers a stoma-free, bile canaliculus and a marked reduction in bile acid–
reversible biliary diversion, in which the distal 15% of the dependent bile flow. Bile acids retained within hepato-
ileum is removed from the intestinal mainstream and cytes cause progressive injury and, with efflux of bile salts
made into a self-emptying blind loop. This results in loss back into the blood, a progressive increase in serum bile
 25 Transplantation for Cholestatic Liver Disease in Children 295

acid concentrations. The low biliary bile acid concentra- were highly variable and included newborn cholestasis
tions seen in patients with PFIC-2 may be insufficient to and cholesterol lithiasis (low phospholipid content). Het-
release γ-GTP from biliary epithelium, with the result erozygous mutations lead to IHC of pregnancy. Liver
that serum γ-GTP levels remain paradoxically normal in biopsy findings were also variable. In neonates, bile duct
these severely cholestatic patients.63 proliferation and inflammatory infiltration dominates;
PFIC-2 patients have high serum alanine amino- portal and periportal fibrosis progressing to cirrhosis
transferase and α-fetoprotein levels, severe lobular ensues at a later stage.77
lesions with giant hepatocytes, early liver failure, chole- De Vree et al72 hypothesized that patients who do not
lithiasis, hepatocellular carcinoma, and very low biliary respond to UDCA therapy have a complete defect in
bile acid concentrations.67 They lack the relapsing phospholipid secretion and that partial UDCA replace-
course seen in the early stages of PFIC-1 but instead ment is insufficient to reduce the increased bile salt
have a more rapidly progressive course to fibrosis. Ther- toxicity in phospholipid-free bile of these patients.
apy is ineffective, and relatively rapid progression to Patients who do respond to UDCA therapy may have a
cirrhosis is the rule. Partial external biliary diversion has partial defect, and the residual phospholipid concentration
been successful in few patients.68 Management is the in bile, combined with a partial UDCA replacement, may
same as that for PFIC-1, and liver transplantation is be sufficient to reduce the bile salt toxicity below a critical
required in many cases.3 The development of de novo threshold. Management is the same as for PFIC-1.72
bile salt transporter antibodies after liver transplanta-
tion can induce an alloimmune reaction, which varies in North American Indian Cholestasis
severity, may be responsive to immunosuppression, and
can lead to graft failure requiring retransplantation.69-71 North American Indian childhood cirrhosis (NAIC),
closely resembling PFIC-1, is a distinct, rapidly evolving
form of familial cholestasis that was originally described
Progressive Familial Intrahepatic Cholestasis,
in children from northwestern Quebec. It typically pres-
Type 3
ents with transient jaundice in an infant who is otherwise
Patients with PFIC type 3 (PFIC-3) can be distinguished healthy and progresses to biliary cirrhosis and portal
from those with the other types by high serum γ-GTP hypertension. Early-onset portal hypertension and vari-
activity and liver histologic findings that show portal ceal hemorrhage necessitate portosystemic shunts in the
fibrosis with ductular proliferation and inflammatory majority of patients.78,79 The histological features of
infiltrate in the early stages despite patency of intrahe- NAIC show early bile duct proliferation and rapid devel-
patic and extrahepatic bile ducts. PFIC-3 may present in opment of portal fibrosis and biliary cirrhosis, suggesting
neonates, often mimicking biliary atresia, or later in life; a cholangiopathic phenomenon. Ultrastructural analysis
it carries a higher risk for portal hypertension and gastro- of liver specimens from children with NAIC suggested
intestinal bleeding and ends in liver failure at a later age. microfilament dysfunction.78 Genetic analysis points to
It is characterized by a mild and variable pruritus, moder- an autosomal recessive inheritance and a carrier frequency
ately raised concentrations of serum bile acids, and nor- of 10%. CIRH1A is located on chromosome 16q22.79
mal concentrations of biliary primary bile acids.72,73 It is The perinatal appearance of NAIC is thought to be
attributed to a genetic defect in the MDR3 (ABCB4 attributed to the role of Cirhin as a transcriptional regula-
gene), which encodes a phospholipid translocase that flips tory factor of NF-kappaB, which plays an important role
phosphatidylcholine from the inner to the outer layer of during development.80 Currently liver transplantation is
the canalicular membrane. The gene is located on chro- the only effective therapy for patients with advanced dis-
mosome 7q21.72 The liver pathological condition may be ease.81 No recurrence of NAIC was observed 10 years
caused by a toxic effect of bile acids on bile canaliculi and after transplant.79
the biliary epithelium in the absence of biliary phospho-
lipids.74,75 Biliary phospholipids normally protect ductu-
Fatal Familial Cholestasis Syndrome in
lar epithelial cells from the toxicity of bile acids by Greenland Eskimo Children
forming mixed micelles. In patients with PFIC-3, cho-
lestasis results from the toxicity of bile in which detergent Cholestasis familiaris groenlandica (CFG), a Byler-like
bile acids are not inactivated by phospholipids. The disease, is a common recessive disease and is a severe form
absence of phospholipid would be expected to destabilize of intrahepatic cholestasis described among indigenous
micelles and promote lithogenic bile and crystallized Inuit families in Greenland. Patients present with jaun-
cholesterol-induced small bile duct obstruction. MDR3 dice, pruritus, bleeding episodes, malnutrition, growth
mutations exhibit significant phenotypic variation, retardation, steatorrhea, thrombocytosis, osteodystro-
including gallstone formation, biliary fibrosis, and IHC phy, and dwarfism, with death in childhood resulting
of pregnancy.76 from end-stage liver disease. It was suggested to be a form
MDR3 deficiency (PFIC-3) is clinically similar to of PFIC-1, associated with a missence mutation in the
other forms of PFIC, with onset of cholestatic liver dis- FIC1 gene.82 CFG has been linked to chromosome 18q;
ease early in life. The characteristic difference is the ele- different haplotypes follow the disease gene among Inuits
vated level of γ-GTP in serum. Jacquemin et al77 studied in West Greenland, and a possibility of locus heterogene-
31 patients who had MDR3 deficiency and reviewed the ity of CFG between East and West Greenland exists in
clinical, morphological, and genetic variations of the dis- this population.83 Despite marked cholestasis, the serum
ease. The clinical manifestations of MDR3 mutations cholesterol levels are low to normal. Of the 16 patients
296 PART III Patient Evaluation: Pediatric

described, 50% died by 3 years of age because of bleeding remission having a normal serum bilirubin concentration
or infection.84 The reported early histological findings by 3 years of age. Some of the patients progress to liver
were variable, with canalicular cholestasis and rosette for- failure in early infancy, some experience prolonged cho-
mation of the hepatocytes around dilated canaliculi followed lestasis before the development of cirrhosis and liver failure,
by zone 3 fibrosis, zone 1 fibrosis, and cirrhosis.85 Ultra- and some have a normal life span. Patients with chronic
structural examination revealed granular material in bile clinical or biochemical evidence of hepatobiliary injury
canaliculi with a bandlike condensation of microfilaments later in life are at risk for developing cirrhosis.91,92
similar to the coarsely granular Byler bile described in The histological findings in the liver are consistent
patients with PFIC-1.82,85 There are no reports of liver with a giant-cell transformation in the early biopsy speci-
transplantation for patients with fatal familial cholestasis men. Lymphedema in the lower extremities begins in
syndrome in Greenland Eskimo children. A suggested later childhood and has been attributed to lymphatic
care plan for these patients is the same as outlined for vessel hypoplasia. The relationship between the periph-
patients with PFIC-1. eral lymphatic obstruction and liver disease is uncertain.
Aagenaes postulates a hepatic lymph hypoplasia or a
functional defect in lymphatic flow leading to cholestasis.
Benign Recurrent Intrahepatic Cholestasis
Cholestasis in patients with Aagenaes syndrome has not
BRIC is a syndrome characterized by multiple transient been shown to be caused by a primary defect of bile acids
episodes of cholestasis of varying duration followed by or other biliary constituents but might be a consequence
spontaneous remission. Patients have several episodes of of other factors, such as a primary defect in the lymphatic
pronounced jaundice with intense pruritus and biochemi- circulation. Diagnosis of a sporadic case of this syndrome
cal evidence of cholestasis, with increased serum bile acid has so far been impossible until lymphedema develops,
levels and a mild increase in aminotransferase levels. Char- which may be moderate and therefore overlooked in
acteristically, serum γ-GTP activity is low, and normal some cases. Lymphatic hypoplasia in the liver would
liver structure is preserved.86 Liver biopsy specimens may probably not be observed in the histological examination,
show bile plugs; intrahepatic and extrahepatic bile ducts are not even through electron microscopy. Study of reported
normal on cholangiography. cases supports an autosomal recessive mode of inheri-
Approximately 20% of patients experience their first tance.91 Genetic linkage analysis in Norwegian patients
attack by 1 year of age; other patients have the onset during points to abnormalities in chromosome 15q.93
adolescence or in their late 20s. Multiple family members Treatment is limited to avoiding complications of mal-
are affected. BRIC is an autosomal recessive liver disease. absorption during episodes of cholestasis, particularly fat-
Additional clinical features overlap with those seen in soluble vitamin deficiency. Lymphedema tends to become
patients with PFIC, but complete clinical and biochemical the dominant symptom of disease later in life and can be
resolution followed by recurrent attacks establishes the disabling in some patients. It may improve later in life and
diagnosis. BRIC can be linked to specific mutations in the can be controlled in some patients by symptomatic treat-
FIC1 (ATP8B1) gene, which is called BRIC-1.87 Although ment such as physiotherapy and wrapping of the lower
PFIC-1 and BRIC-1 are clinically distinct diseases, their extremities.91 Liver transplantation was described in
phenotypes may be linked to specific types of mutations in infants and young children with advanced liver disease.92
the same gene.88 BRIC can also be linked to mutations in
ABCB11, which is named BRIC-2.89,90 Inborn Errors of Bile Acid Biosynthesis
The goal of the treatment is primarily nutritional sup-
port and relief of symptoms, specifically of pruritus, but Defective bile acid biosynthesis occurs in the presence of a
this is generally unsatisfactory. Liver transplantation is primary deficiency of enzymes responsible for catalyzing
not indicated in patients with BRIC. A suggested care key reactions in the synthesis of primary bile acids, as well
plan includes the following: as secondary metabolic defects that affect primary bile
• Effort to ascertain a precise diagnosis acid synthesis and include peroxisomal disorders such as
•  Institution of nutritional support and vitamin Zellweger syndrome and related disorders, and Smith-
supplementation Lemli-Opitz syndrome. Inborn errors of bile acid biosyn-
• Treatment of the associated pruritus thesis are responsible for approximately 2% of persistent
• Close follow-up cholestasis in infants.94 Defects in bile acid biosynthesis
lead to the loss of the trophic and choleretic effect of pri-
mary bile acid and the accumulation of hepatotoxic metab-
Hereditary Cholestasis with Lymphedema
olites; progressive liver damage is inevitable. Secondary
(Aagenaes Syndrome)
effects of impaired bile acid production are cholestasis and
Hereditary cholestasis with lymphedema is a syndrome of malabsorption of fat-soluble vitamins. Exogenous admin-
intrahepatic cholestasis and lymphedema of the legs that istration of bile acid can supply adequate luminal concen-
was first described by Aagenaes et al91 in 1968 in 16 trations of bile acids and also inhibit the biogenesis of
patients from the southwest of Norway. Jaundice is con- toxic intermediate metabolites. Early recognition allows
sistently present during the neonatal period through the the institution of targeted bile acid replacement, which
first few years of life, with later recurrence in childhood; reverses the hepatic injury.
precipitating factors are infection, trauma, surgery, The primary bile acids are synthesized from choles-
puberty, and pregnancy.91 The cholestatic liver disease terol by 17 enzymatic steps. There are several known
tends to improve with age, with most patients going into enzymatic defects in this pathway that result in a defective
 25 Transplantation for Cholestatic Liver Disease in Children 297

transformation of the steroid nucleus or the cholesterol cholestasis, particularly in infants and immunocompro-
side chain, with identified genes.95 Clinical presentation mised individuals. Severe cholestatic jaundice caused by
varies among these disorders; however, jaundice, cholestasis, intrahepatic cholestasis (and not hemolysis) has also been
fat-soluble vitamin deficiency, elevated aminotransferase observed in patients with acute Plasmodium falciparum
levels, variable γ-GTP, and low serum bile acid levels are infection.104 Perinatal infection with Treponema pallidum
the hallmarks of the disease. Defects in specific enzymatic and Toxoplasma gondii causes a multisystem disease with
steps have been identified via testing the urine for normal hepatomegaly and cholestasis.105,106 Likewise, congenital
and abnormal bile acids by fast atom bombardment infection with CMV presents as a systemic disease with
ionization–mass spectrometry and gas chromatography– devastating sequelae, such as cardiovascular malformations,
mass spectrometry.87 hearing loss, and mental retardation; however, the liver
Deficiency of 3β-hydroxy-Δ5-C27-steroid dehydroge- injury resolves, and progression to cirrhosis is extremely
nase (3β-HSD), the enzyme that catalyzes the second rare.107,108 Acute liver failure109 and death caused by
step in the principal pathway for the synthesis of bile CMV infection have been reported.110 CMV infection
acids, is the most common bile acid synthetic defect has been recognized as one of the major pathogens
described. Affected subjects have an autosomal recessive responsible for infantile hepatitis and prolonged intrahe-
mutation in the encoding gene, HSD3B7, on chromo- patic cholestasis.111,112 Herpes simplex and enterovirus
some 16p11.2-12.96 Patients with 3β-HSD present with infections of the neonate have a more aggressive pattern
prolonged neonatal jaundice, increased serum amino- and may cause hepatic necrosis. In these cases the infec-
transferase levels, and hepatomegaly. The histological tions involve other organs, and when the use of antiviral
findings are variable, ranging from giant cell hepatitis to agents and supportive care achieve recovery, the liver
chronic hepatitis. It may also present between the ages of disease subsides, although there is a potential for large
4 and 46 months with jaundice, hepatosplenomegaly, and areas of necrosis and ensuing liver failure. Viral-induced
steatorrhea (a clinical picture resembling PFIC).97 Bile multiorgan failure makes these patients poor candidates
acid replacement with cholic acid is effective in reversing for transplantation, and the presence of a disseminated
the hepatic injury, leading to clinical and biochemical viral infection is a relative contraindication because of
improvement in children with 3β-HSD.98 the immunosuppression required in the postoperative
The enzyme 3-oxo-Δ4-steroid 5β reductase catalyzes the period.109 Echovirus types 11, 14, and 19 have been asso-
fourth step in the pathway of primary bile acids synthesis.99 ciated with hepatic necrosis (similar to that caused by
The genetic defect was attributed to AKR1D gene mutation herpes simplex virus) and progressive liver failure in the
on chromosome 7q32-33.100 Congenital deficiency mani- first week of life.113-117 Residual cirrhosis may develop
fests as severe cholestasis and liver failure developing shortly after the infant recovers from the acute infection, and
after birth with coagulopathy and metabolic liver injury.101 liver transplantation is the ultimate therapeutic option.
3-oxo-delta 4-5 beta-reductase deficiency has been found in a One patient with echovirus 11–associated liver failure
number of patients presenting with what resembles neona- underwent transplantation in our series with no recur-
tal hemochromatosis.102 Hepatic histological findings are rence of the infection to date. The hepatotropic viruses
nonspecific with lobular disarray and giant cell transforma- (hepatitis viruses A, B, C, D, and E) are not responsible
tion, pseudoacinar transformation, and canalicular bile sta- for neonatal cholestasis.118,119
sis. Mass spectrometry analysis documents increased urinary Extrahepatic bacterial infections or inflammatory
bile acid excretion and the predominance of oxo-hydroxy processes can lead to cholestasis referred to as sepsis-
and oxo-dihydroxy cholenoic acids. Biochemical, histologi- associated cholestasis.120 This type of cholestasis is caused
cal, and clinical features normalize with treatment with by the systemic effects of microbial products such as
cholic acid and UDCA.95,101 endotoxins released during the infectious process lead-
Although rare, oxysterol 7α-hydroxylase deficiency ing to the activation of proinflammatory cytokines, with
provides insight into the developmental physiology of subsequent reductions in bile flow. The expression and
bile acid metabolism. A 10-week-old boy (whose parents function of key hepatobiliary transporters that normally
were first cousins) presented with severe cholestasis and mediate hepatic uptake and biliary excretion of bile acid
liver synthetic failure; his serum γ-GTP level was normal. and various non–bile acid organic anions (e.g., bilirubin)
The liver biopsy specimen revealed progressive peripor- are suppressed in response to inflammatory signaling.
tal hepatitis with bridging fibrosis, giant cell transforma- These cytokine effects are reversible, and bile secretory
tion, bile duct proliferation, and severe intralobular function is restored upon disappearance of the inflam-
cholestasis. He was found to have a genetic defect in matory injury. Cholestasis is very common in gram-
CYP7B, chromosome 8q21.3; this finding confirmed that negative neonatal septicemia, affecting up to 42% of
the acidic pathway is quantitatively the most important in patients. The onset of cholestasis is seen by day 3 of
early human life. Oral UDCA therapy led to deteriora- sepsis but ultimately resolves within 60 days.121 The
tion in liver function test results, and oral cholic acid was most common organism isolated in this series was
ineffective. The patient subsequently died after ortho- Klebsiella pneumoniae,121 although urinary tract infection
topic liver transplant at 4½ months of age.103 caused by Escherichia coli was previously reported as the
most common cause of infection-induced cholestasis in
infants.1,122,123 Jaundice might be the only clinical sign
Infectious Hepatitis of urinary tract infection in asymptomatic infants.
Various infectious agents such as CMV, herpes simplex Infants with the onset of jaundice after 8 days of age,
virus, leptospirosis, and toxoplasmosis can induce when physiological jaundice is expected to have
298 PART III Patient Evaluation: Pediatric

improved or resolved, or with conjugated hyperbilirubi- used for more than 2 months, and 90% if used more than
nemia were more likely to have a urinary tract infec- 3 months.136 Abnormal liver test results are first evident
tion.123 In adults, sepsis-induced cholestasis occurs within 2 weeks after TPN is initiated and resolve in
mostly in patients with gram-negative sepsis. In most approximately 4 weeks following discontinuation of
cases the primary site of infection is intra-abdominal TPN.136,137 Continuation of TPN promotes persistence
(e.g., appendicitis, diverticulitis, peritonitis), but it has of cholestasis.134,137 The onset of jaundice in infants
also been reported in association with other bacterial receiving TPN is often associated with systemic illnesses,
infections in the absence of sepsis (e.g., pneumonia, and cholestasis is detected as part of routine laboratory
endocarditis). Other specific infections known to cause tests.138 The increase in serum bilirubin, bile acid, and
jaundice are infections of the hepatobiliary tree, clostridial aminotransferase levels is insidious, and hepatomegaly
infection, typhoid fever, and legionella.124 Cholestasis may also be present.139 Sludge has been reported in 44%
usually develops within a few days of the onset of bacte- of neonates receiving TPN for a mean duration of 10
remia but can occur before other clinical features of the days,140 and in all adults receiving TPN for more than 6
underlying infection become apparent.124,125 Dispro- weeks.141
portionate elevation of conjugated serum bilirubin level The pathogenesis of TPN-associated cholestasis is
in serum is the predominant biochemical feature of poorly defined. Multiple factors have been considered,
jaundice of sepsis, with moderate elevations of serum including direct toxicity of TPN to the liver because of
ALP and γ-GTP levels and normal to slightly elevated contaminants and other nonnutrient substances present in
serum aminotransferase levels. Serum bilirubin levels parenteral nutrition formulations, such as phytosterol in
usually peak between 5 and 10 mg/dL (characteristically lipid emulsion,142 aluminum,143 and di(2-ethylhexyl)
75% to 80% conjugated bilirubin), but levels as high as 30 phthalate–containing infusion systems.144 Proposed mech-
to 50 mg/dL have been reported. Hepatomegaly occurs anisms for phytosterols-induced cholestasis include reduc-
about half the time.124,125 Liver histological findings are tion of bile acid–dependant bile flow, impairment of the
nonspecific and show intrahepatic cholestasis.124,126 Liver function of important transport proteins involved in the
biopsy usually is not indicated for the diagnosis. Success- secretion of bile because of the increased phytosterol con-
ful therapy for the underlying infection normally results tent in the cell membrane, and inhibition of cholesterol
in resolution of the liver function abnormalities in 2 to 30 7-α-hydroxylase.145 Molecular studies demonstrated that
days. If it persists, jaundice associated with sepsis carries a phytosterols contribute to bile acid–induced hepatocyte
poor prognosis with high mortality rates.125 In the absence damage by antagonizing FXR (NR1H4), a nuclear recep-
of sepsis, cholestasis accompanying extrahepatic bacterial tor involved in hepatoprotection from excess bile acid.146
infections is usually mild. Some nutrients added to the TPN such as manganese and
copper127,138 might be hepatotoxic; therefore these ele-
Total Parenteral Nutrition–Associated ments are usually withheld in patients with evidence of
liver dysfunction. Hepatic nutritional deficiencies result-
Cholestasis ing from the nutritional inadequacies of TPN such as cho-
Total parenteral nutrition (TPN) has an important role line and taurine deficiency132,147 and free oxygen radical
in the nutrition of low-birth-weight premature neonates, generation from peroxidation of infused lipids may play a
infants with short gut syndrome secondary to extensive role in TPN-associated liver disease.148 Calorie excess
intestinal resection (because of congenital anomalies of caused by glucose and lipid overload may result in liver
the gut or necrotizing enterocolitis), and children with toxicity, thus causing hepatic steatosis and cholestasis.149
intestinal failure secondary to dysmotility.127 Prolonged The infusion of lipids in doses higher than 1 g/kg/day
TPN administration results in the development of liver correlates with liver dysfunction.150,151 The introduction
disease, with a spectrum that ranges from asymptomatic of neonatal-specific amino acid parenteral nutrition
elevation of liver enzyme levels and steatosis to severe allowed infants to receive higher concentrations of pro-
cholestasis and cirrhosis. Although the incidence and tein. Although protein calories are often out of proportion
severity of TPN-associated hepatic dysfunction have of nonprotein calories, the protein-to-nonprotein-calorie
decreased because of improvements in clinical manage- ratio was not found to be a contributing factor in the
ment and early initiation of enteral feeding, hepatobiliary development of cholestasis in low-birth-weight infants
complications of TPN remain a major cause of morbidity receiving TPN.152 Lack of enteral intake and inadequate
and mortality in these patients.128,129 Hepatobiliary stimulation of the enterohepatic circulation and bowel
abnormalities may reflect underlying disease or effects of function leading to reduction of gut hormone secretion,
pharmacological agents130; current evidence suggests that bile flow, and biliary stasis may be important mechanisms
TPN itself contributes to intrahepatic cholestasis and in the development of cholestasis, biliary sludge, and
biliary sludge in infants, and it may lead to steatosis, ste- cholelithiasis.138,153
atohepatitis, biliary sludge, cholelithiasis, and cholestasis The high prevalence of TPN-associated cholestasis in
in adults.131,132 premature infants is attributed to the relative immaturity
Cholestasis is the most frequent manifestation of of the hepatic canalicular transporters mediating bile
TPN-associated liver disease,133 especially in premature, secretion.54 Premature neonates have a decreased bile acid
low-birth-weight infants.134,135 In a series of 62 prema- pool and impaired hepatic mitochondrial function.129 The
ture infants receiving TPN, cholestasis (defined as direct immature liver has lower basal and bile acid–stimulated
bilirubin level > 1.5 mg/dL) was present in 23% of bile flow rates and decreased response to choleretic hor-
patients, with an incidence of 80% if exclusive TPN was mones (secretin and glucagon). Immature hepatocytes
 25 Transplantation for Cholestatic Liver Disease in Children 299

also produce abnormal, potentially toxic bile acid metabo- fatty acids has contributed to a paradigm shift in the
lites (monohydroxy bile acids, such as lithocholate).154 management of TPN–associated liver disease. Their use
Lack of the physiological effect of enteral intake culmi- in patients with short bowel syndrome allowed, in some
nates in the pathogenesis of TPN-induced cholestasis cases, avoidance of liver transplantation because of
through the loss of cholecystokinin release contributing improvement of liver function while receiving the
to bile stasis and biliary sludge formation,155,156 lack of omega-3 fatty acids–based lipid emulsion.171 Similar
enteral alimentation results in intestinal stasis, enterocyte improvements also occurred by withholding or reducing
hypoplasia, and impaired gut immunity,157 predisposing standard lipid emulsions. Concerns exist regarding pos-
to bacterial overgrowth and increased bacterial transloca- sible untoward effects of an inadequate supply of omega-6
tion,158 with subsequent accumulation of hepatotoxic sub- fatty acids with parenteral fish oil only. Clearly the
stances such as endotoxin and increased production of observed improvement of parenteral nutrition–associ-
secondary toxic bile acids such as lithocholic acid. ated cholestasis on the omega-3 fatty acids–based lipid
Liver biopsy specimens show accumulation of bile pig- emulsion deserves further exploration.172 A randomized
ment in liver cells, canalicular bile plugs, and a mild, controlled trial was recently completed to gain evidence
chronic inflammatory portal infiltrate. Portal expansion, of efficacy and safety of fish oil–based emulsions in par-
ductular proliferation, and portal and lobular fibrosis sim- enteral nutrition–associated cholestasis.173
ilar to that seen in biliary atresia have been reported.159,160 When continued over a duration of 6 weeks, TPN-
A progression in the severity of histopathological changes induced cholestasis persists and may lead to advanced
in relation to duration of TPN administration was fibrosis and micronodular cirrhosis.12,161,174 Liver trans-
reported. Whereas patients with TPN of less than 2 weeks plantation is a therapeutic option for TPN-induced end-
had no fibrosis or only mild degrees of fibrosis, patients stage liver disease; an improved outcome can be achieved
with more than 6 weeks of TPN developed moderate to via combined liver and small bowel transplantation in
severe fibrosis.161 patients with short bowel syndrome or intestinal failure.
Overall these clinical, biochemical, and histological
criteria are not specific. Parenteral nutrition–related cho-
lestasis remains a diagnosis of exclusion; affected infants CONCLUSIONS
must be evaluated for treatable causes of cholestasis.
Approximately 10% of patients have an alternative, spe- The development of jaundice with conjugated hyperbili-
cific cause such as cystic fibrosis and galactosemia.162 In rubinemia in infancy and childhood requires immediate
the neonatal setting, TPN can often be discontinued as evaluation to identify treatable and life-threatening con-
the respiratory and multisystem diseases improve; clinical ditions. Biliary atresia needs to be excluded in a timely
and histological changes are reversible if TPN has been fashion to avoid late performance of the portoenteros-
used for less than 90 days.159 The significant hepatobiliary tomy, which is associated with poor prognosis. One needs
consequences are seen in infants with poor intrauterine to look for known causes of intrahepatic cholestasis, such
growth, low birth weight, young gestational age, delayed as α1-antitrypsin deficiency and cystic fibrosis. When the
institution of enteral feedings, necrotizing enterocolitis, origin remains obscure, the differential diagnosis is aided
and sepsis161,163 and in children with extensive intestinal by syndromic features, documentation of pruritus, serum
resection or total aganglionosis. Every attempt should be levels of γ-GTP, and bile acids. Also, the liver biopsy
made to initiate oral feeding; even continuous, slowly specimen must be carefully examined, which will provide
administered small volumes of any enteral intake might parameters for initial grouping into functional defects.7
aid in halting the progression to cholestasis or decrease Molecular studies like the Jaundice Chip are useful in
the severity of hepatobiliary complications.164,165 identifying the underlying genetic causes of cholestasis
Interventions used to prevent TPN-related liver dis- and confirming the diagnosis.
ease can be instituted even after liver abnormalities have When evaluating an infant with cholestasis, the pri-
developed. The specific caloric needs; constituents such mary goal is to establish a precise diagnosis followed by
as carbohydrates, proteins, and lipids; and the ratios of aggressive medical therapy and follow-up by doing the
carbohydrates to lipids need to be carefully assessed and following:
readjusted. Although the initial study was promising,166 • Providing nutritional support and vitamin
cholecystokinin was not proven to be effective in the supplementation
prevention of parenteral nutrition–associated cholestasis • Using choleretic agents to alleviate pruritus
when used in high-risk neonates on TPN.167 UDCA • Monitoring growth and clinical and biochemical
supplementation enriches the bile acid pool and reduces parameters
the potentially toxic lithocholic acid, favorably influenc- • Optimizing psychosocial development and assess-
ing cholestasis. In TPN-related hepatic dysfunction, ing quality of life
UDCA improved conjugated bilirubin and liver enzyme • Gauging success, including searching for
levels, but its usefulness in reversing cholestasis was not complications
proven.168,169 In a case series of patients with TPN- Despite the success, major challenges in the care of these
induced cholestasis, serum bilirubin levels decreased patients still exist, especially as their disease progresses to
markedly after the parenteral administration of an cirrhosis and they are considered for liver transplantation.
omega-3 fatty acids–based fat emulsion.170 Patients tol- These include improved preoperative management to
erated this therapy, and no adverse reactions attributed ensure adequate growth and nutrition, a balanced post-
to its use were observed. The use of parenteral omega-3 transplant management of immunosuppression to ensure
300 PART III Patient Evaluation: Pediatric

graft viability and avoidance of lymphoproliferative disease, Pearls and Pitfalls—Cont’d

early recognition of CMV and Epstein-Barr virus infec-
tion, and provision of services in a more cost-effective • Severe allograft steatosis progressing to steatohepa-
manner.175 Before liver transplantation is performed in a titis and cirrhosis has been described in patients with
patient with a cholestatic disease, other surgical options PFIC-1 after liver transplantation, especially when
should be considered, such as PEBD in patients with using living, related donors. Steatosis may be associ-
intractable pruritus and decompression shunts in patients ated with diarrhea and attributed to altered bile acid
with portal hypertension. Indications for liver transplanta- enterohepatic circulation. Resin therapy may be useful
tion consist primarily of severe growth failure, poor quality in controlling the diarrhea and delaying the progres-
sion of the graft steatosis.
of life, end-stage liver disease (bleeding, coagulopathy), or • Inborn errors of bile acid synthesis should be consid-
when the risks of complications of the original liver disease ered in children with cholestasis, low or undetectable
outweigh the risks of liver transplantation. serum bile acid levels, and liver histological features
suggestive of giant cell transformation. The diag-
nosis is confirmed by urinary bile acid analysis using
Pearls and Pitfalls gas chromatography–mass spectrometry. Bile acid
replacement results in considerable clinical and bio-
• Cholestasis is a pathological condition of altered bile chemical improvement, avoiding liver transplantation.
synthesis or flow. There is retention of substances nor- • Neonates are prone to sepsis and total parenteral nutri-
mally excreted into bile. Cholestasis manifests as con- tion (TPN)-induced cholestasis resulting from immatu-
jugated hyperbilirubinemia or elevated serum bile acid rity in the processes of bile-acid uptake, transport, and
levels. Cholestasis in the pediatric patient is associated excretion. In these patients the use of a fish oil–based
with infectious, toxic, metabolic, and anatomical con- lipid emulsion may be efficacious and hepatoprotec-
ditions and genetic disorders. tive in TPN-induced liver disease. Lipid-sparing TPN
• Idiopathic neonatal cholestasis is a term that has been strategies and continuous, small-volume enteral feeds
traditionally used to describe a clinical syndrome might also aid in halting the progression to advanced
manifested by prolonged jaundice in the neonate.    liver disease.
This description is now used less frequently because
advances in the understanding of the molecular basis
of cholestatic syndromes has allowed for definitive
diagnoses in many cases.
• Patients with neonatal cholestasis require a thorough REFERENCES
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Eur J Clin Nutr. 2011;65(6):743-749. nutrition. In: Popper SF, Popper H, Schaffner F, eds. Progress in
129. Hofmann AF. Defective biliary secretion during total parenteral liver disease. Philadelphia: Saunders; 1989:567.
nutrition: probable mechanisms and possible solutions. J Pediatr 155. Innis SM. Effect of cholecystokinin-octapeptide on total parenteral
Gastroenterol Nutr. 1995;20(4):376-390. nutrition-induced changes in hepatic bile secretion and composi-
130. Forchielli ML, Walker WA. Nutritional factors contributing to tion in the rat. J Pediatr Gastroenterol Nutr. 1986;5(5):793-798.
the development of cholestasis during total parenteral nutrition. 156. Kaminski DL, Rose RC, Nahrwold DL. Effect of pentagastrin on
Adv Pediatr. 2003;50:245-267. cholecystokinin and secretin choleresis in the dog. J Surg Res.
131. Carter BA, Shulman RJ. Mechanisms of disease: update on the 1974;17(1):26-29.
molecular etiology and fundamentals of parenteral nutrition asso- 157. Alverdy J, Chi HS, Sheldon GF. The effect of parenteral nutrition
ciated cholestasis. Nat Clin Pract Gastroenterol Hepatol. 2007;4(5): on gastrointestinal immunity. The importance of enteral stimula-
277-287. tion. Ann Surg. 1985;202(6):681-684.
132. Buchman AL. The addition of choline to parenteral nutrition. 158. Spaeth G, Berg RD, Specian RD, et al. Food without fiber pro-
Gastroenterology. 2009;137(5 Suppl):S119-S128. motes bacterial translocation from the gut. Surgery. 1990;108(2):
133. Naini BV, Lassman CR. Total parenteral nutrition therapy and 240-247.
liver injury: a histopathologic study with clinical correlation. Hum 159. Cohen C, Olsen MM. Pediatric total parenteral nutrition. Liver
Pathol. 2011;43(6):826-833. histopathology. Arch Pathol Lab Med. 1981;105(3):152-156.
134. Postuma R, Treenen CL. Liver disease in infants receiving total 160. Body JJ, et al. Total parenteral nutrition-induced cholestasis
parenteral nutrition. Pediatrics. 1979;63(1):110-115. mimicking large bile duct obstruction. Histopathology. 1982;6(6):
135. Whitington PF. Cholestasis associated with total parenteral 787-792.
nutrition in infants. Hepatology. 1985;5(4):693-696. 161. Zambrano E, El-Hennawy M, Ehrenkranz RA, et al. Total paren-
136. Beale EF, Nelson RM, Bucciarelli RL, et al. Intrahepatic cho- teral nutrition induced liver pathology: an autopsy series of 24
lestasis associated with parenteral nutrition in premature infants. newborn cases. Pediatr Dev Pathol. 2004;7(5):425-432.
Pediatrics. 1979;64(3):342-347. 162. Farrell MK, Balistreri WF. Parenteral nutrition and hepatobiliary
137. Merritt RJ. Cholestasis associated with total parenteral nutrition. dysfunction. Clin Perinatol. 1986;13(1):197-212.
J Pediatr Gastroenterol Nutr. 1986;5(1):9-22. 163. Robinson DT, Ehrenkranz RA. Parenteral nutrition-associated
138. Kelly DA. Liver complications of pediatric parenteral nutrition– cholestasis in small for gestational age infants. J Pediatr.
epidemiology. Nutrition. 1998;14(1):153-157. 2008;152(1):59-62.
304 PART III Patient Evaluation: Pediatric

164. Dunn L, Hulman S, Weiner J, et al. Beneficial effects of early hypo- 170. Puder M, Valim C, Meisel JA, et al. Parenteral fish oil improves
caloric enteral feeding on neonatal gastrointestinal function: prelimi- outcomes in patients with parenteral nutrition-associated liver
nary report of a randomized trial. J Pediatr. 1988;112(4):622-629. injury. Ann Surg. 2009;250(3):395-402.
165. Costa S, Maggio L, Sindico P, et al. Preterm small for gesta- 171. Diamond IR, Sterescu A, Pencharz PB, et al. Changing the para-
tional age infants are not at higher risk for parenteral nutrition- digm: omegaven for the treatment of liver failure in pediatric
associated cholestasis. J Pediatr. 2010;156(4):575-579. short bowel syndrome. J Pediatr Gastroenterol Nutr. 2009;48(2):
166. Teitelbaum DH, HanMarkey T, Drongowski RA, et al. Use of 209-215.
cholecystokinin to prevent the development of parenteral nutri- 172. Koletzko B, Goulet O. Fish oil containing intravenous lipid emul-
tion-associated cholestasis. JPEN J Parenter Enteral Nutr. sions in parenteral nutrition-associated cholestatic liver disease.
1997;21(2):100-103. Curr Opin Clin Nutr Metab Care. 2010;13(3):321-326.
167. Teitelbaum DH, Tracy TF, Aouthmany MM, et al. Use of chole- 173. [Clinicaltrials.gov [Internet]. Bethesda (MD): National Library of
cystokinin-octapeptide for the prevention of parenteral nutrition- Medicine (US) 2000- [cited 2009 Oct 1]:Available from: http://w
associated cholestasis. Pediatrics. 2005;115(5):1332-1340. ww.clinicaltrials.gov/ct2/show/NCT00512629.].
168. Levine A, Maayan A, Shamir R, et al. Parenteral nutrition-associ- 174. Mullick FG, Moran CA, Ishak KG. Total parenteral nutrition: a
ated cholestasis in preterm neonates: evaluation of ursodeoxycholic histopathologic analysis of the liver changes in 20 children. Mod
acid treatment. J Pediatr Endocrinol Metab. 1999;12(4):549-553. Pathol. 1994;7(2):190-194.
169. Chen CY, Tsao PN, Chen HL, et al. Ursodeoxycholic acid 175. Balistreri WF. Transplantation for childhood liver disease: an
(UDCA) therapy in very-low-birth-weight infants with parenteral overview. Liver Transpl Surg. 1998;4(5 Suppl 1):S18-S23.
nutrition-associated cholestasis. J Pediatr. 2004;145(3):317-321.
 CHAPTER 26

Transplantation for
Biliary Atresia in Children
Robert S. Venick • Ronald W. Busuttil

CHAPTER OUTLINE

HISTORY SURGICAL MANAGEMENT

INCIDENCE The Kasai Operation and Its Modifications
Timing and Outcome
GENETICS OF BILIARY ATRESIA Liver Transplantation
ETIOLOGY Indications
Defect in Morphogenesis Transplantation as Primary Therapy
Viral Infections Technical Considerations
Immune-Mediated Injury Technical Variants
CLASSIFICATION Pediatric End-Stage Liver Disease Score and
Waiting List
HISTOLOGICAL FEATURES Pretransplant Workup
CLINICAL FINDINGS AND DIAGNOSTIC Complications
EVALUATION Outcomes
MEDICAL MANAGEMENT FUTURE DEVELOPMENTS

Biliary atresia (BA) is the result of an idiopathic, pro- that BA was the most common cause of obstructive jaun-
gressive, fibroinflammatory process that affects intra dice in infants, with most of Gross’s patients having
hepatic and extrahepatic bile ducts. It typically presents “noncorrectable” biliary ductal occlusion. Unfortunately,
in the first few weeks of life and without early recogni- over the next 20 years little progress was made in surgical
tion and surgical treatment progresses rapidly to biliary management of the noncorrectable forms of BA.
cirrhosis, leading to either liver transplantation or death In 1968 Kasai5 reported a 10-year experience in
by 2 years of age. This chapter provides clinicians and achieving operative relief of BA through hepatic portoen-
surgeons with a detailed overview of the history, inci- terostomy in infants previously thought to be noncor-
dence, etiology, clinical forms and findings, histology, rectable. This report ultimately led to the acceptance of
and medical and surgical management of BA and also hepatic portoenterostomy as the treatment of choice in
provides a specific focus on BA from a transplant patients with BA. With increased experience it became
perspective. apparent that early diagnosis and timely operations were
essential to successful restoration of bile flow, yet long-
term success was still rare. Starzl and colleagues6 intro-
HISTORY duced liver transplantation as a treatment option for BA
in 1963. Indeed, the first attempted liver transplantation
The first major review of BA1 was written by Thompson1A (LT) in humans was performed on March 1, 1963, by
in 1891. In his review of 50 reported cases from the litera- Starzl in a 3-year-old child with BA. However, it was not
ture, Thompson described the signs, symptoms, gross until the introduction of cyclosporine in the early 1980s
pathological characteristics, and natural history of this that LT became a viable therapeutic option for children
inflammatory lesion. Among the reported patients, 16% with BA. Today the strategy for surgical therapy in most
were thought to be theoretically amenable to surgical patients involves an initial Kasai procedure with subse-
correction. Holmes2 in 1916 added to this review and quent LT when biliary drainage cannot be successfully
reinforced the concept of “correctable” and “noncorrect- reestablished or when progressive complications of end-
able” conditions. It was not until 1928, however, that the stage liver disease develop. BA is the leading indication
first successful reconstruction of the correctable type of for pediatric LT, accounting for up to 75% of transplants
BA was reported by Ladd.3 In 1953 Gross4 documented in children under 2 years of age.6A BA has been

305
306 PART III Patient Evaluation: Pediatric

responsible for innovations and technical advancements associated malformations (10% to 20%), the most com-
in the field of liver transplantation over the past 50 years. mon of which is the polysplenia syndrome. In this syn-
drome the combination of BA and splenic abnormalities
(polysplenia or asplenia) is often accompanied by other
INCIDENCE malformations, including intestinal malrotation, abdomi-
nal situs inversus, annular pancreas, gastrointestinal tract
BA is among the most common causes of chronic cho- atresia, renal anomalies, cardiac defects, and vascular
lestasis in children.6B The disease occurs worldwide and abnormalities (such as a preduodenal or absent portal
affects an estimated 1 in 5000 to 18,000 live births (1 in vein, an interrupted retrohepatic vena cava, and anoma-
5000 in Taiwan, 1 in 12,000 in the United States, 1 in lous hepatic arterial circulation).15-15 Patients with the
18,000 in Europe) with a slight female preponderance.7,8 fetal form also have been reported by some as having
8A,8B In the United States 250 to 400 new cases of BA are worse surgical outcomes.14,17,18 In contrast to the fetal
reported per year.8C Some reports have cited the highest form, the perinatal form of BA does not have associated
risk for BA in nonwhite children and those born during congenital anomalies.
the winter through early springtime.9 BA is the leading
cause for pediatric LT, accounting for over 40% of chil-
dren undergoing their first transplant.10
Viral Infections
A favored theory in the development of the acquired or
perinatal form of BA has implicated viral infections as
GENETICS OF BILIARY ATRESIA activating an exaggerated inflammatory response that tar-
gets bile duct epithelia and results in progressive bile duct
Genetic association of BA remains unclear. Although BA injury and secondary biliary cirrhosis.19
does not generally occur in siblings, there are case reports Several viruses have been implicated, and the three
of twins with BA, and some studies have suggested a genetic most extensively studied are reovirus type 3, rotavirus
predisposition.11,12 Recent genome-wide association stud- type C, and cytomegalovirus. It is postulated that these
ies from China have revealed a strong association of BA viral infections may initiate cholangiocyte apoptosis and
with two genes found on chromosome 10q24 that are release of antigens that trigger a host immune response.
expressed in biliary epithelia and potentially are involved in There are animal models in which these viruses can
immune dysregulation and fibrosis.12A These include induce BA, but no consistent data support these viruses as
X-prolyl aminopeptidase P1(XPNPEP1), which is involved a cause of BA in humans.20-22 The search for a viral cause
in the metabolism of inflammatory mediators, and adducin or environmental toxin began after it was proposed that
3 (ADD3), which could be responsible for excessive deposi- there was seasonal variation or time-space clustering of
tion of actin and myosin and contribute to biliary fibrosis. cases of BA. At least two studies of the epidemiology of
The single nucleotide polymorphisms (SNPs) identified in BA do not support the theory that there is time-space
this study require further investigation to validate whether clustering of cases.23,24
these genetic defects are applicable to all ethnicities. None-
theless, genetic predisposition alone does not seem to be
enough to explain the cause of BA.
Immune-Mediated Injury
It has been proposed that patients with BA may have an
abnormality in their immune system or inflammatory
ETIOLOGY response.25 Indeed there is some evidence of immune
activation in BA patients in comparison to controls.
At one time it was widely postulated that BA resulted Patients with BA have been reported to have an increase
from failed recanalization of embryonic bile ducts. This in the number of CD68+ macrophages and a correspond-
theory has for the most part been abandoned, and it is ing increase in serum interleukin-18.26-28 Other potential
generally felt that there are two major forms of BA: the proposed mechanisms include an exaggerated TH1
embryonic/fetal form and the acquired/perinatal form. immune response, overactive humoral immunity, and a
Ongoing areas of research into the cause of BA include possible role for regulatory T cells.19 Whether the
defects in morphogenesis, viral and environmental fac- immune system is reacting to a stimulus in a genetically
tors, and immune-mediated injury. predisposed host is yet to be determined.

Defect in Morphogenesis CLASSIFICATION

The fetal form of BA accounts for less than 20% of all
children with BA and is associated with other extrahe- BA is classified with a comprehensive system based on the
patic congenital anomalies described in the following macroscopic and cholangiographic appearance of the
paragraph.13,14 Several investigators have described inter- biliary ducts. Type 1 BA consists of atresia of the com-
ruption in the normal remodeling of the biliary tree dur- mon bile duct with or without cystic dilatation of the dis-
ing embryogenesis.15 These patients have ductal plate tal patent duct. Type 2 is defined as atresia of the common
malformations on histological examination.15 hepatic duct, and type 3 has atresia of the right and left
Clinically infants with the fetal form of BA have no hepatic ducts up to the porta hepatis. Type 3 is the most
jaundice-free interval after birth and a high frequency of common type and occurs 70% to 90% of the time. The
 26 Transplantation for Biliary Atresia in Children 307

three major types can be further subdivided according to will worsen, and by 3 to 4 months of age, failure to thrive,
the pattern of the distal bile ducts and the pattern of the hepatosplenomegaly, muscle wasting, ascites, coagulopa-
hepatic hilar radicles. This further classification, how- thy, and cirrhosis will develop.
ever, appears to have little bearing on operative The diagnosis of BA is often missed because of confusion
outcomes. with physiological or breast milk jaundice, both of which are
associated with unconjugated hyperbilirubinemia.33 BA on
the other hand presents with conjugated hyperbilirubinemia
HISTOLOGICAL FEATURES defined as greater than 2.0 mg/dL or greater than 10% of
the total bilirubin. Such laboratory findings should prompt
Microscopically, three specific types of biliary structures an urgent referral to a pediatric gastroenterologist for fur-
appear at the transected hilar surface: bile ducts, collect- ther assessment.34 It is imperative to intervene before 2 to
ing ductules, and biliary glands.29 Only the microscopic 3 months of age, and ideally as early as 30 to 45 days of life,
bile ducts are believed to communicate with the intrahe- to give the Kasai operation its best chance of success.8B,35 All
patic biliary system. Bile flow may be anticipated after children with jaundice after 2 weeks of age need to undergo
hepatic portoenterostomy when these ductal structures a laboratory evaluation that includes total and conjugated
are present, even if they are severely deformed by inflam- bilirubin. Improving early recognition of BA among parents
mation. The number of these ducts, however, decreases and pediatric health care providers has been the focus of
progressively with age as they are replaced by fibrous tis- successful educational campaigns and screening programs in
sue. It is thought that if flow can be maintained through Taiwan.35A
these ducts for the first few months after surgery, they Although the differential diagnosis of a neonate with
will ultimately act as internal biliary fistulas. Many studies cholestasis is extensive (Table 26-1), many of the dis-
have tried to correlate the number and size of these ductal eases included do not have the same clinical features as
structures with the success rate of hepatic portoenteros- BA. TORCH (toxoplasmosis, other agents, rubella,
tomy, unfortunately with conflicting results.29,30 Although cytomegalovirus, herpes simplex) infections must be
the presence of larger ducts usually portends success, the considered in infants with cholestasis.35B Additional
absence of such does not necessarily condemn one to viruses that can lead to direct hyperbilirubinemia or
failure. acute liver failure in neonates include enterovirus, her-
Histopathological examination of the ductal remnant pesvirus, and parvovirus. In children with vomiting,
in BA demonstrates chronic inflammation and granula- encephalopathy, and hyperammonemia with or without
tion resulting in complete obstruction. As with any severe coagulopathy, a workup for metabolic liver dis-
obstructive process in this age-group, there is initial ease should be performed.
hepatocellular and canalicular cholestasis and eventually The vast majority of cholestatic neonates will have BA
an accompanying proliferation of the biliary ductules in or neonatal hepatitis, so one of the challenges in the
the portal tracts. As the unrelieved obstruction pro-
gresses, focal hepatocyte necrosis occurs, multinucleated
giant hepatocytes and an inflammatory infiltrate appear, TABLE 26-1 D
 ifferential Diagnosis of
portal tracts are widened by edema, and intralobular Cholestatic Neonates
fibrosis develops. These findings, however, are also clas-
sic features of neonatal hepatitis, and the similarities Biliary atresia
between early BA and neonatal hepatitis result in low Neonatal hepatitis
specificity of percutaneous biopsies performed early in Metabolic disease
life. Nonetheless, by 4 to 8 weeks of age, three classic α1-Antitrypsin deficiency
findings of BA can usually be seen: (1) bile plugs in the Galactosemia
ductules, (2) portal fibrosis, and (3) biliary ductular prolif- Cystic fibrosis
eration. Nonetheless, distinguishing between BA and dis- Disorders of bile acid synthesis
orders such as neonatal hepatitis, total parenteral Choledochal cyst
nutrition–associated liver disease, and α1-antitrypsin defi- Ductal paucity
ciency also requires laboratory testing, imaging, and Alagille syndrome
detailed clinical information.31,32 Nonsyndromic paucity of ducts
Progressive familial intrahepatic cholestasis
Infection
CLINICAL FINDINGS AND DIAGNOSTIC Escherichia coli
EVALUATION TORCH
Syphilis
The typical BA patient is a normal-sized, full-term infant HHV6
who initially gains weight well, then develops jaundice HIV
with conjugated hyperbilirubinemia persisting and pro- Enteric viral sepsis
gressing beyond 2 weeks of age. Hepatomegaly, pruritus, Endocrine
and coagulopathy may be noted depending on the age of Hypopituitarism
presentation and the clinical progression of the disease. HHV6, Human herpesvirus 6; HIV, human immunodeficiency virus;
There may be dark urine, and stools will be progressively TORCH, toxoplasmosis, other agents, rubella, cytomegalovirus,
acholic. If no intervention is performed, the liver disease herpes simplex.
308 PART III Patient Evaluation: Pediatric

Laboratory workup Additional laboratory studies when

clinically indicated
ALT, AST, GGTP, alkaline phosphatase,
total bilirubin, conjugated bilirubin, TORCH titers, viral cultures, sweat
prothrombin time, complete blood count, chloride level, TSH level, serum bile acid
α1-antitrypsin level, urine culture, and levels, ferritin, and total iron binding
urine-reducing substances capacity

Ultrasonography

MRC ERCP HIDA scan Choledochal cyst

Bile ducts not Biliary ducts Excretion No excretion Surgery

visualized visualized into the gut into the gut

Liver biopsy

Consistent Consistent
with biliary with neonatal
atresia hepatitis

Intraoperative Prevent complications of

cholangiogram and Kasai cholestasis and observe until
cholestasis resolves
FIGURE 26-1 n Algorithm for the workup of neonatal jaundice. ALT, Alanine aminotransferase; AST, aspartate aminotransferase; ERCP,
endoscopic retrograde cholangiopancreatography; GGTP, γ-glutamyl transpeptidase; HIDA, hepatoiminodiacetic acid; MRC, mag-
netic resonance cholangiography; TORCH, toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex; TSH, thyroid-
stimulating hormone.

diagnostic workup is to define the role of various labora- certainly not diagnostic of BA. Other findings on ultraso-
tory and imaging studies and biopsy findings in differen- nography, such as the triangular cord sign and the shape
tiating the two. Figure 26-1 is an algorithm for the and thickness of the gallbladder and its wall, have been
workup of a cholestatic neonate. The workup begins with used to support the diagnosis of BA.36,37
laboratory evaluation. Alanine aminotransferase and After ultrasonography the workup of BA depends on
aspartate aminotransferase levels are typically mildly ele- the expertise available at the institution, degree of suspi-
vated in patients with BA. Alkaline phosphatase and cion of the infant having BA, and the age of the patient.
γ-glutamyl transpeptidase (GGTP) levels are always ele- Tc 99–labeled hepatoiminodiacetic acid (HIDA) scans
vated in BA. In contrast, progressive familial intrahepatic can be performed. If they demonstrate excretion into the
cholestasis types I and II and primary disorders of bile gut, BA is essentially ruled out. Patients undergoing
acid synthesis are associated with low or normal GGTP HIDA scans should be pretreated with phenobarbital
levels. The prothrombin time should be checked to (5 mg/kg/day for 5 days) before the test in order to
ensure that there is not a significant coagulopathy sec- enhance biliary excretion of the isotope and the sensitiv-
ondary to vitamin K deficiency. Complete blood counts ity of the procedure. In patients with severe cholestasis of
and platelets should be checked before any invasive pro- other causes, the liver may not excrete tracer.38 Recently
cedure and may be abnormal in patients with neonatal institutions have begun to perform magnetic resonance
hepatitis (hemolysis) or viral infection (thrombocytope- cholangiography (MRC) with various levels of
nia). Serum α1-antitrypsin levels and phenotypes should ­sensitivity.39,40 MRC has advantages over other modali-
also be determined. Urine should be sent for culture and ties in that it is noninvasive, although for infants it will
testing for reducing substances. The presence of reduc- require sedation to obtain good-quality images.
ing substances is suggestive of galactosemia, in which case Liver biopsy can be the most sensitive and specific test
galactose-1-phosphate uridyl transferase levels should be to delineate between BA and other causes of neonatal
determined. Ultrasonography should be performed on cholestasis.41 The procedure is a cornerstone of the diag-
every infant with cholestasis to rule out structural defects nostic workup of infants with cholestasis and can be per-
such as choledochal cysts. If no gallbladder is seen after a formed percutaneously, safely, and with timely results. If
4-hour fast, the findings can be consistent with but the biopsy findings are consistent with BA, the child
 26 Transplantation for Biliary Atresia in Children 309

should undergo definitive testing with an intraoperative peritonitis can occur in patients with ascites, and infants
cholangiography and a Kasai procedure. If the biopsy with abdominal pain and fever should be assessed and
results are inconsistent with BA (i.e., paucity of intrahe- treated urgently.
patic bile ducts), the child should be treated and moni- Splenomegaly may increase intra-abdominal pressure
tored closely. If other biopsy findings are present, further and exacerbate ascites, respiratory distress, and poor oral
workup should be pursued to elucidate the cause of the intake. Thrombocytopenia secondary to hypersplenism
cholestasis. Liver biopsy by itself can be a challenging increases the risk for bleeding and should be monitored
means of making the diagnosis of BA given that the histo- closely. Encephalopathy may be difficult to diagnose in
logical features of many cholestatic disorders of infancy small children but should be suspected in any child with a
may overlap and change depending on the age of the change in sleep patterns (including insomnia or fatigue),
infant.42 In addition to its diagnostic role, the liver biopsy chronic irritability, or a change in personality. Treatment
can yield important prognostic information, including with lactulose or rifaximin should be instituted in those
the degree of fibrosis, which may help clinicians and sur- with encephalopathy.
geons predict outcome after Kasai procedure. Gastrointestinal bleeding is potentially the most sig-
nificant manifestation of portal hypertension. Once gas-
trointestinal hemorrhage occurs, initial management
MEDICAL MANAGEMENT should focus on establishing hemodynamic stability. The
bleeding can be controlled by the administration of
Medical management of children with BA aims to treat octreotide and by endoscopic sclerotherapy or band-
complications of end-stage liver disease. BA patients who ing.53,54 Endoscopic band ligation has been shown to be
remain cholestatic either before or after portoenteros- as effective as sclerotherapy and safer, although for logis-
tomy will be unable to absorb fats or fat-soluble vitamins tical reasons it is a challenge to perform in children under
effectively, and complications of fat-soluble vitamin defi- 5 years of age.55 Bleeding that cannot be controlled by
ciency develop if vitamins A, D, E, and K are not supple- endoscopic or medical management may be controlled by
mented. Cholestasis also can cause a deficiency in essential transjugular intrahepatic portosystemic shunt.56
phospholipids and fatty acids (linoleic acid and arachi- Prophylaxis against variceal bleeding can be accom-
donic acid), which improves with supplementation and plished endoscopically.54,55 In pediatric studies, therapy
treatment with ursodeoxycholic acid (UDCA).43,44 with propranolol has been shown to be safe, although fur-
As liver disease progresses, several factors, including ther studies are needed to establish the efficacy and the
fat malabsorption, increased energy expenditure, and physiological parameters of these treatments.57
early satiety secondary to ascites and organomegaly, con-
tribute to poor growth and development. This is a preva-
lent problem, with growth failure reported in 40% of
children with BA who underwent LT in the Studies of
SURGICAL MANAGEMENT
Pediatric Liver Transplantation (SPLIT) registry.45 Mal- The Kasai Operation and Its Modifications
nutrition has been associated with poor outcomes both
before and after LT.45,46 Nutritional supplementation Before the development of adequate surgical therapy, the
consisting of a formula rich in medium-chain triglycer- natural history of untreated BA was progressive cirrhosis
ides administered orally or via a combination of oral and and, in the overwhelming majority of patients, eventual
nasogastric or gastric tube supplementation is often death from variceal bleeding, infection, or hepatic decom-
needed. Recently, s­ingle-center reports of parenteral pensation by 2 years of age.59 When Kasai and Suzuki59
nutrition supplementation in BA patients awaiting LT first introduced hepatic portoenterostomy in 1959, the
have demonstrated improvements in pre-LT growth and procedure was regarded with skepticism. Since that time,
post-LT outcomes.47 the Kasai procedure has become the mainstay of initial
Pruritus can also be a complication of cholestatic liver surgical therapy by providing the dissected hepatic hilar
disease. UDCA relieves pruritus in a small percentage of plate with intestinal drainage.
patients.48,49 Diphenhydramine, hydroxyzine, topical Over the years, surgeons have attempted to modify the
skin care, cholestyramine, rifampin, or naltrexone can original Kasai procedure to overcome some of its techni-
also be used and may be effective in more than 50% of cal shortcomings—specifically, problems with inadequate
patients with intractable pruritus.50,51 Long-acting opiate drainage and postoperative cholangitis. Drainage of the
antagonists can be used in patients who do not respond to hilar plate depends on the presence of sufficient biliary
rifampin.52 structures in the transected surface of the hepatic hilum.
Another complication that arises in patients with BA is To improve the probability of encountering such struc-
portal hypertension. It can be manifested as gastrointesti- tures, the operation has evolved over time to incorporate
nal bleeding, ascites, hypersplenism, and encephalopathy. a wider dissection of the porta hepatis. Because the oblit-
Treatment of portal hypertension should be directed at erated hepatic ducts usually form a cone-shaped fibrous
preventing complications. remnant anterior and cranial to the bifurcation of the por-
Ascites accumulates because of the poor synthetic func- tal vein, many authors advocate separating the bile duct
tion of the liver, with resultant hypoalbuminemia and the remnants from the right and left portal vein branches and
hyperaldosteronism seen in chronic liver disease. Medical extending the dissection as posteriorly as possible between
treatment consists of nutritional supplementation, salt the right and left portal veins.60-63 Extended medial and
restriction, and diuretic therapy. Spontaneous bacterial lateral dissection may also improve drainage.64,65
310 PART III Patient Evaluation: Pediatric

The early success of the Kasai procedure is measured liver. Although improved postoperative management, has
clinically by the reestablishment of bile flow into the led to nearly comparable biliary drainage in patients
intestine, which correlates clinically with the presence of undergoing surgery as late as 80 days of age at some cen-
cholic stools, and the normalization of serum bilirubin ters,74 clearly, survival rates with native liver are still dra-
levels. Indeed, a serum total bilirubin level of 6.0 mg/dL matically affected by the timing of operative intervention.
or higher at 3 months after portoenterostomy has been A review of the Tohoku University Hospital experience
associated with poor short-term outcome and can be used showed a steady decrease in 10-year survival rates with
as a marker for a failed Kasai procedure.66 increased age at surgery (72% 10-year survival rate in
After Kasai portoenterostomy, adjunct perioperative patients operated on before the age of 60 days, 41% in
steroid therapy has been promoted by some to help estab- patients 61 to 70 days old, 30% in patients 71 to 90 days
lish bile flow. Several studies have demonstrated improved old, and only 13% in those operated on after
survival in steroid-treated patients.17,67,68 Meyers and 3 months of age).74 Other series show 5- and 10-year
associates17 compared 14 patients receiving steroids, actuarial survival rates to vary widely (each ranging from
UDCA, and a combination of intravenous and oral anti- around 25% to 60%) and to depend on such factors as age
biotics with 14 patients receiving oral antibiotics and of the patient at time of portoenterostomy, extent of
intermittent UDCA. Survival without LT or cholestatic hepatic fibrosis, surgical era, number of cholangitis epi-
liver disease was significantly better in the first group. sodes after surgery, and anatomy of the atretic bile ducts.
Although this study suggests a beneficial effect of ste- Barring the presence of severe fibrosis on liver biopsy and
roids, this area remains controversial. More recently a advanced age at the time of diagnosis, children with BA
multicenter, double-blind Steroids in Biliary Atresia should undergo hepatic portoenterostomy as the first sur-
Randomized Trial (START), which was conducted in gical procedure. Nonetheless 70% of children with BA
140 infants, did not show a statistically significant differ- who undergo a Kasai procedure will go on to develop cir-
ence in bile drainage at 6 months posthepatoportoenter- rhosis and ultimately require LT during their pediatric
ostomy with the use of postoperative steroids (58.6% of years.75 Even in patients in whom progressive liver disease
steroids group versus 48.6% of placebo group; p = .43).68B continues to develop as a result of an inadequate or failed
UDCA has been shown by some to improve biochemi- Kasai procedure, the operation allows for continued
cal and nutritional parameters without adverse effects in growth and development, up to an average of 47 months
children with BA, although improved survival without in one study,76 before undergoing LT. This additional
transplantation has not been demonstrated.48,49 time and growth gives the patient access to more potential
The most common complication after portoenteros- donors and enhances the chance for a less complicated
tomy is ascending cholangitis, which occurs in 30% to postoperative course. The Kasai procedure can be viewed
60% of children.69,70 The diagnosis of cholangitis in in this setting not as a cure for BA, but rather as a bridge
infants is suggested by fever, leukocytosis, and increasing and a means of preventing rapid progression of disease.
bilirubin levels. Positive blood cultures with appropriate
organisms are actually seen somewhat infrequently.
Cholangitis increases the risk for cirrhosis and decreases Liver Transplantation
patient survival,69,71 which is why it must be recognized Indications
promptly and treated aggressively with parenteral antibi-
otics. Recent studies have demonstrated a benefit of pro- BA accounts for 40% to 50% of all pediatric liver
phylactic oral antibiotics in preventing cholangitis.72 The transplants.8B Signs and symptoms of a failing portoenter-
study of Meyers and colleagues17 suggests that longer, ostomy should result in prompt referral for LT. Specific
more aggressive antibiotic therapy may increase the suc- leading indications for LT in children with BA are poor
cess of portoenterostomy. Antibiotics that are frequently early response to hepatoportoenterostomy, failure to
prescribed include trimethoprim-sulfamethoxazole and thrive and develop, late-onset cholestasis, primary
ciprofloxacin. To reduce the incidence of cholangitis, approach in late initial presentations, recurrent cholangi-
surgeons have attempted various modifications of the tis, portal hypertension, and peritonitis.70 Less common
original Kasai procedure, which used a 30-cm-long Roux- indications include hepatopulmonary syndrome, portopul-
en-Y jejunal limb. Modifications have included the use of monary hypertension, hepatorenal syndrome, intractable
a longer Roux-en-Y limb (40 to 70 cm in length), partial pruritus, intractable ascites, hepatocellular carcinoma,
and total diversion of the biliary drainage limb with the osteoarthropathy, and encephalopathy.
use of various stomas, creation of intussuscepted intesti-
nal valves, and the use of physiological intestinal valves
Transplantation as Primary Therapy
(i.e., the ileocecal valve).73 Such modifications have not
been shown to improve outcomes. With few exceptions, it appears that children older than
3 months with advanced cholestasis and fibrosis gain little
from hepatic portoenterostomy. With improvement in
Timing and Outcome
posttransplant outcomes and more accepted use of seg-
Nearly every major series has confirmed the relationship mental grafts from both deceased and living donor
between age at the time of hepatic portoenterostomy and sources, primary therapy with LT should be considered in
resolution of cholestasis. Kasai procedures performed children who manage to escape diagnosis before the onset
before 2 to 3 months of age, or if possible as early as 30 to of severe hepatic dysfunction.77 In addition, primary LT
45 days of life, appear to produce the best opportunity for should be considered in infants with BA who have signifi-
restoring bile flow and preventing further scarring of the cant ascites or who have had variceal bleeding.70
 26 Transplantation for Biliary Atresia in Children 311

preferred site of anastomosis. If not technically feasible,

Technical Considerations
an interposition vein graft can be performed by using
The fundamental principles of organ procurement, standard deceased donor sources or a donor ovarian vein,
recipient hepatectomy, and liver grafting have been inferior mesenteric vein, or saphenous vein if the graft
described extensively elsewhere. Several factors, how- was provided by a living donor.80
ever, are unique to children with BA, such as the frequent Successful hepatic arterial anastomosis is of the utmost
occurrence of previous portal dissection and anatomical importance. Like others, we have found that implementa-
anomalies. The majority of patients with BA have already tion of microvascular techniques and use of the operating
had considerable dissection in the porta hepatis from microscope have dramatically improved results.78,81,82
their Kasai procedure. Such dissection can result in sig- Smaller vessels, such as those encountered in infant recip-
nificant intra-abdominal adhesions, particularly if reop- ients and with segmental grafts, are typically anastomosed
erative salvage has also been attempted. Dense, bloody in an end-to-end manner by using the operating micro-
portal hilar adhesions, especially in smaller patients, who scope and interrupted 8–0 or 9–0 monofilament sutures.
do not tolerate significant blood loss, can make the opera- When the recipient is older and the vessels are larger
tion challenging. As described by Goss and colleagues,78 (>4 mm), we use the branch patch technique. In the case
we recommend first approaching the hepatic hilum from of aberrant arterial anatomy, the supraceliac aorta is the
the right posterolateral aspect by reflecting the transverse inflow vessel of choice. The use of arterial conduits and
colon and second portion of the duodenum from the usu- the infrarenal aorta is avoided if possible. We currently
ally unscarred posterior right lobe. In doing so, the Roux- administer an intraoperative and postoperative heparin
en-Y jejunal limb is then encountered crossing the infusion along with aspirin therapy postoperatively. In all
transverse mesocolon and can be traced to the hilum. operations involving small vascular anastomoses, we now
Here, the jejunal limb is transected with a linear stapler use implantable Doppler probes to monitor vessel patency
and reflected inferiorly to allow better exposure of the in the postoperative period.83 The probes are placed at
hilum and continued dissection of the hepatic arteries the conclusion of the transplant, before closure of the
and portal vein. We typically ligate and divide the right abdomen, and are held in proximity to the vessel with
and left hepatic arteries and both the right and left portal fibrin glue (Fig. 26-2). The ability to continuously moni-
vein branches. If the portal vein is small and sclerotic tor hepatic arterial and portal venous flow has facilitated
from previous operations or bouts of cholangitis, the por- early recognition of impaired flow resulting from
tal vein is dissected proximally to the confluence of the increased intra-abdominal pressure and other technical
splenic and superior mesenteric veins. When transplant- problems and has allowed early graft salvage in these
ing a whole organ or a reduced-size graft with the donor instances. The technique has also minimized the postop-
cava, the recipient’s retrohepatic cava is preferentially erative use of operator-dependent ultrasonography,
resected with the liver and replaced. When segmental which was previously used to confirm vessel patency.
grafts are used, the cava is left intact and the liver is dis- The biliary reconstruction is straightforward and uses
sected until only the hepatic vein branches remain intact. the previous Roux-en-Y limb of the hepatic portoenter-
If the inferior vena cava is congenitally absent, control of ostomy if suitable; otherwise, a 40-cm Roux-en-Y jejunal
the hepatic veins is achieved as they traverse the dia- limb is created. An internal stent and interrupted 6–0
phragm and enter the right atrium. absorbable monofilament sutures are used to create the
When a whole organ is transplanted, we proceed with choledochojejunostomy (or hepaticojejunostomy in the
orthotopic transplantation in the standard fashion. With case of a segmental graft).
a significant number of pediatric patients receiving seg-
mental grafts, however, certain adjustments in technique
Technical Variants
are made to accommodate the donor and recipient ves-
sels. Venous outflow obstruction was a critical complica- Approximately 10% to 20% of BA patients have multiple
tion in many of the early recipients of segmental liver other malformations, such as situs inversus, absent infe-
grafts. We use the technique first described by Emond rior vena cava, preduodenal portal vein, and other mani-
and associates79: triangulation of the recipient hepatic festations of the polysplenia syndrome (Fig. 26-3).
vein orifice along the anterior vena cava together with the Although such anatomical abnormalities make LT in
corresponding wall of the donor hepatic vein and triangu- these patients technically challenging, they do not appear
lation of the anastomosis. By creating as short and as wide to have a significant impact on outcome.18,84-87
an anastomosis as possible, the incidence of hepatic vein
stenosis can be minimized. This technique also allows the
Pediatric End-Stage Liver Disease Score
graft to be slightly rotated, which facilitates access to the
and Waiting List
hilar structures and better aligns the inflow vessels.
Portal inflow is accomplished with an end-to-end For children 12 years of age and under with BA awaiting
anastomosis of the donor and recipient portal veins when- LT in the United States, the Pediatric End-Stage Liver
ever possible. If a size disparity exists, a branch patch of Disease (PELD) scoring system is used to prioritize their
the recipient’s right and left portal veins can be used. position on the waiting list. The components that go into
Often, however, the recipient portal vein is sclerotic or the PELD score are albumin level, bilirubin level, inter-
thrombosed as a result of previous hepatic portoenteros- nationalize normalized ratio, age, height, and weight. The
tomy or cholangitis episodes. If the confluence of the initial studies that validated the PELD score as a reliable
splenic and superior mesenteric veins is patent and the predictor of waiting list mortality should a child awaiting
donor portal vein will reach, this confluence is the next LT not receive such a transplant in the subsequent 90
312 PART III Patient Evaluation: Pediatric

Hemiazygos vein

Heart

Hepatic veins
Azygos vein
Multiple
spleens?
A
Liver
Atretic
bile ducts

Anomalous
hepatic Pancreas
artery?
Preduodenal
portal vein
Interrupted IVC
Renal vein

FIGURE 26-3 n Anatomical variants associated with biliary atre-

sia. IVC, Inferior vena cava.

B Pretransplant Workup
FIGURE 26-2 n A, Implantable Doppler probe. B, Fibrin glue
placed on probes located on the surface of the hepatic artery
Children being evaluated for listing for LT should be
and portal vein to stabilize the probes. seen by transplant surgeons, pediatric transplant hepa-
tologists, transplant nurse coordinators, and social work-
ers. In addition, given the relatively high incidence of
congenital heart disease in patients with BA, it is recom-
days, included a large percentage of children with BA. mended that these children also be seen by cardiologists
According to relatively recent United Network for Organ and undergo pretransplant echocardiogram. When pos-
Sharing (UNOS) data, the median waiting time from list- sible it is also beneficial to have the children seen by
ing to LT for children with BA was 90 days, and the members of the anesthesia and critical care teams who
median PELD score at the time of LT was 15.88 Children will be involved in the peri-LT and post-LT manage-
listed in the United States with a calculated PELD score ment. Children with BA should undergo abdominal
greater than 25 who require intubation/mechanical venti- ultrasound examination with Doppler, and given the rela-
lation, renal replacement therapy, or greater than 30 mL/ tively high frequency of vascular anomalies associated
kg of packed red blood cells transfusion within a 24-hour with BA, we recommend a low threshold for magnetic
period are prioritized even higher on the waiting list as resonance venogram of the abdomen if the child’s vascu-
status 1B. The past decade has seen a call among pediatri- lar anatomy is in doubt.
cians and surgeons for increased splitting of donor organs,
as well as national organ sharing to help prevent waiting Complications
list mortality. In the SPLIT registry 3% of children with
BA awaiting LT died on the waiting list.45 The majority The complications in patients transplanted for BA are
of these children had calculated PELD scores above 20 seen in other pediatric LT recipients, although potentially
and growth failure. more frequently in the setting of BA given the relatively
 26 Transplantation for Biliary Atresia in Children 313

young age and small size of the average recipient. Possible independent of the number of previous surgical proce-
surgical complications, including vascular and biliary dures or trauma at the time of LT.98,99 A high index of
problems, enteral leaks, reoperations, and large-for-size suspicion, rapid diagnostic imaging, and early operative
grafts, are covered in the ensuing pages. Infection, rejec- reexploration may be the only means of effectively treat-
tion, and complications of long-term immunosuppression ing this often lethal complication.
following pediatric LT are nonspecific to children with Reoperations following LT occur relatively commonly
BA and are covered extensively in other chapters. in children with BA. Specifically in the SPLIT registry,
Hepatic artery thrombosis is among the most devastat- 48% of children underwent subsequent operations.45
ing early complications. Clinical findings can range from Large-for-size grafts are defined as graft weight–to–
essentially no symptoms to episodes of relapsing bactere- recipient weight ratio of greater than 4%. Given organ
mia to fulminant graft necrosis and failure. Despite metic- shortages, large-for-size grafts are encountered in BA
ulous surgical technique, antiplatelet and anticoagulation recipients, and in such cases attention must be paid to
therapy, arterial thrombosis is reported in 5% to 15% of proper wound management to avoid tension and possible
children undergoing LT for BA78,89-92 and it remains ischemia on the graft. Techniques, including skin-only
among the leading causes of early graft failure and the pri- closure, temporary closure with prosthetic material, or
mary indications for retransplantation. With microvascu- back-table reduction of a large graft, can be used effec-
lar techniques and loupe magnification employed at most tively in these scenarios.95D,100
centers, however, rates of hepatic artery thrombosis have
declined significantly.81,93-95B Potentially a better under- Outcomes
standing of the hepatic microvasculature and its response
to ischemia-reperfusion and acute rejection may permit Since the first days of pediatric LT, transplant teams
the development of methods to further decrease the inci- have gained significant experience in the intraoperative
dence of this complication. Complications involving the and postoperative care of pediatric LT recipients.
portal vein are reported in 6% to 14% of BA patients Although complications after pediatric LT can be
undergoing LT.92,95A,95C The rate of portal vein thrombo- severe, the rewards are great and the results generally
sis is speculated to be higher in children with BA than in quite good. Improvements in surgical techniques, intra-
other pediatric recipients given the hypoplastic nature of operative management, and pediatric critical care, along
the portal vein and anatomical considerations seen in syn- with a greater understanding of the long-term medical
dromic BA.95D Early postoperative portal vein occlusion management of pediatric LT recipients have combined
can be manifested in a variety of ways, ranging from no to yield ever-improving results after LT for BA. Table
overt symptoms to progressive liver failure. If diagnosed 26-2 summarizes the reported experience of some of the
promptly, early reoperation and thrombectomy can poten- larger centers with liver transplantation for BA. The
tially salvage the graft. In general, portal venous complica- 5-year actuarial survival rates reported by these centers
tions occur at higher rates than venous outflow problems. for children with BA are comparable to those for pediat-
In a single-center review of 600 pediatric LTs, the rate of ric patients undergoing LT for all causes. Indeed in our
portal vein complications was 7.2%, whereas the incidence own pediatric LT experience, children with BA enjoyed
of hepatic vein or vena cava outflow problems was 2.3%. among the best outcomes of all children undergoing
Long-term portal venous complications may be treated LT. Of note in most series is the significant percentage
with venoplasty, surgical shunt, or retransplantation. Bili- of patients with BA who are transplanted with segmental
ary tract complications occur in up to 20% of children with grafts.101 The ability to expand the donor pool in this
BA who undergo LT.95A,96 Late biliary strictures and cho- fashion has enabled many patients with BA to undergo
lestasis are often the result of chronic rejection or ischemia. LT before the development of decompensated hepatic
Frequently, subtle elevations in serum alkaline phospha- failure. The use of segmental grafts from both living and
tase or GGTP levels may be the only clue to the diagnosis. deceased donors in conjunction with the ability to trans-
Noninvasive imaging may be unreliable, and percutaneous plant these recipients in a generally healthier state has
transhepatic cholangiography is often necessary, not only resulted in a significant survival benefit.
to confirm the diagnosis but also to provide drainage and Some of the larger studies have elucidated predictors of
allow for dilation and stenting when necessary. Intrahe- outcomes for children with BA undergoing LT. As previ-
patic strictures pose a much greater problem and may ulti- ously discussed, pre-LT nutritional status affects both
mately require retransplantation. patient and graft survival in the large SPLIT analysis. Other
Postoperative enteral leak or intestinal perforation has potentially important predictors include recipient age at
been reported in 4% to 20% of children undergoing LT LT, retransplantation, UNOS status 1, and tacrolimus ver-
for BA.95A,97 Such problems ought to be suspected in sus cyclosporine as primary immunosuppression.95D
cases of unexplained sepsis or clinical deterioration not
otherwise explained. Leaks from the biliary enteric anas-
tomosis are commonly associated with hepatic artery FUTURE DEVELOPMENTS
thrombosis, although they can also occur in the absence
of a vascular complication. Leaks or breakdown of the Although it is clear that significant advancements have
jejunojejunostomy and the intestinal staple lines, or both, been made for children with BA with regard to their early
may also be seen in the early postoperative period. diagnosis and medical and surgical management, ongoing
Spontaneous intestinal perforation occurs surprisingly research is still needed. The Biliary Atresia Research
often in the early postoperative period and appears to be Consortium was formed in 2002 as a National Institutes
314 PART III Patient Evaluation: Pediatric

TABLE 26-2 Results of Liver Transplantation For Biliary Atresia

Segmental 5-Year Patient 5-Year Graft Series
Author Number of Patients Grafts (%) Retransplantation (%) Survival Rate (%) Survival Rate (%)
Diem et al92 328 62 16 83 72
Goss et al78 190 18 16 78 76
Ishikawa et al102 73 47 14 74 N/A
Nagral et al76 64 63 23 84 69
Peeters et al103 52 N/A 21 70 64
Fouquet et al91 280 60 16 82 73
Utterson et al45 567 31 11 NA NA
Barshes et al88 1976 22 NA 87 76

N/A, Data not available.

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31. Russo P, Magee J, Boitnott J, et al. for the Biliary Atresia Research agement in children. Semin Pediatr Surg. 1999;8:193–201.
Consortium. Design and Validation of the Biliary Atresia Research 55. Zargar SA, Javid G, Khan BA, et al. Endoscopic ligation com-
Consortium Histologic Assessment System for Cholestasis in pared with sclerotherapy for bleeding esophageal varices in chil-
Infancy. Clinical Gastroenterology and Hepatology. 2011;9:357–362. dren with extrahepatic portal venous obstruction. Hepatology.
32. Morroti R, Jain D. Pediatric Cholestatic Disorders Approach to 2002;36:666–672.
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33. Hartley J, Harnden A, Kelly D. Biliary Atresia. BMJ. hepatic portosystemic shunt creation in children: Initial clinical
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34. Guideline for the Evaluation of Cholestatic Jaundice in Infants: 57. Shashidhar H, Langhans N, Grand RJ. Propranolol in prevention
Recommendations of the North American Society for Pediatric of portal hypertensive hemorrhage in children: A pilot study.
Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroen- J Pediatr Gastroenterol Nutr. 1999;29:12–17.
terol Nutr. 2004;39:115–128. 58. Karrer FM, Lilly JR, Stewart BA, et al. Biliary atresia registry,
35. Chardot C, Carton M, Spire-Bendelac N, et al. Epidemiology of 1976 to 1989. J Pediatr Surg. 1990;25:1076–1080. discussion 1081.
biliary atresia in France: A national study 1986-96. J Hepatol. 59. Kasai M, Suzuki S. A new operation for “non-correctable” biliary
1999;31:1006–1013. atresia: Hepatic portoenterostomy. Shujutsu. 1959;13:773–779.
35A. Lien TH, Chang MH, Wu JF, et al. Effects of the infant stool 60. Ohi R, Ibrahim M. Biliary atresia. Semin Pediatr Surg.
color card screening program on 5-year outcome of biliary atresia 1992;1:115–124.
in Taiwan. Hepatology. 2011;53(1):202–208. 61. Endo M, Katsumata K, Yokoyama J, et al. Extended dissection of
35B. McCracken GH Jr, Shinefield HM, Cobb K, et al. Congenital the porta hepatis and creation of an intussuscepted ileocolic con-
cytomegalic inclusion disease. A longitudinal study of 20 patients. duit for biliary atresia. J Pediatr Surg. 1983;18:784–793.
Am J Dis Child. 1969;117:522–539. 62. Ito T, Nagaya M, Ando H, et al. Modified hepatic portal enteros-
36. Park WH, Choi SO, Lee HJ. Technical innovation for noninvasive tomy for biliary atresia. Z Kinderchir. 1984;39:242–245.
and early diagnosis of biliary atresia: The ultrasonographic “trian- 63. Toyosaka A, Okamoto E, Okasora T, et al. Extensive dissection at
gular cord” sign. J Hepatobiliary Pancreat Surg. 2001;8:337–341. the porta hepatis for biliary atresia. J Pediatr Surg. 1994;29:896–899.
37. Farrant P, Meire HB, Mieli-Vergani G. Improved diagnosis of 64. Schweizer P, Kirschner HJ, Schittenhelm C. Anatomy of the porta
extrahepatic biliary atresia by high frequency ultrasound of the hepatis (PH) as rational basis for the hepatoporto-enterostomy
gall bladder. Br J Radiol. 2001;74:952–954. (HPE). Eur J Pediatr Surg. 1999;9:13–18.
316 PART III Patient Evaluation: Pediatric

65. Ando H, Seo T, Ito F, et al. A new hepatic portoenterostomy with 87. Falchetti D, de Carvalho FB, Clapuyt P, et al. Liver transplanta-
division of the ligamentum venosum for treatment of biliary atre- tion in children with biliary atresia and polysplenia syndrome.
sia: A preliminary report. J Pediatr Surg. 1997;32:1552–1554. J Pediatr Surg. 1991;26:528–531.
66. Shneider BL, Brown MB, Haber B, et al. A multicenter study of 88. Barshes N, Lee T, Balkrishnan R, et al. Orthotopic liver trans-
the outcome of biliary atresia in the United States, 1997 to 2000. plantation for biliary atresia: the U.S. experience. Liver Transpl.
J Pediatr. 2006;148:467–474. 2005;11:1193–1200.
67. Muraji T, Higashimoto Y. The improved outlook for biliary atresia 89. Stevens LH, Emond JC, Piper JB, et al. Hepatic artery thrombosis in
with corticosteroid therapy. J Pediatr Surg. 1997;32:1103–1106. infants. A comparison of whole livers, reduced-size grafts, and grafts
discussion 1106-1107. from living-related donors. Transplantation. 1992;53:396–399.
68. Dillon PW, Owings E, Cilley R, et al. Immunosuppression as 90. Stringer MD, Marshall MM, Muiesan P, et al. Survival and out-
adjuvant therapy for biliary atresia. J Pediatr Surg. 2001;36:80–85. come after hepatic artery thrombosis complicating pediatric liver
68B. Bezerra JA, Spino C, Magee JC, et al. Use of corticosteroids after transplantation. J Pediatr Surg. 2001;36:888–891.
hepatoportoenterostomy for bile drainage in infants with biliary 91. Fouquet V, Alves A, Branchereau S, et al. Long-term outcome of
atresia. The START Randomized Clinical Trial. JAMA. 2014; pediatric liver transplantation for biliary atresia: a 10-year follow-
311(17):1750–1759. up in a single center. Liver Transpl. 2005;11:152–160.
69. Wu ET, Chen HL, Ni YH, et al. Bacterial cholangitis in patients 92. Diem HV, Evrard V, Vinh HT, et al. Pediatric liver transplanta-
with biliary atresia: Impact on short-term outcome. Pediatr Surg tion for biliary atresia: Results of primary grafts in 328 recipients.
Int. 2001;17:390–395. Transplantation. 2003;75:1692–1697.
70. Ueider B, Mazariegos G. Biliary Atresia: A Transplant Perspec- 93. Millis JM, Cronin DC, Brady LM, et al. Primary living-donor
tive. Liver Transpl. 2007;13:1482–1495. liver transplantation at the University of Chicago: Technical
71. Lunzmann K, Schweizer P. The influence of cholangitis on the aspects of the first 104 recipients. Ann Surg. 2000;232:104–111.
prognosis of extrahepatic biliary atresia. Eur J Pediatr Surg. 94. Chan KL, Fan ST, Saing H, et al. Paediatric liver transplantation:
1999;9:19–23. Queen Mary Hospital experience. Chin Med J (Engl). 1998;111:
72. Bu LN, Chen HL, Chang CJ, et al. Prophylactic oral antibiotics 610–614.
in prevention of recurrent cholangitis after the Kasai portoenter- 95. Shackleton CR, Goss JA, Swenson K, et al. The impact of micro-
ostomy. J Pediatr Surg. 2003;38:590–593. surgical hepatic arterial reconstruction on the outcome of liver
73. Ohi R. Biliary atresia. In: Balistreri WF, Ohi R, Todani T, et al., transplantation for congenital biliary atresia. Am J Surg. 1997;173:
eds. Hepatobiliary, Pancreatic, and Splenic Disease in Children: Medi- 431–435.
cal and Surgical Management. New York: Elsevier; 1997:249–251. 95A. Chen C, Concejero A, Wang C, et al. Living donor liver trans-
74. Ohi R. Surgery for biliary atresia. Liver. 2001;21:175–182. plantation for biliary atresia: a single-center experience with first
75. Hartley JL, Davenport M, Kelly DA. Biliary Atresia. Lancet. 100 cases. Am J Transplant. 2006;6:2672–2679.
2009;374(9702):1704–1713. 95B. Heffron T, Welch D, Pillen T, et al. Low incidence of hepatic
76. Nagral S, Muiesan P, Vilca-Melendez H, et al. Liver transplanta- artery thrombosis after pediatric liver transplantation without the
tion for extra hepatic biliary atresia. Tohoku J Exp Med. use of intraoperative microscope or parenteral anticoagulation.
1997;181:117–127. Pediatr Transplant. 2005;9:486–490.
77. Wood RP, Langnas AN, Stratta RJ, et al. Optimal therapy for 95C. Darwish A, Bourdeaux C, Kader H, et al. Pediatric liver trans-
patients with biliary atresia: Portoenterostomy (“Kasai” proce- plantation using left hepatic segments from living related donors:
dures) versus primary transplantation. J Pediatr Surg. 1990;25: surgical experience in 100 recipients at Saint-Luc University clin-
153–160. discussion 160-162. ics. Pediatr Transplant. 2006;10:345–353.
78. Goss JA, Shackleton CR, Swenson K, et al. Orthotopic liver trans- 95D. Shneider B, Mazariegos G. Biliary Atresia: A Transplant Perspec-
plantation for congenital biliary atresia. An 11-year, single-center tive. Liver Transpl. 2007;13:1482–1495.
experience. Ann Surg. 1996;224:276–284. discussion 284-287. 96. Yamanaka J, Lynch SV, Ong TH, et al. Surgical complications
79. Emond JC, Heffron TG, Whitington PF, et al. Reconstruction of and long-term outcome in pediatric liver transplantation. Hepato-
the hepatic vein in reduced size hepatic transplantation. Surg gastroenterology. 2000;47:1371–1374.
Gynecol Obstet. 1993;176:11–17. 97. Vilca Melendez H, Vougas V, Muiesan P, et al. Bowel perforation
80. Saad S, Tanaka K, Inomata Y, et al. Portal vein reconstruction in after paediatric orthotopic liver transplantation. Transpl Int.
pediatric liver transplantation from living donors. Ann Surg. 1998;11:301–304.
1998;227:275–281. 98. Shaked A, Vargas J, Csete ME, et al. Diagnosis and treatment of
81. Tanaka K, Uemoto S, Tokunaga Y, et al. Surgical techniques and bowel perforation following pediatric orthotopic liver transplan-
innovations in living related liver transplantation. Ann Surg. tation. Arch Surg. 1993;128:994–998. discussion 998-999.
1993;217:82–91. 99. Beierle EA, Nicolette LA, Billmire DF, et al. Gastrointestinal
82. Buell JF, Funaki B, Cronin DC, et al. Long-term venous compli- perforation after pediatric orthotopic liver transplantation.
cations after full-size and segmental pediatric liver transplanta- J Pediatr Surg. 1998;33:240–242.
tion. Ann Surg. 2002;236:658–666. 100. de Ville de Goyet J, Struye de Swielande Y, Reding R, et al.
83. Cronin DC 2nd, Schechter L, Lohman RF, et al. Advances in Delayed primary closure of the abdominal wall after cadaveric and
pediatric liver transplantation: Continuous monitoring of portal living related donor liver graft transplantation in children: a safe
venous and hepatic artery flow with an implantable Doppler and useful technique. Transpl Int. 1998;11:117–122.
probe. Transplantation. 2002;74:887–890. 101. Farmer D, Venick R, McDiarmid S, et al. Predictors of Outcomes
84. Farmer DG, Shaked A, Olthoff KM, et al. Evaluation, operative after Pediatric Liver Transplantation: An Analysis of More Than
management, and outcome after liver transplantation in children 800 Cases Performed at a Single Institution. J Am Coll Surg.
with biliary atresia and situs inversus. Ann Surg. 1995;222: 2007;204:904–916.
47–50. 102. Ishikawa M, Lynch SV, Balderson GA, et al. Liver transplantation
85. Mattei P, Wise B, Schwarz K, et al. Orthotopic liver transplanta- in Japanese and Australian/New Zealand children with biliary atre-
tion in patients with biliary atresia and situs inversus. Pediatr Surg sia: A 10-year comparative study. Eur J Surg. 1999;165:
Int. 1998;14:104–110. 454–459.
86. Maggard MA, Goss JA, Swenson KL, et al. Liver transplantation 103. Peeters PM, Sieders E, De Jong KP, et al. Comparison of out-
in polysplenia syndrome: Use of a living-related donor. Trans- come after pediatric liver transplantation for metabolic diseases
plantation. 1999;68:1206–1209. and biliary atresia. Eur J Pediatr Surg. 2001;11:28–35.
 CHAPTER 27

Transplantation for Metabolic

Disease in Children
Robert S. Venick • Suzanne V. McDiarmid

CHAPTER OUTLINE

α1-ANTITRYPSIN DEFICIENCY DISORDERS OF CARBOHYDRATE METABOLISM

Liver Disease as a Manifestation of α1- Galactosemia and Fructosemia
Antitrypsin Deficiency Glycogen Storage Diseases
Pathological Changes
DISORDERS OF LIPID METABOLISM
Liver Transplantation for α1-Antitrypsin
Deficiency Familial Hypercholesterolemia
Lipoidoses
WILSON’S DISEASE Gaucher’s Disease
Clinical Features Niemann-Pick Disease
Liver Transplantation for Wilson’s Disease Wolman’s Disease
DISORDERS OF AMINO ACIDS Cholesterol Ester Storage Disease
Tyrosinemia DISORDERS OF BILIRUBIN METABOLISM
Clinical Features of Liver Disease in
Tyrosinemia CYSTIC FIBROSIS
Extrahepatic Manifestations Clinical Features
Medical Therapy Liver Transplantation
Liver Transplantation for Tyrosinemia HYPEROXALURIA TYPE 1
Urea Cycle Defects Liver and Kidney Transplantation
Ornithine Transcarbamylase Deficiency
OTHER METABOLIC DISEASES FOR WHICH LIVER
Carbamoyl-Phosphate Synthetase Deficiency
TRANSPLANTATION HAS BEEN PERFORMED
Argininosuccinate Synthetase Deficiency
Neonatal Iron Storage Disease
Other Disorders of Amino Acid Metabolism
Defects of Mitochondrial Function
Methylmalonicacidemia and Propionicacidemia
Mucopolysaccharidoses
Maple Syrup Urine Disease

Liver transplantation has made possible the functional manifestations of metabolic disease affecting the liver are
cure of several metabolic diseases characterized by inher- diverse and range from acute liver failure to cirrhosis
ited genetic defects.1-8 In many pediatric transplantation complicated by hepatoma. However, the indication for
centers, metabolic diseases, most notably α1-antitrypsin liver transplantation may go beyond the recognized compli-
deficiency, are the second or third most common indica- cations of acute or chronic liver failure.17 Life-threatening
tion for liver transplantation after biliary atresia and ful- extrahepatic disease as a result of a deficient enzyme
minant hepatic failure.9-11 The Studies of Pediatric Liver localized to hepatocytes, as occurs, for example, in central
Transplantation (SPLIT) database shows that of the nervous system (CNS) manifestations of the urea cycle
more than 4000 U.S. and Canadian children transplanted defects, can be cured by liver transplantation. Liver trans-
between 1995 and 2011, more than 10% received a trans- plantation has also been advocated to improve the severely
plant for a metabolic disease.12 The number of children impaired quality of life in children who must endure rig-
who underwent liver transplantation for each metabolic idly enforced protein-restricted diets to control the
disease diagnosis is shown in Table 27-1.13 The long- potentially devastating neurological consequences of the
term survival and quality of life of children who undergo organic acidurias.
liver transplantation for metabolic disease is similar to To determine when liver transplantation is appropri-
that of children with other liver diseases.14-16 The ate treatment of metabolic disorders, it is useful to

317
318 PART III Patient Evaluation: Pediatric

transplantation, although some functional improvement

TABLE 27–1 Indications for Liver
usually occurs. The neurological crises do not appear to
Transplantation for Children with
recur after transplantation. Thus in tyrosinemia, liver
Metabolic Liver Disease
replacement not only is lifesaving but also ameliorates the
Total number of children 1187 extrahepatic manifestations of the disease.
transplanted In contrast, in the mucopolysaccharidoses, successful
Transplantation for metabolic 141 11.9%* liver transplantation circumvents the consequences of
disease unremitting liver fibrosis but is unable to overcome the
α1-Antitrypsin deficiency 39 27.7%† widespread extrahepatic expression of the enzymatic defect
Urea cycle defects 22 15.6% and therefore allows continued accumulation, particularly
Tyrosinemia 16 11.3% in the CNS, of abnormal sphingomyelin. Ongoing neuro-
Cystic fibrosis 12 8.5% logical deterioration can be anticipated. In this instance,
Wilson’s disease 10 7.1% liver transplantation alone would not be indicated, but
Neonatal iron storage disease 9 6.4% when combined with a bone marrow transplant, it may be
Primary hyperoxaluria 8 5.7% a more successful approach if attempted early in life.19
Glycogen storage disease 7 5.0% Medical therapies that might preclude or delay trans-
Crigler-Najjar syndrome 6 4.2% plantation should be optimized. In general, the success of
Other 12 8.5% these measures depends on early diagnosis. This is particu-
larly relevant with the use of chelating agents in Wilson’s
From McDiarmid S, Anand R, Lindblad AS: SPLIT Research Group.
Studies of pediatric liver transplantation: 2002 update. An disease; treatment with 2-nitro-4-trifluoromethylbenzoyl-
overview of demographics, indications, timing, and immunosup- 1,3-cyclohexanedione (NTBC), a compound that blocks
pressive practices in pediatric liver transplantation in the United the formation of toxic metabolites in tyrosinemia; and pho-
States and Canada. Pediatr Transplant. 8:284-294, 2004. totherapy in Crigler-Najjar syndrome.20
*Percentage of total children transplanted who have metabolic liver In the future, total liver replacement may become
disease.
†Percentage of children with a given diagnosis and transplanted for obsolete for some categories of metabolic disease.21 In
metabolic liver disease. metabolic diseases in which the liver is structurally nor-
mal, hepatocyte transplantation is an attractive option.
Normal allogeneic hepatocytes have been able to provide
consider two general categories of disease3: (1) metabolic temporary metabolic support in animal models,22 as first
disease with structural liver damage leading to end-stage shown in the Gunn rat model of Crigler-Najjar syn-
liver disease (e.g., α1-antitrypsin deficiency, familial tyro- drome23,24 and later in case studies of children with
sinemia, and Wilson’s disease) and (2) metabolic disease ­Crigler-Najjar syndrome25 and those with ornithine
without structural liver damage (e.g., familial hypercho- transcarbamylase (OTC) deficiency.26 More recently a
lesterolemia, primary oxalosis, and urea cycle defects). limited number of cases have emerged of hepatocyte
In the first group the genetic defect may be localized to transplantation in humans, with the leading indication
the liver itself, such as occurs in the familial cholestatic being children with urea cycle defects. Worldwide there
syndromes (see Chapter 25), but more commonly the liver are reports of over 30 patients with metabolic liver dis-
is one of the end-organs damaged as a result of a more ease safely treated with hepatocyte transplantation as a
widespread defect (e.g., tyrosinemia and α1-antitrypsin treatment for Crigler-Najjar syndrome type I, glycogen
deficiency). When the liver is exclusively involved and also storage disease type IA, infantile Refsum’s disease, pro-
the only site of the metabolic defect, the decision to gressive familial intrahepatic cholestasis type 2, urea cycle
replace the liver is easily made, and liver transplantation defects, familial hypercholesterolemia, and congenital
can be expected to provide complete reversal of the meta- deficiency of clotting factors.27-29 Advantages of hepato-
bolic defect. However, in diseases in which the liver is cyte transplantation include that it is less invasive than
damaged as a consequence of a widespread enzymatic liver transplantation and may be able to offer a bridge for
defect residing in a variety of cells other than hepatocytes, survival in an acute setting. Major challenges include the
determination of whether liver transplantation is indi- fact that these patients still require immunosuppression
cated is more complex. Essential to this decision is precise and the function of the transplanted hepatocytes often
knowledge of the genetic defect itself, the somatic cells in declines by 9 months after infusion, meaning that the
which the cellular defect is expressed, the extent of organ patients will go on to require liver transplantation.
involvement outside the liver, and whether liver replace- A potentially more attractive option involves the use of
ment alone will be sufficient to either prevent further gene therapy to modify the genetic program of the patient’s
deterioration or improve dysfunction in extrahepatic own hepatocytes.30 Harvested hepatocytes infected in vitro
organs. Tyrosinemia is illustrative of these principles.18 with a recombinant retrovirus or adenovirus carrying the
The deficient enzyme, fumarylacetoacetate hydrolase normal human gene are then able to express the normal
(FAH), is not localized to hepatocytes, and the kidneys gene’s protein products. Autologous transplantation of
and CNS are two other major organs affected. However, these genetically reconstituted hepatocytes is then per-
tyrosinemia is associated with a spectrum of severe liver formed. This approach has been used successfully in animal
disease for which liver transplantation is indicated, rang- models for such diseases as familial hypercholesterolemia,31
ing from fulminant hepatitis to cirrhosis with hepatoma the urea cycle defects,32 Crigler-Najjar syndrome,33 and
formation. The Fanconi syndrome–like kidney disease tyrosinemia.34 Alternatively, in vivo modification of hepa-
associated with tyrosinemia often persists after liver tocytes might be achieved by a vector containing the
 27 Transplantation for Metabolic Disease in Children 319

normal gene. Such approaches would avoid the significant deficiency with glomerulonephritis in children and young
morbidity and mortality associated with orthotopic liver adults.40 The frequency of the disease is between 1 in
transplantation and a lifetime of immunosuppression. 2000 and 1 in 7000 in populations of European descent.41
To reverse the metabolic defect, animal models have Liver disease associated with α1-antitrypsin deficiency is
shown that only a small percentage of the total liver cell the most common metabolic disease for which liver trans-
mass needs to be replaced with cells containing viable plantation is performed in children.42
enzyme. However, in clinical reports of hepatocyte trans- α1-Antitrypsin is a major serine protease inhibitor that
plantation for Crigler-Najjar disease, urea cycle defects, is produced primarily in the liver but also to some extent
and hypercholesterolemia, despite transplantation of in neutrophils and macrophages. Its most important
what should have been an adequate cell mass, only partial function is inhibition of neutrophil elastase, a powerful
correction of the defect has been reported. Not only is proteolytic enzyme capable of degrading extracellular
the long-term viability of transplanted cells a problem to structural proteins, particularly elastin.43 The effect of
be overcome, but a limitation of hepatocyte transplanta- low circulating α1-antitrypsin levels is most dramatically
tion is that only about 1% of the liver mass can be replaced seen in the lung, where the unopposed action of neutro-
by transplanted cells. phil elastase leads to progressive destruction of the lung
Recently attention has been focused on the concept of parenchyma, which becomes clinically manifested as
“liver repopulation,” whereby the transplanted cells are emphysema. In contrast, liver disease is the result of
given a growth advantage over the recipient’s own cells.35 retention of the abnormal α1-antitrypsin molecule within
To be successful in animal models, this technique has two hepatocytes.44
specific requirements to provide “the space” for the trans- α1-Antitrypsin is a small, 52-kD glycosylated protein.
planted cells to proliferate. First, the transplanted cells It is encoded for by a single gene located on chromo-
must have an advantage in either proliferation or survival some 14 with codominant expression of the two inher-
in comparison to the endogenous hepatocyte population. ited alleles. At least 75 allelic variants have been
Second, removal of endogenous hepatocytes, usually by described.45 Phenotyping, designated by the Pi (protease
partial hepatectomy, is required to provide the stimulus inhibitor) nomenclature, was originally described by the
for liver regeneration, which selectively allows the trans- relative mobility of the α1-antitrypsin molecule along an
planted hepatocytes to proliferate. In animal models, acid starch gel gradient.46 Variants are described by let-
approaches used to decrease the regenerative capacity of ters of the alphabet. Approximately 70% to 80% of
endogenous hepatocytes include drugs blocking DNA selected populations have the normal phenotype, PiMM.
syntheses and irradiation. By applying these two princi- The α1-antitrypsin deficiency state is most often charac-
ples in animal studies, up to 90% of the host liver cells terized by PiZZ. Other variations have been described
can be replaced by transplanted cells. If such techniques (e.g., PiMZ, PiMS) and are variably associated with
prove applicable to humans, hepatocyte transplantation, low α1-antitrypsin levels (between 15% and 60% of nor-
including the transplantation of genetically altered autol- mal)47,48 and clinical disease.45-50
ogous hepatocytes, would become a clinical reality.
The rapidly advancing field of stem cell transplantation Liver Disease as a Manifestation of
may also have important implications for the correction of
some liver-localized metabolic diseases. Stem cells, whether
α1-Antitrypsin Deficiency
of bone marrow or liver origin, may prove to be the best The first association of α1-antitrypsin deficiency and liver
candidate cells for transplantation into the liver.36-38 disease was made by Freier et al51 in 1968 and expanded by
The following sections systematically describe meta- Sharp et al in 1969.52 Soon thereafter, Sveger’s large pro-
bolic defects for which liver transplantation is indicated. spective screening of 200,000 newborns in Sweden pro-
For each disease entity, a description is provided of the vided the study that still stands as the best description of
metabolic defect and its genetics, inheritance and bio- the natural history of the disease.53,54 In this study 120
chemical effects, pathology, clinical manifestations from PiZZ infants were identified, 12% of whom presented
infancy through the teenage years, indications for trans- with cholestasis within the first 3 months and an additional
plantation, and impact of transplantation on the course of 6% had clinical evidence of liver disease (hepatospleno-
the disease. A familiarity with metabolic liver disease and megaly). In a follow-up study, 73% of PiZZ infants had
an understanding of these concepts, including indication transaminitis by 6 months of age that persisted until age 8
and contraindications, is crucial for hepatologists and years in 59%.55 Overall, about 3% of infants with the PiZZ
transplant surgeons alike to optimize patient selection and phenotype progressed to cirrhosis, which represented
timing of liver transplantation.39 Liver transplantation for about 20% of the PiZZ infants with neonatal cholestasis.
familial cholestasis syndromes and hemopoietic metabolic Since these first observations, additional information has
disease is discussed in Chapter 25 and later in this chapter. allowed an easily remembered generalization to be made.
Of PiZZ infants with cholestasis, cirrhosis will develop in
25% in the first decade, 25% will show persistent transa-
α1-ANTITRYPSIN DEFICIENCY minitis progressing to cirrhosis in the second decade, 25%
will have mild transaminitis without cirrhosis, and the bio-
α1-Antitrypsin deficiency is one of the most common chemical abnormality will resolve completely and show
lethal inherited diseases that affect the white population. only mild fibrosis on liver biopsy in 25%.46
It is characterized by liver disease in children and emphy- Typically in an infant with α1-antitrypsin deficiency and
sema in adults. There is a rare association of α1-antitrypsin cholestasis, the jaundice resolves by about 6 months.54
320 PART III Patient Evaluation: Pediatric

However, the transaminitis usually persists. In those who leads to accumulation in the rough endoplasmic reticu-
progress to cirrhosis, the clinical development of portal lum.69 Retention of abnormally folded proteins in the
hypertension, with or without recrudescence of jaundice, is endoplasmic reticulum is thought to be a protective
a common manifestation later in childhood.49 In many mechanism that allows degradation of abnormal proteins
children the progression to end-stage liver disease may be to prevent further cellular damage. It is now proposed
quite slow.56 Rarely, however, the course progresses rap- that patients with liver disease associated with α1-
idly to end-stage liver disease. The early development of antitrypsin deficiency have a defect in the degradative
ascites with cirrhosis on liver biopsy is an ominous sign and pathway that causes greater accumulation of the puta-
has been reported as early as 2 weeks of age, thus suggest- tively hepatotoxic mutant α1-antitrypsin molecule.66
ing that in some infants the liver insult begins in utero.57 Because liver disease develops in only a small minority of
The severity of the cholestatic liver disease in infancy patients with the ZZ genotype, the defect in degradation
correlates with the appearance of cirrhosis in later child- is thought to be controlled by either other unlinked
hood.58 However, α1-antitrypsin deficiency must still be genetic traits or environmental factors.
considered a cause of cirrhosis in childhood, even without It is now clear that the mechanism of liver injury in α1-
an antecedent history of neonatal cholestasis.59 antitrypsin deficiency is not analogous to the mechanism
Persistent abnormalities in urinary bile acids may also of injury in the lung, which is caused by low tissue levels
predict progression to cirrhosis.60 Other risk factors are of α1-antitrypsin that allow destruction of the paren-
female sex and siblings in whom cirrhosis has also devel- chyma by locally released proteases. This different mech-
oped. Whether early breast-feeding is protective remains anism is substantiated by studies of patients with the rare
debatable.58,61 Pi-Null phenotype, in which no detectable α1-antitrypsin
The PiZZ phenotype is most often correlated with liver is present in serum or hepatocytes and no liver injury
disease. However, both PiMZ and PiSZ individuals have occurs.45 Augmentation of α1-antitrypsin serum levels by
been reported with moderately depressed α1-antitrypsin administering recombinant α1-antitrypsin can be expected
serum levels, as well as clinical and histological evidence of to improve lung function but has not been shown to either
liver disease.45,46,53,62-64 The association of hepatocellular turn off or promote secretion of α1-antitrypsin globules
carcinoma (HCC) in adults with “cryptogenic” cirrhosis accumulated in the liver.70,71
has been linked to previously undiagnosed ZZ and MZ There is no specific medical therapy for α1-antitrypsin
phenotypes.65 deficiency, and infants with this disease are initially man-
aged with supportive care.
Pathological Changes
Liver Transplantation for α1-Antitrypsin
The characteristic pathological changes of the liver in α1-
antitrypsin–deficient patients with liver disease provide
Deficiency
insight into the mechanism of liver injury.66 Abnormal Liver transplantation as an effective cure for α1-antitrypsin
globules of α1-antitrypsin, characteristically periodic deficiency was first performed in 1973.72 The trans-
acid–Schiff positive and diastase resistant, accumulate in planted liver produced normal α1-antitrypsin molecules,
periportal hepatocytes, which are the site of α1-antitrypsin and the α1-antitrypsin serum level normalized. The
production (Fig. 27-1).46,62 On electron microscopy the recipient’s phenotype converted to that of the donor. As
rough endoplasmic reticulum of such cells is distended could be predicted by the restoration of circulating
with similar granules.67,68 It has been postulated that α1-antitrypsin levels to normal, no patients to date have
abnormal folding of the mutant α1-antitrypsin molecule contracted emphysema. However, it should be remem-
bered that the transplanted patient’s original genotype is
unchanged in the germ cell line, so when children trans-
planted for α1-antitrypsin deficiency reach reproductive
age, genetic counseling should be offered.63
Analysis of the United Network of Organ Sharing data-
base reveals 1- and 5-year patient survival rates of 92%
and 90%, respectively, for children with α1-antitrypsin
deficiency who received a liver transplant.73 The excellent
outcomes now reported from many centers for children
undergoing liver transplantation for α1-antitrypsin defi-
ciency associated with end-stage liver disease has changed
the overall prognosis substantially for children with this
disease.74-76 In a large single-center experience in children
with clinical liver disease secondary to α1-antitrypsin defi-
ciency, 27% underwent transplantation. The duration of
jaundice and the severity of the histological features and
biochemical abnormalities predicted outcome at an early
FIGURE 27-1 n α1-Antitrypsin deficiency. In a periodic acid–Schiff– stage of the disease.77 As a group, children undergoing
stained section of the liver after diastase, pink, diastase-resistant
globules of α1-antitrypsin are apparent within hepatocytes, par-
transplantation for α1-antitrypsin deficiency have lower
ticularly in the periportal area. Fibrosis in the portal triad is also mortality and morbidity than other pediatric recipients
evident. do.11,15 This better outcome can be attributed to their
 27 Transplantation for Metabolic Disease in Children 321

generally older age at initial evaluation, which often shows abnormal gene, irrespective of race, is about 1 in 200 to
portal hypertension and bleeding varices. Jaundice is usu- 400.82 Heterozygote carriers occur at a frequency of
ally mild and nutritional status better preserved than in about 1 per 100 in the general population.84
younger children with biliary atresia. In addition, most Because more than 200 mutations have been described,
have had no previous abdominal surgeries. However, as it is currently difficult to screen populations for Wilson’s
with other conditions associated with cirrhosis and portal disease. However, genetic analysis is useful in screening
hypertension, children with α1-antitrypsin deficiency have family members of affected individuals. A single domi-
a propensity for the development of large arteriovenous nant mutation (H1069Q) is found primarily in Slavic
pulmonary shunts and cyanosis before transplantation.78 populations but in only about a third of North American
The degree of shunt and arterial oxygenation should be populations. In addition, there is often a poor correlation
evaluated before transplantation. Although these prob- between patients homozygous for specific alleles and the
lems may resolve over time, large shunts complicate the clinical manifestations of disease, thus implying that
early postoperative period and compromise weaning from additional genetic or environmental factors play a role.
the ventilator.79,80
Rupture of a splenic artery aneurysm has also been
described as a lethal complication after liver transplanta-
Clinical Features
tion in a child with α1-antitrypsin deficiency.81 Such rup- Evolution of the liver injury in Wilson’s disease appears
ture is most likely a reflection of the commonly seen to be related to redistribution of copper within the liver,
severe pretransplantation portal hypertension and not a which may induce oxidant injury in hepatocyte mito-
function of the disease itself. chondria.88 Clinical evidence of disease seldom occurs
Other possibilities for the future treatment of liver dis- before 5 years of age, although one case of jaundice in a
ease associated with α1-antitrypsin deficiency might 2-year-old has been described.83 In children, the liver
include gene therapy to suppress the abnormal Z gene so manifestations of the disease are most frequently mani-
that the mutant molecule is not produced. It will also be fested in their teenage years,83 whereas 40% of adults ini-
difficult to prospectively determine which patients to tially have neurological abnormalities.82 The symptoms
treat because clearly, liver disease does not develop in all of neurological disease are usually subtle in children. Per-
these children. For such preventive strategies to be suc- sonality and behavior changes or poor school perfor-
cessful, a better understanding of the other genetic and mance may be present. The predominantly motor
environmental triggers that predispose patients with abnormalities of tremor, dystonia, and dysarthria become
abnormal phenotypes to the development of liver disease more pronounced with age and are related to the effects
will be needed. of copper accumulation in the extrapyramidal system. In
adult patients with primarily neurological manifestations
of Wilson’s disease, the condition may be misdiagnosed
WILSON’S DISEASE as mental retardation or psychiatric impairment, and the
true origin of their neurological disease is never
Copper accumulation in the liver, CNS, eyes, and kid- appreciated.84
neys is the cardinal clinical feature of Wilson’s disease, an The clinical manifestations of liver impairment in
autosomal recessive disease of copper metabolism with a Wilson’s disease are diverse and range from asymptom-
prevalence of about 1 in 30,000 in most populations. The atic hepatosplenomegaly with an associated low-grade
liver plays an essential role in copper homeostasis inas- transaminitis to fulminant liver failure. The heteroge-
much as about 95% of copper in the portal vein is taken nicity in findings frequently delays the diagnosis.
up by the liver and biliary excretion of copper is the only Chronic active hepatitis progressing to cirrhosis89 may
physiologically important route of copper elimination. remain clinically silent for years before becoming mani-
About 90% of serum copper is bound to ceruloplasmin. fested as acute onset of jaundice, which is often misdiag-
Newborn infants show concentrations of copper within nosed as acute hepatitis. In some adolescents the acute
the liver similar to those of patients with Wilson’s dis- hepatitis–like picture may progress over a period of
ease.82 Normally the liver copper level falls toward adult weeks to severe liver failure, whereas in others, the first
levels by 6 months of age. In Wilson’s disease, copper manifestation of the disease is fulminant liver failure.82-84
first accumulates in the liver and subsequently in the Portal hypertension and bleeding varices are also fre-
CNS and other extrahepatic tissues.82-85 quent initial signs.
In recent years, elucidation of the copper metabolic Physical examination may not be especially helpful in
pathway in the liver and discovery of the genes that making the diagnosis of Wilson’s disease. Hepatospleno-
encode the proteins essential to normal copper metabo- megaly is frequently present, but the liver may be
lism have greatly enhanced our understanding of the shrunken in advanced cases. Kayser-Fleischer rings, seen
molecular and genetic basis of Wilson’s disease.86,87 as a rusty brown ring at the junction of the iris and cornea
Mutations in the ATP7B gene give rise to Wilson’s dis- caused by deposition of copper in Descemet’s membrane,
ease. The gene product for ATP7B is an adenosine tri- are often said to be pathognomonic of Wilson’s disease.
phosphate (ATP)-dependent copper transporter that is The ring first appears as a crescent in the superior aspect
required for the intrahepatocyte delivery of copper to the of the eye but may be difficult to visualize in brown eyes.90
secretory pathway that incorporates copper into apoceru- Slit-lamp examination is often required. However, Kay-
loplasmin, with subsequent transport across the lipid ser-Fleischer rings do not usually appear until midadoles-
bilayer of the hepatocyte into bile. The frequency of the cence and are not unique to Wilson’s disease.91
322 PART III Patient Evaluation: Pediatric

The diagnosis of Wilson’s disease may also be con- In the liver the histological appearance of early Wil-
founded by an often-confusing constellation of test son’s disease includes fatty infiltration and glycogen-filled
results.82-85,91 Classically, serum ceruloplasmin level is hepatocyte nuclei. Distinctive, but not unique, mitochon-
low (<20 mg/dL), serum copper level is low (<80 mg/L), drial abnormalities are present on electron microscopy.
and 24-hour urine copper level is high (>100 mg/24 hr). As the disease progresses, there is continuing fibrosis,
However, 15% of homozygotes with liver disease91 have parenchymal collapse, inflammatory cell infiltrates, and
normal ceruloplasmin levels, and about 20% of carriers of nodular regeneration culminating in frank cirrhosis. In
the Wilson’s disease gene84 have low ceruloplasmin lev- patients presenting with acute liver failure, liver necrosis
els. Low ceruloplasmin levels are likewise seen in severe is the predominant histological factor.82
copper deficiency and fulminant liver failure. Because
ceruloplasmin is also an acute phase reactant, it may be
elevated with ongoing inflammatory liver injury and in
Liver Transplantation for Wilson’s Disease
pregnancy or with estrogen administration. Total serum Orthotopic liver transplantation provides a cure for Wil-
copper level is unreliable as well because free serum cop- son’s disease in patients in whom medical therapy has
per is often increased in untreated or fulminant Wilson’s failed or in those found to have advanced decompensated
disease. The 24-hour urine copper level is also elevated in liver disease at initial evaluation. Medical management
chronic liver disease with cholestasis, acute liver failure, in patients in whom Wilson’s disease is diagnosed in the
and severe proteinuria. Careful collection in copper-free early stages of the disease—and continued lifelong—may
containers is required. abrogate the need for liver transplantation entirely.
The copper content of the liver is the most reliable d-Penicillamine,99 trientine dihydrochloride,100 and tet-
diagnostic test. In Wilson’s disease a copper content rathiomolybdate101 are chelating agents with proven
greater than 250 μg/g dry tissue (normal, <50 μg/g) is fre- success. More recently the use of oral zinc has been
quently seen. Values up to 3000 μg/g are not uncom- advocated in asymptomatic patients after an initial
mon.91 Although an increased copper concentration may cupruresis has been induced with chelating agents or in
also be seen with chronic active hepatitis and primary combination with a chelator in patients with symptoms
biliary cirrhosis, the ceruloplasmin level is either normal related to either liver or neurological disease. In one
or increased in these diseases, and other distinctive fea- report, combination therapy averted liver transplanta-
tures should allow differentiation.89 tion in several patients.86 Oral zinc induces the forma-
If the ceruloplasmin level is normal, a useful adjuvant tion of metallothionein, a copper-binding substrate,
test is to measure the incorporation of radioactive copper within the enterocyte. Ingested copper is then bound
into ceruloplasmin. Wilson’s disease is characterized by within the enterocyte to metallothionein and sloughed
decreased accumulation of radioactive copper.92 This into the gastrointestinal tract, never reaching the sys-
test is of no value if the serum ceruloplasmin concentra- temic circulation.102-104
tion is low.84 Various attempts have been made to ascertain which
Abnormalities in liver function vary depending on the patients with Wilson’s disease should be considered for
clinical manifestation. However, rapid diagnosis of Wil- transplantation.105 Indications include failure of medical
son’s disease in patients with fulminant liver failure is of treatment to improve either liver or neurological func-
critical importance.93 Acute hemolysis frequently accom- tion, fulminant liver failure, and decompensated cirrhosis
panies fulminant Wilson’s disease because massive at initial evaluation. On the basis of a scoring system,
amounts of copper are released into the circulation and Nazer et al accurately predicted which patients had a
lyse red blood cell membranes.83 The association of acute poor prognosis when treated medically. Elevations in
hemolysis with liver failure in an adolescent should be bilirubin level, serum glutamic-oxaloacetic transaminase
diagnosed as Wilson’s disease until proved otherwise. In level, and prothrombin time predicted increased mortal-
addition, the characteristic pattern of mildly elevated ity. Jaundice and ascites also correlated with a poor out-
transaminase levels with a high serum bilirubin level and come.106 More recently the group at King’s College
an unexpectedly normal alkaline phosphatase concentra- Hospital has updated its Wilson’s Disease prognostic
tion should prompt consideration of Wilson’s disease index with over 35 years' (n = 74 patients) worth of pedi-
over most other causes of acute fulminant liver failure.94,95 atric data. The updated scoring system incorporates
In one study of emergency liver transplantation, 11.4% of serum bilirubin level, international normalized ratio,
children with fulminant liver failure had Wilson’s dis- aspartate aminotransferase level, and white cell count at
ease.96 Of the 703 children enrolled in the latest report of presentation and is 93% sensitive and 98% specific, with
the Pediatric Acute Liver Failure Study Group, 3.3% had a positive predictive value of 88% in predicting the need
Wilson’s disease.97 for liver transplant.107
Deiss et al describe four stages of Wilson’s disease Successful liver transplantation for Wilson’s disease
before treatment.98 In stage 1, copper accumulates in with complete reversal of the metabolic manifestations
the cytosol of the hepatocyte, and the patient remains was first reported by Dubois et al in 1971.108 By the
asymptomatic. In stage 2, copper is redistributed into early 1980s, orthotopic liver transplantation had become
lysosomes, with some copper being released into the the standard treatment of Wilson’s disease manifested
circulation. Liver fibrosis, cirrhosis, or liver failure may as fulminant liver failure or decompensated chronic dis-
occur. In stage 3, copper accumulates asymptomati- ease. The results of transplantation, particularly in
cally in the CNS, which leads to neurological symp- patients with fulminant Wilson’s disease, have been
toms in stage 4. impressive.109,110 In reported series, fulminant liver
 27 Transplantation for Metabolic Disease in Children 323

failure, which occurs more frequently in females by a

2:1 ratio, is the indication for liver transplantation in the
DISORDERS OF AMINO ACIDS
majority of patients.111,112 In one of the largest single-
center reports, in which 45 patients underwent trans-
Tyrosinemia
plantation for Wilson’s disease, 42.2% were younger Hereditary tyrosinemia type I is an autosomal recessive
than 18 years at transplantation, and two thirds of the disease in which FAH, the terminal enzyme in tyrosine
patients received transplants for either fulminant or metabolism, is deficient. The more than 30 mutations of
subfulminant liver failure; 73.3% of these patients sur- the gene located on chromosome 15124 account for the
vived more than 5 years after transplantation.112 Based wide clinical variability of the disease.125 The distribution
on Organ Procurement and Transplantation Network of the genetic abnormality varies considerably with popu-
data from 2007, 1-and 5-year patient survival rates for lation groups. In Quebec, where the disease was first
Wilson’s disease patients who require liver transplanta- described in 1967 by Larochelle et al,126 the incidence of
tion are 89% and 84%, respectively.39 Aggressive tem- the disease is 1 in 10,000 but rises to 1 in 800 births in one
porizing strategies may be needed to maintain patients geographically isolated area. In comparison, the inci-
with acute fulminant liver failure secondary to Wilson’s dence in Scandinavia is 1 in 50,000.18,127
disease until a liver can be found. Treatments have The diagnosis of tyrosinemia is made by demonstrat-
included d-penicillamine in conjunction with hemofil- ing reduced activity of FAH, the enzyme responsible for
tration in patients with kidney failure113 and heterotopic cleaving fumarylacetoacetate into fumaric and acetoace-
transplantation.114 tic acids.128 The accumulation of these acids leads to an
In successful liver recipients, an initial period of cupru- increase in succinylacetone, a byproduct whose presence
resis is followed by normalization of serum copper, ceru- is suggestive of tyrosinemia. In Quebec, neonatal screen-
loplasmin, and liver copper content.115 The characteristic ing programs on dried blood spots are important for early
Kayser-Fleischer rings resolve slowly, in some cases more detection in this high-risk population.129,130
than 3 years.116 Adult patients with neurological or psy-
chological impairments have shown complete117 or partial
Clinical Features of Liver Disease in
recovery,118 although such recovery may take several
Tyrosinemia
months. In general, patients transplanted for Wilson’s dis-
ease enjoy an excellent quality of life.119 A still-contentious Lethal liver disease, neurological crises, and a Fanconi
issue is whether liver transplantation is justified for neuro- syndrome with hypophosphatemic rickets characterize the
logical disease without severe liver disease. This debate is disease. Although serum tyrosine, methionine, and phe-
exemplified by a report of a 15-year-old without signifi- nylalanine levels are elevated in serum, these elevations are
cant liver disease who was bedridden with severe incapaci- not thought to mediate the toxic injury. Accumulation of
tating dysarthria despite maximal medical therapy. This fumarylacetoacetate and maleylacetoacetate most likely
patient reportedly returned almost to normal after liver mediates the cellular toxicity.131-136 These alkylating
transplantation.120 agents are thought to inflict damage at the DNA level in
The use of a living related donor for Wilson’s disease, hepatocytes and renal tubular epithelial cells.
usually a parent who is a heterozygote carrier, carries the Liver disease in tyrosinemia can be manifested as
risk that copper metabolism may remain abnormal after either acute or chronic disease. Tanguay et al demon-
transplantation. In a recent report of two children who strated no FAH activity in the acute form, whereas in the
each received a graft from a parent, it was shown that the chronic form, FAH activity was about 20% of normal.18
liver copper content was slightly elevated, not exceeding Acute disease becomes apparent in infancy with the
250 μg/g dry weight. However, serum copper and cerulo- onset of fulminant liver failure. Frequently infants pres-
plasmin levels were lower and urinary copper excretion ent with a bleeding diathesis, and liver failure is diag-
higher than normal. The long-term outcome is as yet nosed secondarily. Tyrosinemia should be considered in
unknown.121 It would seem prudent to avoid living related an infant with coagulopathy even without other clinical
donors whenever possible for Wilson’s disease or to per- evidence of liver failure.137 A few of these infants respond
form gene analysis preoperatively if the procedure is to be to a diet low in tyrosine, phenylalanine, and methionine,
attempted.122 but most succumb if no other intervention is made. In
The future holds the promise that gene therapy or iso- these infants the liver may be pale and enlarged with
lated hepatocyte transplantation may offer definitive already-apparent micronodular cirrhosis, bile duct pro-
therapy for patients identified very early in the disease liferation, steatosis, and pseudoacinar arrangements of
process. Transplantation of normal hepatocytes into hepatocytes.132
Long-Evans cinnamon rats, an animal model of Wilson’s The chronic form of tyrosinemia-induced liver disease
disease, showed that a viable transplanted hepatocyte has a more insidious onset. Although it often develops
mass of 4% to 20% prevented the development of Wil- after the first year of life, it should be considered even in
son’s disease.123 infants or toddlers—particularly those with unexplained
Identification of any child with Wilson’s disease, rickets or Fanconi syndrome. The liver is enlarged and
regardless of whether liver transplantation is a therapeu- coarsely nodular with progression from micronodular to
tic option, should always prompt a systematic investiga- macronodular cirrhosis.132,133 There may be clinical evi-
tion of all family members. Early detection and treatment dence of portal hypertension and decompensated cirrho-
of asymptomatic homozygotes may prevent the necessity sis with jaundice, ascites, and loss of synthetic function.
for subsequent liver transplantation. Before the use of NTBC (see later), even with strict
324 PART III Patient Evaluation: Pediatric

dietary management children with tyrosinemia showed a

Medical Therapy
frightening propensity for the development of HCC after
the age of 2 years. The malignancy is multifocal within A major advance in the medical management of tyrosin-
the liver and may have metastasized at the time of emia has been made since 1991 when the first patient was
diagnosis.134 treated with NTBC, a compound that inhibits tyrosine
degradation and blocks the enzymes responsible for accu-
Extrahepatic Manifestations mulation of the toxic metabolites (particularly succinylace-
toacetate) that induce the liver injury (Fig. 27-2).140
Neurological crises, which usually occur after 1 year of By 2000, more than 300 patients had been enrolled in
age, may also be a fatal consequence of tyrosinemia. The an international study,141 and more than 100 of these
defining features of the syndrome are the acute onset of patients had been treated for longer than 5 years. The
profound weakness or paralysis, painful dysesthesias, often starting dose is 1 mg/kg/day, but up to 2 mg/kg/day may
with hypertonic posturing, and self-mutilation. Respira- be required in infants. The greatest benefit was seen in
tory muscle paralysis may lead to sudden death. Seizures children in whom the disease was diagnosed and treated
and sustained arterial hypertension are other common fea- before 6 months of age. In this cohort 90% responded—
tures. Mitchell et al reported a 42% incidence of neuro- including some with an acute manifestation. Of the 10%
logical crises with an associated mortality of 70% in 48 with no clinical response, five children died and three
tyrosinemic children hospitalized in Quebec.135 others underwent liver transplantation. The least amount
The clinical features of the neurological crises closely of benefit was seen in those beginning therapy after 2
resemble those of acute porphyria, and indeed, as in por- years of age. This population was heterogeneous, with
phyria, elevated serum δ-aminolevulinic acid is common. tyrosinemia newly diagnosed in some children and oth-
These elevated levels are due to inhibition of aminolevu- ers managed for often long periods by dietary restriction
linic acid dehydrase by succinylacetone, a metabolite of alone. In this group the main reason for withdrawal from
tyrosine degradation. Treatment of neurological crises is NTBC therapy was suspicion of HCC. Maintenance of a
largely supportive, although hematin, which decreases tyrosine-restricted diet is still essential with NTBC
aminolevulinic acid production, may shorten the course.136 treatment, as shown in both animal and human studies.
Emergency liver transplantation may be required for Rigorous monitoring of tyrosine levels is required. It is
severely affected children, particularly those in respiratory important to avoid tyrosine levels greater than 500
failure, and averts any further crises.138 μmol/L, which are associated with corneal lesions, hyper-
The kidneys are the third major organ affected by keratotic lesions of the palms and soles, and potentially
hereditary tyrosinemia. Kidney biopsies have shown nervous system abnormalities.
glomerulosclerosis and interstitial fibrosis.132 Autotoxic- The critical question remains whether early NTBC
ity of the kidneys by the local production of succinylac- treatment can eliminate the risk for HCC. In children
etone has been proposed as the mechanism of tubular treated early in life, HCC developed in 2 (1%) during the
dysfunction.139 first year of treatment.141 In a single-center report, 2 of

TYROSINE

4-hydroxyphenyllactate 4-hydroxyphenylpyruvate

Inhibition by NTBC

homogentisate

maleylacetoacetate
succinylacetoacetate
Toxic metabolites

CO2 fumarylacetoacetate
succinylacetone
Tyrosinemia type I

fumarate + acetoacetate
5-ALA porphobilinogen
FIGURE 27-2 n The metabolic pathway for tyrosine degradation. Note the proximal site of action of 2-nitro-4-trifluoromethylbenzoyl-
1,3-cyclohexanedione (NTBC), which blocks formation of the toxic metabolites. The site of the enzymatic defect is also shown. ALA,
Aminolevulinic acid. (Modified from Holme E, Lindstedt S. Nontransplant treatment of tyrosinemia. Clin Liver Dis. 2000;4:805-814.)
 27 Transplantation for Metabolic Disease in Children 325

10 children failed NTBC treatment, with hepatic dyspla- difficulties because serum α-fetoprotein levels cannot
sia developing in 1—the other was a nonresponder.142 generally be used as a marker. α-Fetoprotein levels,
Until further information is available, it would seem pru- often in the thousands, are characteristic of children
dent to be vigilant in monitoring for the development of with tyrosinemia, even without tumor. Similarly, com-
HCC in children treated with NTBC—particularly after puted tomographic scans and ultrasonograms may show
2 years of age. Serial imaging studies of the liver, immedi- liver nodules, even very early in the course of the dis-
ate biopsy of any suspicious lesions, and frequent mea- ease, that may not be malignant.
surement of serum α-fetoprotein levels (in children with Unfortunately, maintenance of normal tyrosine levels
low levels during NTBC therapy) remains necessary. by dietary means is no protection against the develop-
In a recent report of 45 French children with tyrosin- ment of hepatoma or the progression of liver disease. In a
emia who were treated with NTBC for a mean of 4 years review of 10 patients, 9 of whom had been on a strict diet,
9 months, only 3 patients required liver transplantation 3 had HCC before transplantation, 2 had incidental car-
for cirrhosis or HCC.143 However, 17 of the 45 showed cinoma diagnosed at transplantation, and 9 had hepato-
persistent abnormalities on liver imaging, and 15 of these cyte dysplasia.154
children had persistently elevated α-fetoprotein levels, The decision regarding transplantation is more easily
highlighting the question of the risk for developing HCC. made when the infant presents with fulminant liver fail-
ure.151 In such infants the severity of their disease usually
precludes a trial of NTBC. As experience has accrued
Liver Transplantation for Tyrosinemia
with liver transplantation in small infants, the fear of a
Before the advent of NTBC therapy, liver transplanta- poor outcome in such young recipients has been allayed.
tion was lifesaving in children with hereditary tyrosin- Esquivel et al147 reported an 80% survival rate in infants
emia and remains so for children who are nonresponders younger than 1 year who underwent transplantation for
to NTBC, those who already have cirrhosis at initial tyrosinemia. In very young infants a trial of dietary man-
evaluation, and children with evidence of hepatic dyspla- agement and NTBC is reasonable only if some stabiliza-
sia or malignant change. In 1976 the first patient with tion in liver function can be achieved.
tyrosinemia underwent transplantation.144 The metabolic Although many of the clinical features of tyrosinemia
abnormalities were promptly reversed, although the resolve,155,156 liver transplantation does not guarantee
patient did have HCC with a pulmonary metastasis at the complete reversal of the kidney impairment seen in
time of transplantation. In 1985 Starzl et al145 reported hereditary tyrosinemia. Not all patients reported156 have
the successful outcome of four children with chronic shown complete normalization of tubular dysfunction or
tyrosinemia and made the important point that trans- the glomerular filtration rate (GFR),157 and many con-
plantation should be considered early, before hepatoma tinue to have some, albeit reduced, amounts of succinyl-
develops. The concern for malignant transformation is acetone in their urine. The ongoing endogenous
further justified by reports of liver cell dysplasia and production of succinylacetone is the most likely explana-
HCC in explanted livers from children undergoing trans- tion, but heterogeneity in local expression of tyrosin-
plantation.146,147 Esquivel et al reported tumor in 5 of 10 emia in the kidney is evident by the variation in kidney
children who underwent transplantation for tyrosinemia. function reported after liver transplantation.158 How-
All 5 children were younger than 2 years at transplanta- ever, because the GFR is frequently impaired before
tion, and in 3, both lobes were involved. Recurrent tumor transplantation and ongoing posttransplant kidney
has occurred in 1 child.147 A further observation that 37% impairment secondary to calcineurin inhibitor use is
of children older than 2 years will have hepatoma134 likely, careful posttransplant management of renal func-
prompted most authors, before the use of NTBC ther- tion is necessary. Paradis et al159 monitored the GFR in
apy, to recommend elective transplantation at about 2 tyrosinemic children after transplantation and fraction-
years of age, a concept supported by the excellent results ated their cyclosporine doses, which avoided further
reported from several centers.148-151 nephrotoxicity.
One hundred twenty-five children with tyrosinemia in A mouse model of FAH deficiency is now allowing
the United Network for Organ Sharing (UNOS) data- experimental approaches to gene therapy for tyrosin-
base have received liver transplants at a mean age of 2.5 ± emia.160 This approach will be of particular benefit in
3.6 years. Overall, 5-year patient survival was 90%. high-risk populations in which routine screening of new-
Importantly, the rate of liver transplantation for children borns, siblings of index cases, and infants with early mani-
with tyrosinemia has decreased and age at transplant festation of disease is performed.
increased over the last decade because of early diagnosis
and treatment with NTBC.152
The dilemma still persists regarding when to offer
Urea Cycle Defects
transplantation to children with chronic tyrosinemia in Biosynthesis of urea is dependent on six enzymes, all of
whom decompensated end-stage liver disease has not which are localized in the liver.161 Defects in the urea
yet occurred.153 Evidence from NTBC studies suggests cycle lead to the accumulation of nitrogenous waste prod-
that children older than 2 years do not have a clear ben- ucts that can be neurotoxic. Inherited defects of urea syn-
efit from NTBC therapy, and because the risk for HCC thesis are frequently manifested soon after birth as severe
is of increasing concern after 2 years of age, liver trans- and often fatal syndromes marked by hyperammonemia,
plantation rather than NTBC therapy is the preferred coma, and devastating CNS impairment. The cornerstone
choice. The diagnosis of hepatoma itself is fraught with of medical management is dietary protein restriction
326 PART III Patient Evaluation: Pediatric

combined with attempts to increase the excretion of of life, before neurological damage is evident and without
ammonia and avoid a catabolic state. Exchange transfu- the considerable risks of liver transplantation.
sion, peritoneal dialysis, and hemodialysis can acutely
lower ammonia concentrations but are impractical for
Ornithine Transcarbamylase Deficiency
long-term management. Sodium benzoate, either orally
or intravenously, also lowers ammonia levels by allowing The most common of the urea cycle defects, OTC defi-
the excretion of nitrogen as hippurate. Phenylacetate, ciency is an X-linked dominant disease.172 Affected
arginine, glucose, and insulin infusions have also been males are usually seen in the first days of life with leth-
used.162 However, medical interventions have high associ- argy, irritability, and poor feeding rapidly progressing
ated morbidity and mortality in the long-term ameliora- to convulsions, apnea, and coma. The diagnosis is sug-
tion of these disorders. Long-term risks include protein gested by markedly elevated serum ammonia levels, low
deficiency, growth retardation, accidental overdose of or normal blood urea, low serum citrulline levels, and
drugs used to lower ammonia levels, and the unpredict- severe oroticaciduria. Liver biopsy is not necessary for
able recurrence of coma leading to devastating neurologi- diagnosis and in fact has been associated with precipitat-
cal injury.161,163 ing hyperammonemic crises and subsequent death.
Indeed a recent report of a 25-year open-label study of Although liver dysfunction is not clinically significant in
sodium phenylacetate and sodium benzoate therapy for OTC deficiency, transaminitis with fibrosis and glyco-
patients with urea cycle disorders highlights the chal- genosis on liver biopsy has been described.173
lenges in managing these patients.164 Among 299 patients With intensive early intervention, sometimes includ-
enrolled, there were 1181 episodes of acute hyperammo- ing hemodialysis, some boys with either the complete or
nemia reported. The overall survival rate was 84%, but incomplete form of OTC deficiency have survived beyond
56% sustained neurological impairment following such the neonatal period with protein restriction.174 However,
episodes. hyperammonemic crises, frequently precipitated by cata-
Liver transplantation, either complete or auxiliary, bolic stress such as acute illness, may still occur with the
could be predicted to cure urea cycle defects with nor- attendant risk for further neurological damage.
malization of ammonia levels reported with 24 hours of Heterozygote girls may show a spectrum of clinical
transplantation.165 Three of the six enzymopathies of disease consistent with the Lyon hypothesis of random
urea synthesis have now been treated by liver transplanta- inactivation of the normal X chromosome.175 Some are
tion.166-168 The difficulty lies in successfully implement- clinically normal, whereas others may be identified in
ing the procedure in the neonatal period, when many of either infancy or later childhood by episodes of lethargy,
these infants are identified, before irreversible CNS dam- irritability, and even coma precipitated by increased pro-
age occurs. The barrier to liver transplantation in the tein intake. A fatal clinical course of OTC deficiency was
very young is being lowered as the technique of and described in a heterozygous woman.176 Diagnosis of
expertise in transplantation have become perfected, as OTC deficiency in female heterozygotes is often difficult
demonstrated by successful liver transplantation in a and requires a high index of suspicion. Provocative test-
14-day-old for a urea cycle defect.166 Five-year patient ing with protein loads or allopurinol challenge is not
survival for patients with urea cycle disorders who have always conclusive, and DNA analysis does not detect the
received a liver transplant is 90%.169 Long-term data on mutation in some cases. Measures of in vivo urea cycle
developmental and neurological outcomes of these recip- activity may be more sensitive.177 Several reports of liver
ients are emerging, and as may be expected, development transplantation in girls have shown complete correction
seems to be tied to pretransplant metabolic management, of the defect.175
age at transplant, and early childhood intervention.170 The success of liver transplantation in reversing the
The liver in patients with urea cycle defects is structur- metabolic defect in OTC deficiency is well described.166,178
ally normal. Although either complete or auxiliary liver Early diagnosis and aggressive management to lower
replacement can result in a metabolic cure because only ammonia levels in the newborn period are essential to
about 3% to 5% of hepatocytes with normal OTC limit the degree of neurological injury sustained before
expression are required to reverse the clinical manifesta- transplantation.167 Such injury can often be difficult to
tions of the disease, isolated allogeneic hepatocyte trans- predict given that many of these children are evaluated
plantation or genetic modification of the patient’s own for transplantation before 1 month of age. Generally the
hepatocytes could also achieve a functional cure. In a case younger the child at transplantation, the better the neu-
report of an infant with OTC deficiency treated by infu- rological prognosis. In our experience of eight boys with
sion of batches of isolated hepatocytes over a 4-week a median age of 6.2 months at the time of liver transplan-
period, hyperammonemia resolved temporarily but tation, 100% have survived with a median follow-up of
returned after 31 days. The viability of allogeneic hepato- 133.9 months. Four of these boys have mild to moderate
cytes, despite immunosuppression, remains the hurdle to neurological impairments that seem to correlate with
overcome for this modality to be successful in the long pretransplant cognitive function and became more
term.26 In a rodent model, virus-mediated transfer of noticeable as they approached school age. In all, serum
human argininosuccinate synthetase has already been ammonia levels and serum arginine levels are normal, but
accomplished.32 The helper-dependent adenoviral vec- before supplementation, citrulline levels were low because
tors may offer the best chance of long-term gene expres- of the persistent deficiency of OTC in the intestinal
sion.171 Once perfected in humans, this modality would mucosa.179 Auxiliary liver transplantation has also been
allow correction of the metabolic defect in the first days performed in both boys and heterozygous girls with
 27 Transplantation for Metabolic Disease in Children 327

OTC deficiency.178,180 In the first report of this proce- parents. In both, the hyperammonemic episodes resolved.
dure,178 an already neurologically impaired 14-month- In one, plasma citrulline levels remained high,189 and in the
old underwent transplantation to improve his quality of other they normalized.182
life. The recipient’s left lobe was removed, and segments
II and III of the liver graft were placed in an orthotopic
position. Normalization of serum ammonia levels on a
Other Disorders of Amino Acid Metabolism
full diet without any medications was achieved. Both the The more common organic acidurias methylmalonicacide-
native liver and the graft are functional. This case exem- mia, propionicacidemia, and maple syrup urine disease
plifies the principle that only a portion of a normal liver is have in common a wide spectrum of clinical manifestations
required to provide enough normal enzyme activity to characterized by metabolic acidosis, lethargy, poor feeding,
reverse the metabolic deficit. hepatomegaly, and various degrees of neurological impair-
Liver transplantation using a related living donor, ment. Medical management primarily relies on strict
particularly a mother, raises the concern of using a het- dietary protein restriction. However, despite good dietary
erozygous OTC-deficient graft. Death of a recipient compliance, these children may suffer life-threatening cri-
who received a graft from a deceased donor with unsus- ses. Although the enzymatic defects are not confined to the
pected OTC deficiency has already been reported.181 liver, several children have undergone liver transplantation
Although success has been reported with the mother with variable success.
used as a donor, other living donor programs advocate
allopurinol loading tests to exclude heterozygote Methylmalonicacidemia and
donors.182 Propionicacidemia
Of the organic acidemias, liver transplantation for meth-
Carbamoyl-Phosphate Synthetase Deficiency
ylmalonicacidemia is the most commonly reported with
Inherited as an autosomal recessive trait, the neonatal over 30 cases of liver and combined liver-kidney trans-
form of carbamoyl-phosphate synthetase deficiency pres- plantation, reported in the medical literature.184,190,191
ents a clinical picture similar to OTC deficiency. The Children present with hepatomegaly, increased ammo-
diagnosis is differentiated from OTC deficiency by the nia and transaminase levels, hypoglycemia, and variable
absence of oroticaciduria.161 degrees of neurological impairment. A significant num-
Partial carbamoyl-phosphate synthetase deficiency, in ber of patients with methylmalonicacidemia have been
which episodic hyperammonemia may be manifested in reported to have renal insufficiency at the time of trans-
the first weeks or months of life, has also been described. plant. Indeed end-stage kidney disease develops in long-
Developmental retardation is seen in both forms. term survivors, which should prompt evaluation for
There are a handful of reports of liver transplantation combined liver-kidney transplantation by the medical
in children with carbamoyl-phosphate synthetase defi- teams involved with these patients. Despite medical
ciency. A 14-day-old boy successfully underwent trans- management with dietary protein restriction and carni-
plantation with a newborn deceased donor liver and has tine supplementation, disease exacerbations with vomit-
had complete normalization of serum ammonia levels on ing, dehydration, acidosis, and hypoglycemia may occur
an unrestricted diet. He has some delay in developmental and be manifested as acute emergencies.192 Some chil-
milestones, which the authors attribute to a brain abscess dren with methylmalonicacidemia appear to have mini-
after transplantation.166 Another child, who underwent mal CNS involvement and have undergone liver or
transplantation at 20 months, already had developmental kidney transplantation (or both), but with mixed
delay. Although his serum ammonia levels normalized, results.193-195 Of particular concern are the late appear-
citrulline levels remained undetectable and dietary sup- ance of metabolic stroke and progressive neurological
plementation was needed.183 The group at Stanford Uni- disability that have been reported.196,197 It is widely
versity has recently reported on two children with accepted that liver transplantation will not reverse neu-
carbamoyl-phosphate synthetase deficiency who pre- rological deficits sustained before surgery. At this time
sented with altered mental status, hyperammonemia, and liver transplantation appears to have a dubious role in
poor nutrition who were transplanted at 140 ± 91 months providing long-term benefit to most of these patients.195
of age and have survived long-term with a degree of However, given the decrease that is seen in methylmalo-
developmental delay.184 nic acid levels and in the number of episodes of meta-
bolic decompensation, others have considered the
improvement in quality of life a justification for liver
Argininosuccinate Synthetase Deficiency
transplantation, even if some neurological impairment is
High citrulline levels characterize the rare autosomal reces- present.14
sive condition of argininosuccinate synthetase deficiency. A The clinical manifestations of the propionicacidemias
severe neonatal form has been described, with some survi- are very similar to those of the methylmalonicacidemias,
vors beyond the neonatal period161 who were successfully and a neonatal-onset form has been described. The defec-
transplanted.168,185 A variant, usually seen in adult patients tive enzyme in patients with propionicacidemia, propionyl
of Japanese descent, has been treated by liver transplanta- coenzyme A carboxylase, is expressed in the liver as well as
tion with reversal of the neurological defects associated other tissues not corrected by liver transplantation.
with hyperammonemia.26,166,186-188 Two Japanese children Several case reports in the literature, including a recip-
have received living donor grafts from heterozygous ient of a living donor graft198 and another of an auxiliary
328 PART III Patient Evaluation: Pediatric

graft,199 relate that liver transplantation reduced serum no significant change noted 1 year later. Interestingly, six
ammonia levels, allowed less restricted dietary protein of these patients were involved in domino transplants.
intake, and appears effective in reducing or eliminating
acidotic episodes.200
Over 14 cases of orthotopic liver transplantation for DISORDERS OF CARBOHYDRATE
propionicacidemia have been reported in the medical lit-
erature with 1- and 5-year patient survival reported at
METABOLISM
72% and 56%, respectively.201 Recently the group at Galactosemia and Fructosemia
King’s College reported on five children with propionic-
acidemia who underwent orthotopic liver transplantation Galactosemia and hereditary fructosemia can both be
at a median age of 1.5 years with a median follow-up time manifested in infancy as fulminant liver failure.207 The
of 7.3 years.202 They report normal graft function and normal conversion of galactose to glucose occurs via a
good quality of life with a protein-unrestricted diet and series of four enzymatic steps. Galactosemia is caused by a
no further metabolic decompensations in all patients. deficiency in galactose 1-phosphate uridyltransferase.
Cardiomyopathy is a well-described late complication of Galactosemia occurs in the first few days after milk feeding
propionicacidemia occurring in up to one third of chil- begins and produces a life-threatening illness with vomit-
dren in the first decade of life. Recent reports suggest that ing, jaundice, hepatomegaly, liver failure, and kidney-type
cardiomyopathy may be reversible by liver transplanta- Fanconi syndrome. Acute decompensations in the neona-
tion.203 Regardless, for children with propionicacidemia tal period frequently are associated with Escherichia coli
undergoing liver transplantation, peritransplant and bacteremia. Infants are acidotic, and galactose, a reducing
posttransplant cardiology follow-up and serial echocar- substance, can be demonstrated in the urine. Most infants
diograms are essential. in the United States are identified with newborn screen-
ing,208 and elimination of all milk products from the diet
Maple Syrup Urine Disease reverses the acute liver and kidney decompensation, and
emergency liver transplantation is not necessary. The
Maple syrup urine disease is an autosomal recessive dis- enzymatic defect also occurs in many other extrahepatic
order of branched-chain amino acid metabolism. sites such as red blood cells, skin fibroblasts, and intestinal
Impaired activity of the branched-chain 2-oxoacid dehy- mucosal cells. Several clinically milder variants have been
drogenase complex results in the accumulation of described. Although dietary management can control this
branched chain l-amino acids (leucine, isoleucine, and disease, even small amounts of ingested galactose can
valine) and 2-oxoacids. The increased leucine levels apparently lead to progressive liver injury culminating in
appear to exert most of the neurotoxic effects. Children cirrhosis with the subsequent development of HCC. At
often present in infancy with obtundation, coma, and least two young adults have undergone liver transplanta-
seizures, with some succumbing to cerebral edema. Very tion for cirrhosis with HCC secondary to galactosemia.209
high serum leucine levels are the diagnostic tip-off. Nonetheless galactosemia should be managed medically
Neurological sequelae can be averted by aggressive and should not require liver transplantation.
medical management during crises, including growth Hereditary fructosemia (fructose 1-phosphate aldolase
hormone and insulin infusions, hemofiltration or dialy- deficiency) is recognized in the first few months of life
sis, and rigorous management of cerebral edema. With after the introduction of fruit sugars and sucrose to the
very strict control of dietary protein, which requires gas- diet. The clinical features are quite similar to those of
trostomy tube feeding in infants, further neurological galactosemia and consist of failure to thrive, vomiting,
crises can be avoided in some children. However, crises fulminant liver failure, and Fanconi syndrome. The
can occur even with full compliance with the protein- infants are characteristically hypoglycemic with hypo-
restricted diet and can be precipitated by any catabolic phosphatemia and lactic acidosis. However, with the
stress, such as an intercurrent illness, exercise, fasting, elimination of fructose, sucrose, and sorbitol from the
or dehydration. The risk for sustaining neurological diet, complete recovery occurs and liver transplantation
damage from such episodes continues throughout life. is not necessary.207
Although modern management of maple syrup urine
disease in dedicated centers has been associated with
good neurological outcome,204 the quality of life in these
Glycogen Storage Diseases
children as they grow older, combined with the ongoing At least 12 glycogen storage diseases have been identified,
risk for CNS injury, has led some specialists in this dis- most of which can be controlled by dietary means. Hepa-
ease to recommend liver transplantation. Liver trans- tomegaly and hypoglycemia are common to most of the
plantation should be considered in children without variants. The enzymatic deficiency, however, is not local-
significant neurological damage who have already ized to the liver, and glycogen storage is readily seen in
proved difficult to control with dietary protein restric- biopsy samples of other tissues, particularly the heart,
tion alone.205 skeletal muscle, and CNS.207 For this reason, caution
A recent report indicates that 54 children have under- should be practiced when recommending liver transplan-
gone liver transplantation in the United States for Maple tation for the glycogen storage diseases.209
syrup urine disease with patient and graft survival of 98% In general, liver transplantation is indicated for patients
and 96%, respectively.206 One third of these patients with glycogen storage disease with unmanageable meta-
were mentally impaired (IQ <70) before transplant, with bolic dysfunction, decompensated cirrhosis, or those at
 27 Transplantation for Metabolic Disease in Children 329

risk for developing hepatocellular carcinoma. Liver trans- the heart and skin (Fig. 27-3). These authors postulated
plantation has been most commonly considered for glyco- that microchimerism, in which enzymatically normal
gen storage diseases types I, III, and IV.210 cells migrate from the graft to the periphery, may be the
Type IV glycogen storage disease is a rare autosomal mechanism by which the diffuse cellular enzymatic defect
recessive condition caused by a brancher enzyme deficiency can be ameliorated.216 To date at least 17 children have
that results in the accumulation of an abnormal glycogen been reported in the world literature as undergoing
resembling amylopectin, a plant starch. The gene is located orthotopic liver transplantation for type IV glycogen
on chromosome 3p14, and several mutations have been storage disease210 with good long-term outcomes.
described, thus accounting for the variability in clinical Type IA glycogen storage disease, an autosomal reces-
findings.211 Usually the disease develops early in life, with sive defect caused by glucose-6-phosphatase deficiency,
rapidly progressive liver injury leading to cirrhosis.212 was the first liver enzyme deficiency described. Normally,
There is also evidence for amylopectin accumulation in the the enzyme is expressed in the liver, kidneys, and intestine.
CNS, heart, and skeletal muscle. In such patients, dietary Hepatomegaly, hypoglycemia, lactic acidosis, and growth
management is not successful, and death from cirrhotic failure occur in infancy but can generally be well controlled
liver disease occurs within the first few years of life unless by frequent glucose and starch feeding and avoidance of
liver transplantation is performed. However, because the lactose and sucrose. Hyperuricemia may lead to kidney
enzymatic defect is not limited to hepatocytes, ongoing stone formation and requires allopurinol treatment.207
accumulation in extrahepatic tissue can occur. Selby et al 213 Some patients with type IA glycogen storage disease
reported seven children with type IV glycogenosis who have difficulty complying with restricted diets and con-
underwent liver transplantation. No evidence was found of tinuous feedings as they enter childhood and are thus sus-
progressive amylopectin accumulation in extrahepatic sites, ceptible to episodes of severe hypoglycemia with seizures.
and a reduction in cardiac amylopectin was described in one For such life-threatening complications, liver transplan-
child. However, Sokal et al214 reported increasing amylo- tation has been successfully performed with complete
pectin deposition in the heart after liver transplantation, resolution of the metabolic defect, good catch-up growth,
which ultimately led to the patient’s death. In a more recent and improved quality of life.212,215,217 However, liver
report of 13 children transplanted for type IV glycogen replacement cannot be expected to correct the intestinal
storage disease with up to 13 years of follow-up, only 1 had and kidney deficiency of glucose-6-phosphatase. Focal
evidence of cardiac or neuromuscular complications.215 segmental glomerulosclerosis, which has been associated
In 1993 Starzl et al reported two children with type IV with type IA glycogen storage disease, has occurred after
glycogen storage disease, both of whom had a decrease in liver transplantation.217 In the type IB glycogen storage
cardiac amylopectin after liver transplantation. In both disease variant, the associated neutrophil dysfunction has
patients, donor-derived cells could be demonstrated in also persisted after liver transplantation.215

A C
FIGURE 27-3 n Type IV glycogen storage disease. Immunocytochemical analysis of the heart, transplanted liver, and native liver in a
patient with type IV glycogen storage disease shows chimerism. A, Green fluorescence (arrows) identifies cells with the donor’s phe-
notype (HLA-DR1, HLA-DR4) in the interstitium of the heart. B, Positive green-staining donor cells (HLA-DR1, HLA-DR4) in the trans-
planted liver. C, Negative control shows absence of donor cells in the recipient’s native liver. All sections were stained with a single
monoclonal antibody specific for HLA-DR1 and HLA-DR4. The yellow globules are autofluorescent intracellular pigment. (Reprinted,
by permission, from Starlz TE, Demetris AJ, Trucco M, et al. Chimerism after liver transplantation for type IV glycogen storage disease and
type 1 Gaucher’s disease. N Engl J Med. 1993;328:745-749.)
330 PART III Patient Evaluation: Pediatric

Cirrhosis is rarely a consequence of type I glycogen or the receptor itself is abnormal and unable to bind LDL.228
storage disease; however, poor metabolic control can lead As a consequence, LDL levels in plasma rise, and total cho-
to the development of hepatic adenomas in adolescents lesterol level may be as high as 700 to 1000 mg/dL in homo-
and young adults. Malignant transformation of these ade- zygotes. Disease in such patients is also refractory to
nomas has been described and is an indication for liver treatment with drugs that lower plasma cholesterol levels
replacement. This complication generally occurs in post- because both bile-sequestrating agents and the 3-hydroxy-
pubertal patients, with an incidence varying between 22% 3-methylglutaryl coenzyme A reductase inhibitors (e.g., lov-
and 75% and an estimated risk that 10% will undergo astatin) depend on induction of LDL receptors for their
malignant transformation.218 Whether assiduous control therapeutic effect.229 In contrast, heterozygote carriers of
of hypoglycemia decreases the potential for malignancy is the familial hypercholesterolemia gene are able to be suc-
unknown.219 This potentially fatal complication has cessfully treated by medical means because their one normal
already been averted by liver transplantation.220 However, gene allows adequate induction of LDL receptors.
the difficulty lies in detecting when the malignant change The concept that liver replacement may be the ther-
occurs. Because the adenomas are usually multiple, surgi- apy of choice was supported by evidence from animal
cal resection does not typically provide definitive treat- studies in which it was shown that 50% to 70% of the
ment. As children with glucose-6-phosphatase deficiency body’s total LDL receptors resided on hepatocytes.230
survive longer, they should be regularly screened for the Subsequently in 1984 Starzl et al reported successful
development of adenomas, with subsequent biopsy of dis- simultaneous heart and liver transplantation in a 6-year-
covered adenomas. If either dysplasia or malignant change old girl with heart failure who had previously undergone
is found, liver transplantation should be considered. two coronary bypass operations.231 Within 10 weeks of
Given the lack of a useful biomarker to predict HCC transplantation the girl’s serum cholesterol levels had
transformation, the clinical dilemma is how many lesions fallen from a pretransplant value of more than 1000 mg/
should undergo biopsy and how often. dL to 270 mg/dL. One year after transplantation the
A single experience of allogeneic hepatocyte transplan- child’s cholesterol levels were normalized with adjunctive
tation was recently reported in a 47-year-old woman with lovastatin therapy.232 The child remained asymptomatic
type IA glycogen storage disease, who 9 months after hepa- with no evidence of recurrent coronary artery disease.
tocyte transplantation could eat an unrestricted diet and Other reports quickly followed of isolated liver trans-
fast for 71 hours without hypoglycemia. Two billion hepa- plantation with coronary bypass,233 sequential heart and
tocytes in two separate infusions were given through an liver transplantation,234 or combined liver-heart trans-
indwelling portal vein catheter, and triple-drug immuno- plantation.235,236 In all patients, LDL cholesterol, total
suppression was administered.221 This report suggests that cholesterol, and apolipoprotein B levels decreased. High-
isolated hepatocyte transplantation may become a treat- density lipoprotein (HDL) levels increased, and the LDL/
ment option for patients before the development of adeno- HDL ratio was decreased.235,237 The dramatic fall in
mas. Subsequent reports of hepatocyte transplantation for serum cholesterol levels after sequential heart and liver
glycogen storage disease have appeared in the literature transplantation is shown in Figure 27-4. Patients have had
with a transient improvement in metabolic function.222 regression of their xanthomas and normal coronary
Type III glycogen storage disease has clinical features
similar to but typically less severe than those of type I
disease. However, hepatic fibrosis leading to cirrhosis and Heart transplantation
1300
adenomas is not uncommon. Typically hepatic adenomas
associated with type III glycogen storage disease are
Total plasma cholesterol (mg/dL)

fewer in number and smaller in size than in type I glyco- 1100

Liver transplantation
gen storage disease.223 Successful liver transplantation
has been reported.210,215,224,225 Reports exist of children 900
with type III glycogen storage disease developing ven-
tricular hypertrophy; therefore echocardiogram, electro- 700
cardiogram, and cardiac consultation should be part of
their liver transplant evaluation. 500

300
DISORDERS OF LIPID METABOLISM
100 0 1 23
Familial Hypercholesterolemia
Type IIA familial hypercholesterolemia is an autosomal 0 1 2 3 4 5 6
recessive disease characterized by markedly elevated serum Weeks Months after liver transplantation
low-density lipoprotein (LDL) cholesterol levels, early- FIGURE 27-4 n Familial hypercholesterolemia. Changes in total
onset atherosclerosis, multiple xanthomas, and left ventricu- plasma cholesterol level after liver transplantation for familial
lar outflow obstruction.226,227 As a consequence, premature hypercholesterolemia type IIA. (Reproduced with permission
from Valdivielso P, Escolar JL, Cuervas-Mons V, et al. Lipids and
death from myocardial infarction occurs in the second or lipoprotein changes after heart and liver transplantation in a patient
third decade. The gene encoding for LDL receptors appears with homozygous familial hypercholesterolemia. Ann Intern Med.
to be defective, so either LDL receptor expression is absent 1988;108:204-206.)
 27 Transplantation for Metabolic Disease in Children 331

angiograms. The majority have not required additional variceal hemorrhage. The patient was neurologically nor-
cholesterol-lowering medications or restrictive diets. Our mal before transplantation but died 2½ months afterward
group has performed a combined liver-heart transplanta- with intractable rejection.244 At autopsy the liver graft
tion in a teenager with familial hypercholesterolemia and showed a threefold increase in glucosylceramide level in
severe coronary artery disease who had sustained previous comparison to controls, thus indicating only partial correc-
myocardial infarcts. This young man continues to do well tion of the defect. A second patient also underwent trans-
with stable graft function over 2.5 years after transplant. plantation for complications of cirrhosis, but 1 year later a
Liver transplantation alone, before the onset of coro- liver biopsy showed a scattering of “wrinkled paper” Gau-
nary artery disease, may be the optimal choice.238,239 cher cells, although fibrosis had not yet been established.245
Some authors have advocated placement of a portocaval A 61% increase in hepatic glucocerebrosidase activity 9
shunt early in life to at least partially reduce cholesterol months after surgery was noted in a 42-year-old man.246
levels, followed by liver transplantation.240Although the Subsequently long-term reports of patients with Gau-
liver in familial hypercholesterolemia is structurally nor- cher’s disease and severe hepatic impairment who have
mal, liver replacement provides normal numbers of LDL been successfully treated with liver transplantation have
receptors so that serum cholesterol level falls and the life- emerged, although enzyme replacement therapy with
threatening complications of coronary artery disease are recombinant glucocerebrosidase is now considered the
prevented. Two experimental models that might avoid mainstay of treatment.247-249
the considerable risks of complete liver transplantation
hold promise. The first is transplantation of allogeneic Niemann-Pick Disease
hepatocytes with normal expression of LDL. In the
Watanabe rabbit model of heritable hyperlipidemia, Niemann-Pick disease types A and B are autosomal reces-
intraperitoneal injection of normal hepatocytes lowered sive, heterogenous disorders resulting from acid sphingo-
LDL cholesterol level by 45% for 4 weeks.241 Another myelinase deficiency that result in the deposition of
approach is transfection of harvested hepatocytes with a sphingomyelin in the lysosomes of multiple cell lines
recombinant retrovirus expressing a functional LDL throughout the viscera and brain.251 Type A is often man-
receptor gene.31 Again in the Watanabe rabbit model, ifest in early childhood with prolonged neonatal jaundice,
this approach resulted in a temporary reduction in serum hepatosplenomegaly, and severe progressive neurological
cholesterol level. Unfortunately, in both these experi- damage. Early death is inevitable. Type B often presents
mental models, cell death of the transplanted hepatocytes in childhood to adolescence with growth retardation,
precluded a long-lasting effect, a problem that remains hyperlipidemia, pancytopenia, and hepatosplenomegaly
unsolved. progressing to cirrhosis.252 Pulmonary involvement is
also seen, but the CNS is spared.
Liver transplantation has been reported with Nie-
Lipoidoses mann-Pick disease type B.246 The sphingomyelin con-
The lipoidoses are rare inherited defects in which abnor- tent in the liver graft was normal, but the peripheral
mal lipid compounds are stored in multiple organs. In blood leukocytes continued to show very low sphingo-
general the enzymatic defects are widespread, and affected myelinase levels. Daloze et al reported a boy with spas-
patients often suffer severe neurological impairment, ticity and myoclonus secondary to type A Niemann-Pick
with death occurring in infancy and childhood. Patients disease who received a liver transplant at 2 years of
with milder clinical variants of two types of lipoidoses, age.253 For 2 years after transplantation the boy’s neuro-
Gaucher’s disease and Niemann-Pick disease, have logical function improved, the lipid infiltrates in the
undergone liver transplantation in an attempt to amelio- retina regressed, and sphingomyelin did not reaccumu-
rate the liver manifestations of the disease. In general, late in the graft. However, electron microscopic studies
most reported patients have continued to show extrahe- of the liver graft 540 days after transplantation continued
patic storage of the abnormal lipid. to show the small lucent vacuoles described in Niemann-
Pick disease (Fig. 27-5). He died of respiratory and infec-
tious complications. At autopsy, several tissues, including
Gaucher’s Disease
the brain, showed accumulation of sphingomyelin. Bone
Gaucher’s disease is the most common lysosomal stor- marrow transplantation has been performed in multiple
age disease. This autosomal recessive inherited defi- patients with Niemann-Pick disease types A and B with
ciency of glucocerebrosidase results in the accumulation varying results.254
of glucosylceramide in the liposomes of reticuloendo- Niemann-Pick disease type C results from defects in
thelial cells distributed throughout the body.242 The intracellular cholesterol transport and manifests also as a
acute infantile forms are characterized by severe neuro- neurovisceral storage disease characterized by sea-blue
logical impairment, as well as hepatosplenomegaly, histiocytes in the bone marrow, with patients often pre-
osteolytic bone lesions, and pancytopenia. The adult senting with neonatal jaundice or hepatitis and eventual
variants of the disease (types 1 and 3) do not have signifi- hepatosplenomegaly. Transplantation has been attempted
cant neurological involvement, and the course of the dis- for Niemann-Pick disease type C.255 Liver cirrhosis and
ease is more insidious.243 severe neurological impairment had occurred by 6 years
The first patient who underwent liver transplantation of age, when the liver transplant was performed. An inci-
for Gaucher’s disease experienced portal hypertension sec- dental HCC was found in the excised liver. After an initial
ondary to hepatic fibrosis with subsequent life-threatening period of stabilization, the patient continued to show
332 PART III Patient Evaluation: Pediatric

or adulthood. In a few cases, accumulation of cholesteryl

esters within hepatocytes has resulted in progressive fibro-
sis and portal hypertension. Liver transplantation has
been successful in patients with life-threatening variceal
bleeding but minimal extrahepatic involvement.258-260

DISORDERS OF BILIRUBIN METABOLISM

The hallmark of Crigler-Najjar syndrome, first described
in 1952, is severe nonhemolytic unconjugated hyperbili-
rubinemia, usually beginning in the newborn period.
The autosomal, recessively inherited enzyme defect lies
A within the group of uridine diphosphate glucuronyltrans-
ferases (UDPGTs), which conjugate bilirubin within the
hepatocyte. Mutations in the UGT1 gene complex encod-
ing the defective enzyme have been identified and may
facilitate prenatal diagnosis.261 Two forms of the syn-
drome exist with quite different prognoses. In type I,
UDPGT activity is undetectable, the profound hyper-
bilirubinemia is unresponsive to phenobarbital therapy,
and without treatment kernicterus develops, which is
inevitably fatal.262 In type II Crigler-Najjar syndrome,
some UDPGT activity is preserved and can be induced
by phenobarbital, thereby allowing successful medical
management of these patients. Bilirubin levels fall to less
than 4 mg/dL, and any long-term CNS sequelae are
completely avoided.263
B The mainstay of early therapy for type I Crigler-Najjar
syndrome is phototherapy. With exposure to high-inten-
FIGURE 27-5 n Niemann-Pick disease. Electron micrographs of
the liver before (A) and after (B) liver transplantation. The sity irradiation, frequently for more than 12 hours per
numerous large electron-lucent membrane-bound vacuoles day, the total bilirubin level can initially be maintained at
seen before transplantation are no longer visible, but small stor- less than 20 mg/dL and the development of kernicterus
age vacuoles are seen in the graft 540 days after transplantation. averted.264,265 However, intense long-term phototherapy,
(From Daloze P, Delvin EE, Florieux FA, et al. Replacement therapy
for inherited enzyme deficiency: liver orthotopic transplantation in
during which the infant’s eyes are patched and activities
Niemann-Pick disease type A. Am J Med Genet. 1977;1:229-239.) are curtailed, is difficult to continue in an active toddler.
A further problem is that as the child grows, subcutaneous
tissue increases and surface area decreases, and as a result,
progressive neurological deterioration, and Kupffer cells phototherapy becomes less effective. Although it is not
within the liver graft again reaccumulated the ceroid stor- clearly established at what level of unconjugated bilirubin
age material.256 For these reasons liver transplantation is kernicterus develops, most experts recommend that total
generally not recommended. bilirubin level not exceed 20 to 25 mg/dL in an older
infant.266 Of concern is that the devastating consequences
Wolman’s Disease of kernicterus have been noted to develop unpredict-
ably.267 Classically occurring in the neonatal period, a sec-
Wolman’s disease257 is the severe infantile form of lyso- ond incidence peak of kernicterus also occurs in puberty.
somal acid lipase deficiency. Inherited absence of this Bilirubin-lowering medications such as tin protoporphy-
enzyme results in the accumulation of cholesterol esters rin and oral calcium phosphate,268 which bind unconju-
and triglycerides within lysosomes in the intestinal mucosa, gated bilirubin, may have some benefit but are still under
vascular endothelium, lymph nodes, spleen, leukocytes, investigation.269,270
and bone marrow. Infants present with vomiting and diar- Although anatomical liver disease is mild and usually
rhea, abdominal distention, and marked hepatosplenomeg- limited to elevated intracellular bilirubin level with cana-
aly. The diagnostic tip-off is bilateral adrenal calcification. licular bile stasis, liver transplantation can be expected to
Infants seldom survive beyond the first year. The condition cure type I Crigler-Najjar syndrome by replacing the
may be amenable to bone marrow transplantation. Enzyme UDPGT-deficient hepatocytes with normal cells.
replacement therapy for lysosomal acid lipase deficiency is Kaufman et al271 reported the first patient with type I
in clinical trials (Synageva BioPharma Corp). Crigler-Najjar syndrome to undergo transplantation. A
permanent and rapid fall in total bilirubin level occurred,
Cholesterol Ester Storage Disease and the patient thrived (Fig. 27-6). This experience was
soon confirmed by others,272,273 and at present, liver
Cholesterol ester storage disease257 is the mild form of transplantation remains the only therapeutic option for
acid lipase deficiency and typically occurs in adolescence these children once phototherapy becomes ineffective or
 27 Transplantation for Metabolic Disease in Children 333

30 were characterized by unconjugated hyperbilirubinemia

as opposed to the usual conjugated hyperbilirubinemia
Total serum bilirubin (mg/dL)
25 typical of rejection.278
Type I Crigler-Najjar syndrome, in which the enzyme
20 defect is localized in an architecturally nearly normal
liver, would also be an ideal target disease for hepatocyte
15
transplantation and gene therapy. The UDPGT-defi-
10 cient Gunn rat, which is a model of the human syndrome,
has allowed experimentation in these concepts, which
5 have been performed in a small number of human sub-
jects.279-285 Ex vivo gene therapy, in which genetically
0 altered hepatocytes are transplanted into the liver, and
0 2 4 6 1 2 10 270 in vivo gene transfer using recombinant viral–based vec-
Hours Days tors have had reported success.280 Both286 these modali-
ties have been successful in lowering total bilirubin level.
FIGURE 27-6 n Crigler-Najjar syndrome. Fall in serum bilirubin
level in a 3-year-old with Crigler-Najjar syndrome during and These alternative therapies, if successful in large-scale
after liver transplantation. Hours 0 and 6 indicate the start and numbers in humans, could avoid the significant risk asso-
completion of surgery. Later lines represent postoperative ciated with whole-liver replacement.
days. (From Kaufman SS, Wood RP, Shaw BW, et al. Orthotopic
liver transplantation for type I Crigler-Najjar syndrome. Hepatology.
1986;6:1259-1262.)
CYSTIC FIBROSIS
impractical.266 If liver transplantation is delayed beyond Cystic fibrosis, which has an estimated incidence of 1 in
midchildhood, the risk for neurological damage 2000 live births in the white population, is one of the
increases.266 In a report of 57 patients from the Crigler- most common inherited lethal diseases.287 In 1989 the
Najjar world registry, brain damage had already occurred abnormal gene, the cystic fibrosis transmembrane con-
in 26%. Thirty-seven percent had received a liver trans- ductance regulator, was localized to the long arm of chro-
plant at an average age of 9.1 years, but of these patients mosome 7.288 Now more than 600 mutations have been
a third already had neurological impairment. The chil- described. The most common mutation in white popula-
dren without neurological impairment were transplanted tions is the ΔF508 mutation, which accounts for about
at a mean of 5.9 years as compared with a significantly 70% of cystic fibrosis alleles. About 2% to 15% of cystic
higher mean age of 14.3 years in children transplanted fibrosis alleles account for 15 to 20 other mutations. Cys-
with already-evident CNS damage.268 In a single-center tic fibrosis mutation analysis, its relevance in different
experience, six children underwent liver transplantation ethnic populations, and particularly its use in prenatal
at a mean age of 52.5 months. All children survived with diagnosis are central topics in the unfolding understand-
normal bilirubin levels, and all but one child transplanted ing of this disease.289,290
at 8 years of age are developmentally normal.274
Particular attention should be paid to the anesthetic
and perioperative care of children with Crigler-Najjar
Clinical Features
syndrome who are undergoing liver transplantation. Cystic fibrosis is characterized by thick viscous secretions
Prager et al outlined the drugs and metabolic conditions causing obstruction in the pancreas, lungs, liver, intes-
that may acutely elevate unconjugated bilirubin, displace tine, and vas deferens.291 In normal individuals the chlo-
bilirubin from albumin, or precipitate kernicterus. Pho- ride ion transporter gene allows chloride channels in cell
totherapy may be required until the transplanted liver is membranes at the luminal surface to open, thereby facili-
functioning sufficiently to conjugate the increased biliru- tating passive transport of chloride and water. In patients
bin load.275 Subsequently multiple reports have appeared with cystic fibrosis the defective opening of chloride
in the literature with regard to liver transplantation for channels results in diminished chloride and water excre-
Crigler-Najjar syndrome.276 tion.292 Therefore secretions become viscid and eventu-
Auxiliary partial orthotopic liver transplantation, ally obstructive.
although presenting technical challenges, is a procedure In early childhood, chronic pulmonary infections and
ideally suited to patients with Crigler-Najjar syndrome pancreatic insufficiency are the predominant manifesta-
inasmuch as it has been shown in Gunn rats that only tions. Previously cystic fibrosis was usually fatal in child-
about 1% to 2% of the normal hepatocyte mass is needed hood. Now, with improved antimicrobial drugs and
for bilirubin conjugation.23 In auxiliary transplantation it nutritional support, the life expectancy of patients with
was shown that a donor liver mass of 12% to 23% of the cystic fibrosis is commonly extended into the third and
whole organ normalized serum bilirubin levels.277 The even fourth decades of life. Therefore the liver disease
advantage of the procedure is that the native liver remains associated with cystic fibrosis, which typically becomes
in place should the graft fail. The King’s College Hospi- manifested in adolescence, is now more frequently
tal has reported a series of seven children who underwent encountered. Cirrhosis occurs in about 20% of older
this procedure. Median serum bilirubin levels were 50 children, with portal hypertension developing in 2%.293
and 23 μmol/L at 5 and 23 days, respectively, after auxil- The liver disease is often clinically silent, with nearly
iary transplantation. Interestingly, rejection episodes normal bilirubin and transaminase levels, and is
334 PART III Patient Evaluation: Pediatric

diagnosed only with the onset of variceal bleeding. The was attributed to the following possibilities: decreased
characteristic histological appearance of the liver is nod- airway inflammation secondary to immunosuppression,
ular biliary cirrhosis with pathognomonic eosinophilic diminished intra-abdominal pressure after liver trans-
concretions in the small bile ducts.287,294 There is not a plantation, and for some a possible improvement in por-
convincing correlation between the presence of liver dis- topulmonary hypertension.
ease and the progression of lung disease in children with In a European multicenter study, 57 cases of liver
cystic fibrosis.295 transplantation for cystic fibrosis–associated liver disease
More unusual is the development of liver disease in performed at 15 centers between 1990 and 2001 were
infants with cystic fibrosis. In the largest reported experi- reported with a median follow-up time of 3.7 years, with
ence, 12 infants, two thirds of whom were boys, were overall 1-and 5-year patient survival of 90% and 80%,
referred at a median age of 6.5 weeks. Conjugated hyper- respectively.303 Despite the fact that the majority of
bilirubinemia was the initial finding in 11 infants and patients were colonized with Pseudomonas, infectious
hypoalbuminemia in 1 other. Of these patients, all but complications were not higher than expected for other
one resolved the cholestasis without evidence of chronic indications of liver transplantation. A significantly higher
liver disease at a median follow-up of 42 months. The risk for mortality was reported for children with severely
long-term outcome is not yet evident. impaired pulmonary function test results (FEV1 < 40% of
predicted for sex and age).
A recent analysis of the UNOS database of patients
Liver Transplantation with cystic fibrosis who underwent isolated liver trans-
Shunt procedures have been the surgical therapy most plantation revealed 5-year survival rates of 86% in chil-
often used for intractable variceal bleeding, but they are dren (n = 148) and 73% in adults (n = 55).304 Multivariate
associated with life-threatening pulmonary and liver analysis comparing these recipients to patients who
decompensation. Although they may delay the need for underwent transplantation for other causes noted signifi-
liver transplantation, the risk is that pulmonary disease cantly lower 5-year survival rates (P < .0001). However,
will progress and prevent later transplantation.296 The compared to those remaining on the waiting list, pediat-
reluctance to perform liver transplantation in children ric and adult transplant recipients with cystic fibrosis
with cystic fibrosis and established pulmonary disease is gained a significant survival benefit (P < .005.)
well founded and borne out by experience.297 The first Combined liver-lung transplantation (with or without
concern is the potential detrimental effect of immuno- the heart) either simultaneously or sequentially has been
suppression on chronic pulmonary infection and the attempted with mixed results. A 70% actuarial 1-year
additional risk for systemic spread. Second, pancreatic survival rate was reported by one center,291 another cen-
insufficiency may cause impaired absorption of immuno- ter reported one death in seven patients receiving com-
suppressants and ongoing nutritional compromise. bined transplants,305 and in another experience four of
Third, although liver transplantation palliates the liver five patients died within 2 months.300 An analysis of the
complications, it would not be expected to have an impact UNOS database for combined liver-lung transplantation
on other systems involved, particularly lung disease, revealed that 15 patients had 5-year graft and patient sur-
which may eventually be life-threatening. However, in vival of 67% and 80%, respectively.306 Successful liver
selected patients with mild to moderate pulmonary dis- and intestinal transplantation have been performed in
ease, some of these obstacles have been overcome, as children with extensive small bowel necrosis as a result of
demonstrated by the good survival rates and improved meconium ileus and intestinal failure/cystic fibrosis–
quality of life in children with cystic fibrosis who undergo associated liver disease.307 The greatest hope for better
liver transplantation.298,299 Several authors300,301 stress management of this disease lies not in transplantation but
that the best results are obtained in younger children with in the rapidly advancing area of gene therapy. Careful
relatively less severe manifestations of both their liver and patient selection must be ensured when considering liver
lung disease. In one center’s experience of 10 children, or combined liver-lung transplantation as a therapeutic
three of the four deaths were related to pulmonary infec- option for this disease.
tion, and all nonsurvivors were less than the 5th percen-
tile for height and weight at transplantation.301
Colonization with Aspergillus was not associated with HYPEROXALURIA TYPE 1
morbidity or mortality. It should be noted that the recipi-
ent bile duct still produces viscid bile, and cholestasis Primary hyperoxaluria type 1 is an autosomal recessive
from inspissated bile in the recipient duct has been disease of oxalate overproduction that results in diffuse
reported.297 oxalate deposition, particularly prominent in the kidneys,
At the University of Pittsburgh 12 children with cystic bone, and heart.308 Usually kidney failure is the ultimate
fibrosis received isolated liver transplants; 3 of these chil- cause of death. However, kidney transplantation is not
dren died of pulmonary complications, but in 8 of the 9 curative because the most commonly defective enzyme,
survivors, pulmonary function test results either improved alanine-glyoxylate aminotransferase, the gene for which
or remained stable when retested at a mean of 52 months is located on chromosome 2q37.5,309 is specific to the
after liver transplantation302 (mean forced expiratory vol- peroxisomes of hepatocytes.310 Medical therapy includes
ume in the first second of expiration [FEV1] 73% of pre- pyridoxine, high fluid intake in those not yet in renal fail-
dicted before liver transplantation versus 83% of ure, and crystallization inhibitors. Despite these treat-
predicted after liver transplantation). This phenomenon ments, end-stage renal failure occurs in 50% of children
 27 Transplantation for Metabolic Disease in Children 335

by 15 years of age, and the overall mortality has been esti- ranged from 27 to 98 mL/min/1.73 m2.322 No further
mated at 30%.311 deterioration in renal function was seen in 3 to 5 years
of follow-up. One justification for liver-alone trans-
plantation is to prevent further systemic accumulation
Liver and Kidney Transplantation of oxalate in a patient for whom renal transplantation
Early in the consideration of transplant options for is planned in the future, but organ availability is a
patients with primary hyperoxaluria, a considerable expe- problem.323 However, using two different donors
rience was reported for kidney transplantation alone. In negates the reported protective immunological effect
some series, early renal allograft survival was superior to that the liver graft appears to confer on a renal graft
that in combined liver-kidney transplantation, but as from the same donor.324,325
would be expected from current knowledge of the After successful liver-kidney transplantation, the usual
enzyme defect site, kidney transplantation alone has strategy to ensure ongoing depletion of the accumulated
repeatedly been proved to not prevent recurrent renal oxalate load is to induce high daily urine output with fluid
failure.311,312 From registry data at 8 years after kidney- loading. In young children, fluid loading via a gastros-
only transplantation, the kidney death–censored graft tomy tube is required. Peritransplant hemodialysis may
survival rate was 76% in patients receiving a liver-kidney also be used. Hyperoxaluria may continue for months
transplant versus 48% for a kidney-alone transplant.313 after transplantation, and very large amounts of urinary
Kidney-alone transplantation can be considered only for oxalate can be measured (up to 10,500 μmol/24 hr in one
pyridoxine-responsive type 1 disease or the less severe case). This increased urinary oxalate load is due to mobi-
type 2 disease. In type 2 hyperoxaluria, the deficiency in lization and excretion of the large body stores of oxalate
glyoxylate reductase is not confined to the liver, and it is and not to decreased activity of alanine-glyoxylate ami-
still uncertain whether liver replacement will correct the notransferase in the liver graft.312,326 As the total-body
metabolic defect.312 oxalate load decreases, gradual radiological and histologi-
Combined liver-kidney transplantation is the treat- cal improvement in serum oxalate osteoarthropathy is
ment of choice in hyperoxaluria when kidney failure has seen (Fig. 27-7).319,327 Serial bone mineral density studies
occurred or is imminent. This strategy was first are useful to track the improvement in oxalate-associated
attempted by Watts et al in 1987.314 Although the
patient ultimately died of infectious complications,
serum oxalate levels fell soon after transplantation.
After this report the successful outcome of combined
liver-kidney transplantation, including that for the
severe infantile form of hyperoxaluria,315 has effected a
cure for this disease.315-319 A key principle is aggressive
medical management before and after transplantation
to decrease systemic oxalate concentrations. In a large
single-center experience of 36 children with primary
hyperoxaluria type 1, combined liver-kidney transplan-
tation was performed in nine and preemptive liver-alone
transplantation in three. Renal function improved to a
mean GFR of 86 mL/min/1.73 m2, but all three chil-
dren with a liver-only transplant had oxalate deposits a
remaining in the kidney. This center’s experience also
emphasized the significant mortality associated with
this disease without transplantation. Of 23 nontrans-
planted children, nine died of systemic complications of
oxalosis, and 14 are alive, including two who at the time c
of publication were listed for transplantation.320
The debate continues regarding whether preemp- d
tive liver transplantation alone is justified before renal
impairment becomes important. The clinical course of
primary hyperoxaluria may be highly variable, with
some children presenting in renal failure in infancy, b
whereas in its mildest forms, renal stones in adults may
be the only manifestation. Even siblings with the same
genotype may have widely varying clinical progression.
FIGURE 27-7 n Primary hyperoxaluria. A radiograph of the lower
In addition, projecting the rate of disease progression extremity shows resolving bone disease after intensive dialysis
in some patients is speculative at best. Clearly the risks followed by combined liver-kidney transplantation. Note the
of liver transplantation and long-term immunosup- periosteal thickening with new bone (a), bone-within-a-bone
pression must be weighed carefully in a child with appearance (b), and the previous hyperdense metaphysis (c)
with new hypodense regions of bone growth (d). There is also
near-normal renal function whose evolution of disease an old fracture site at the metaphysis (arrowhead). (From McDi-
may be quite slow.321 In a series of four children under- armid SV. The liver and metabolic disease of childhood. Liver Transpl
going preemptive liver transplantation, the GFR Surg. 1998;4:S34-S50.)
336 PART III Patient Evaluation: Pediatric

bone disease after transplantation.328 Also reported is OTHER METABOLIC DISEASES FOR
reversal of oxalate-associated cardiomyopathy.329 WHICH LIVER TRANSPLANTATION
In the severe infantile form of the disease, the extra- HAS BEEN PERFORMED
renal systemic complications of oxalate deposition may
be particularly devastating. Deposition of oxalate in the Neonatal Iron Storage Disease
bones results in multiple fractures, severe deformity,
and debilitating chronic pain. Oxalate in the myocar- In neonatal iron storage disease (neonatal hemochro-
dium and pericardium can cause life-threatening heart matosis [NH]),335,336 severe liver insufficiency may be
failure. Compounded with the need for dialysis—not evident at birth or in the first weeks of life, thus suggest-
only for renal failure but also to continue to decrease ing that the process begins in utero.337,338 In a recent
the total-body oxalate load—these infants are often report from the Pediatric Acute Liver Failure Study
chronically ill and malnourished and have increased Group, NH accounted for 13.6% of acute liver failure
susceptibility to infection. The challenge of achieving in infants.339 Neonates at risk are often severely affected
early combined liver-kidney transplantation is to find with hydrops, coagulopathy, hypoalbuminemia, and
appropriately sized organs for these often very small kidney and liver failure. Progressive and severe cho-
children. A kidney combined with a partial-liver graft lestasis is usual with only a slight elevation in transami-
from a larger child or teenager offers one of the best nase levels. The histological findings in the liver are
scenarios for success. Living donor transplantation— nonspecific and consist of diffuse fibrosis, loss of normal
using one donor—has been reported330 but carries with architecture, bile duct proliferation, and sometimes
it increased risk for the donor and possible compromise giant cell transformation. Death usually occurs within
in oxalate metabolism if the donor is a heterozygote the first weeks or months of life.
(parent or sibling) for the disease. Success in four of six Although both sporadic and inherited cases have been
young children after combined liver-kidney, liver first described, the risk for NH recurrence in a gestation sub-
followed by kidney, or isolated liver transplantation has sequent to one ending in an affected baby is as high as
been reported.331 90%.340,341 The underlying pathophysiology in NH
Recommendations for liver or kidney transplantation appears to be as described by Whitington and Kelly341: an
or a combination have emerged from the European expe- immune-mediated disease caused by maternal alloim-
rience. Watts et al332 suggest that (1) when the GFR is mune antibodies directed against a fetal antigen.
less than 25 mL/min/1.73 m2, combined liver-kidney A hallmark of NH is that it presents with increased
transplantation is the treatment of choice; (2) isolated iron stores in other organs.337 The diagnosis of NH is
liver transplantation should be considered if the GFR is made by excluding other causes of fulminant cholestatic
between 25 and 60 mL/min/1.73 m2 and the disease is liver failure in infants and by demonstrating elevated fer-
following an aggressive course; (3) avoidance of pro- ritin levels, increased transferrin saturation, and increased
longed dialysis is important to prevent the necessity of iron content, not only in the liver but in extrahepatic
excreting a large systemic oxalate load after transplanta- organs as well. In contrast to hereditary hemochromato-
tion, which might impair kidney graft function333; and (4) sis (a disease of adults characterized by a specific genetic
if liver transplantation is to be considered, the diagnosis defect), the iron accumulation is predominantly within
must be confirmed by measuring alanine-glyoxylate ami- hepatocytes rather than reticuloendothelial cells. Mag-
notransferase activity in a liver biopsy specimen before netic resonance imaging with T2-weighted scans may be
transplantation. helpful to demonstrate the increased iron content in
Analysis of the SPLIT database revealed that among extrahepatic organs such as the pancreas, along with
children with primary hyperoxaluria, 8 received iso- characteristic sparing of the spleen.342 Biopsy of the lip
lated liver transplantation and 11 received liver-kidney mucosa can also be used to confirm the diagnosis.
transplantation. The mean calculated GFR of the iso- Medical management with antioxidant and chelating
lated liver transplantation recipients before liver trans- agent “cocktails” has had variable success, with reports of
plantation was 36.6 mL/min/1.73 m2. Four of these amelioration of disease in some patients.343 However, in a
patients were on dialysis at listing, and 3 remained on later experience of eight treated children, seven failed and
dialysis within 30 days of liver transplantation. The last died before liver transplantation could be attempted.
available calculated GFRs in the liver-only group were Only one child stabilized sufficiently with therapy to
lower than in the liver-kidney group: 65 mL/min/1.73 m2 allow later successful transplantation.344 Similar poor
versus 93 mL/min/1.73 m2 with a mean follow-up of outcomes with the chelation-antioxidant cocktail have
22.6 months and 29.4 months, respectively. Patient been described by the King’s College group.340
survival after liver with or without kidney transplant The treatment of NH as an alloimmune disease seems
was significantly inferior relative to that of all other to hold the promise. Fifteen women who had previous
patients transplanted in the SPLIT database, despite children with NH were treated with intravenous immu-
lower Pediatric End-Stage Liver Disease (PELD) noglobulin (IVIg) during subsequent pregnancies.
scores and similar time waiting. The requirement for Although this did not necessarily prevent the recurrence
pretransplant dialysis in most patients and early post- of NH, it appeared to reduce its severity and permitted
transplant dialysis in a third of patients may be a con- survival without liver transplantation.345 Along these
tributing factor. Careful selection of patients for same lines, immunotherapy, including exchange transfu-
liver-only transplantation is needed because post–liver sion and high-dose IVIg, when applied in a timely fashion
transplantation renal function appears inferior.334 to infants diagnosed with NH appears to yield long-term
 27 Transplantation for Metabolic Disease in Children 337

transplant-free survival in 75% of patients, representing a muscle. Clinical involvement of the bone marrow, kid-
significant improvement over historical controls (17% ney, and colon has also been described.
transplant-free survival, P < .01).346 Signs and symptoms that suggest mitochondrial disor-
Several authors have now described successful out- ders include (1) association of neuromuscular symptoms
comes in infants who underwent liver replacement for with liver dysfunction, (2) multisystem involvement in
neonatal iron storage disease.8,347 Early diagnosis is patients with acute or chronic liver disease, (3) rapidly
essential to optimizing the chance of response to medical progressive liver disease, and (4) presence of lactic acido-
therapy or to offer early transplantation before multisys- sis, hepatic steatosis, or ketonemia.357 A thorough pre-
tem failure develops. Long-term patient survival of 50% transplant evaluation of potentially affected organ systems
has been cited following liver transplantation for infants is mandatory to exclude mitochondrial hepatopathies in
with NH.340,348 patients with neonatal acute liver failure. Unfortunately,
few of the expanding list of diseases caused by mitochon-
drial defects will be amenable to a functional “cure” by
Defects of Mitochondrial Function liver transplantation.
In recent years there have been major advances in defin- The role of liver transplantation must be carefully
ing the key role that mitochondrial disorders play in the considered in children with suspected mitochondrial dis-
cause of pediatric liver disease of unknown cause. One of ease. Such evaluation is made even more difficult if the
the first recognizable clinical entities was Reye’s syn- child presents in coma with evidence of fulminant liver
drome, which is characterized by previously well children failure without discernible cause. A good example is pro-
presenting with hypoglycemia, vomiting, and lethargy vided by the very similar features of Reye’s syndrome, an
progressing to coma, hyperammonemia, and liver fail- acquired mitochondrial disorder (associated with vari-
ure.350 Liver biopsy specimens showed microvesicular fat cella infection and salicylic acid ingestion), and the pri-
and structurally abnormal mitochondria. Soon after mary mitochondrial disorders of fatty acid oxidation (the
Reye’s syndrome was described, several inherited diseases medium- and long-chain acyl-CoA dehydrogenase defi-
with similarities to Reye’s syndrome were reported in ciencies). In both conditions the onset of coma is early,
which mitochondrial beta oxidation appeared to be the with severe hypoglycemia, hyperammonemia, and coagu-
defect.351-353 These diseases were the medium- and long- lopathy. On liver biopsy the inflammation and necrosis
chain acyl coenzyme A (CoA) dehydrogenase deficien- are unimpressive, but diffuse microvesicular fat is charac-
cies. Frequently unmasked by fasting or infectious disease, teristic. Cerebral edema is frequently severe and is most
these rare syndromes may be misdiagnosed as sudden often the cause of death.360 Liver transplantation is con-
infant death syndrome or Reye’s syndrome. Infants may traindicated because the mitochondrial dysfunction is dif-
be comatose and in apparent noncholestatic liver fail- fuse, particularly that involving the CNS. With aggressive
ure.354,355 Once the condition is diagnosed, these children medical therapy many of these children—especially those
can often be successfully managed by frequent high-­ with fatty acid oxidative defects—will survive without sig-
carbohydrate feedings and carnitine supplementation. nificant neurological impairment, although repeat epi-
Mitochondrial function is essential to several meta- sodes may occur with future catabolic stress.
bolic pathways, including those requiring the key enzyme In contrast, specific mitochondrial respiratory chain
ATP synthase, which carries out oxidative phosphoryla- disorders (i.e., oxidative phosphorylation defects) have
tion and ATP synthesis. The mitochondrial matrix con- been successfully treated by liver transplantation, although
tains the enzymes of the tricarboxylic acid cycle, urea selection of candidates remains problematic.361 In a sin-
cycle, and fatty acid beta oxidation pathways. The inner gle-center study of five children with fulminant liver fail-
mitochondrial membrane contains the electron transport ure, a retrospective study of the explanted liver showed
chain, which is essential for mitochondrial respiration defects in the mitochondrial respiratory chain complexes
and provision of energy for adenosine phosphate synthe- I, III, and IV.362 However, the clinical outcome after liver
sis. This diversity in mitochondrial function accounts for transplantation was variable, with two of the five children
the many different metabolic diseases now attributed to showing ongoing neurological impairment after trans-
mitochondrial disorders. The growing list can be divided plantation that was fatal in one child. In a multicenter
into those in which the mitochondrial defect is the pri- experience of 11 children with mitochondrial respiratory
mary cause of the liver disorder and those in which there chain disorders, six died after liver transplantation, three
is an acquired mitochondrial injury mediated by toxins of whom suffered further neurological injury after trans-
(e.g., cyanide), drugs (e.g., salicylic acid, valproic acid), plantation.363 The key message from these experiences is
or heavy metals (copper and iron overload). A complete that extrahepatic disease present before transplantation
list and discussion of the clinical manifestations and the portends a poor outcome and should exclude children
site of the defect can be found in comprehensive reviews from consideration for liver transplantation—a point
by Sokol.356,357 illustrated by the successful transplantation of a child with
It is now recognized that disorders of mitochondrial mitochondrial respiratory chain deficiency whose only
function may have a wide spectrum of manifestations— manifestation of disease was end-stage liver disease.364
including both acute and chronic liver disease358—and One of the problems in establishing the liver trans-
should also be considered in the differential diagnosis of plantation candidacy of a child in rapidly progressive
neonates with acute liver failure.359 However, mitochon- acute liver failure is the difficulty in quickly establishing
drial disorders generally involve many other organs, par- the diagnosis of a mitochondrial disorder. Readily avail-
ticularly the nervous system and cardiac and skeletal able laboratory test results that are suggestive, but not
338 PART III Patient Evaluation: Pediatric

diagnostic, are a persistent serum lactate level higher than transplant community to address many important ethical
2.5 nM, an increased lactate-pyruvate ratio in plasma and questions, including the prioritization of patients on the
cerebrospinal fluid (>20:1 mol/mol), a β-hydroxide butyr- transplant waiting list, the use of living related donation,
ate to acetoacetate ratio greater than 2:1 mol/mol, and and the optimal time of transplantation.
diffuse microsteatosis on liver biopsy.358 Children with The future holds the promise that for at least some of
chronic liver disease may have a history of vomiting, these conditions, hepatocyte or stem cell transplantation
hypotonia, developmental delay, and hypoglycemia. or gene therapy will make liver transplantation obsolete.
Liver histological features are more variable and includes
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ment of portal hypertension in cystic fibrosis. J Pediatr Surg. 320. Shapiro R, Weismann I, Mandel H, et al. Primary hyperoxaluria
1977;12:201-206. type 1: Improved outcome with timely liver transplantation:
294. Psarcharopoulos HT, Portman B, Howard ER, et al. Hepatic a single-center report of 36 children. Transplantation. 2001;72:
complications of cystic fibrosis. Lancet. 1982;2:78-80. 428-432.
295. Corbert K, Kelleher S, Rowland M, et al. Cystic fibrosis associated 321. Leumann E, Hoppe B. Pre-emptive liver transplantation in pri-
liver disease: a population-based study. J Pediatr. 2004;145:327-332. mary hyperoxaluria type I: a controversial issue. Pediatr Trans-
296. Shapira R, Hadzic N, Francavilla R, et al. Retrospective review of plant. 2000;4:161-164.
cystic fibrosis presenting as infantile liver disease. Arch Dis Child. 322. Nolkemper D, Kemper MJ, Burdelski M, et al. Long-term results
1999;81:125-128. of pre-emptive liver transplantation in primary hyperoxaluria type I.
297. Cox KL, Ward RE, Furgiuele TL, et al. Orthotopic liver trans- Pediatr Transplant. 2000;4:177-181.
plantation in patients with cystic fibrosis. Pediatrics. 1987;80: 323. Bastani B, Mistry BM, Nahass GT, et al. Oxalate kinetics and
571-574. reversal of the complications after orthotopic liver transplantation
298. Revell SP, Robertson NRC, Noble-Jamieson G, Barnes ND. Liver in a patient with primary hyperoxalosis type I awaiting renal
transplantation in cystic fibrosis. J R Soc Med. 1993;86:111-112. transplantation. Am J Nephrol. 1999;19:64-69.
299. Mieles L, Orenstein D, Teperman L, et al. Liver transplantation 324. Creput C, Durrbach A, Samuel D, et al. Incidence of renal and
in cystic fibrosis. Lancet. 1989;1:1073. liver rejection and patient survival rate following combined liver
300. Milkiewicz P, Skiba G, Kelly D, et al. Transplantation for cystic and kidney transplantation. Am J Transplant. 2003;3:348-356.
fibrosis: Outcome following early liver transplantation. J Gastro- 325. Morrissey PE, Gordon F, Shaffer D, et al. Combined liver-kidney
enterol Hepatol. 2002;17:208-213. transplantation in patients with cirrhosis and renal failure: effect
301. Molmenti EP, Squires RH, Nagata D, et al. Liver transplantation of a positive cross-match and benefits of combined transplanta-
for cholestasis associated with cystic fibrosis in the pediatric popu- tion. Liver Transpl Surg. 1998;4:363-369.
lation. Pediatr Transplant. 2003;7:93-97. 326. Ruder H, Otto G, Schutgens RBH, et al. Excessive urinary oxa-
302. Fridell JA, Bond GJ, Mazariegos GV, et al. Liver transplantation late excretion after combined renal and hepatic transplantation
in children with cystic fibrosis: A long term longitudinal review of for correction of hyperoxaluria type 1. Eur J Pediatr. 1990;150:
a single centers experience. J Pediatr Surg. 2003;38:1152-1156. 56-58.
 27 Transplantation for Metabolic Disease in Children 345

327. Toussaint C, De Pauw L, Vienne A, et al. Radiological and histo- 350. Treem WR, Witzleben CA, Piccoli DA, et al. Medium-chain and
logical improvement of oxalate osteopathy after combined liver- long-chain acyl CoA dehydrogenase deficiency: clinical, patho-
kidney transplantation in primary hyperoxaluria type 1. Am J logic and ultrastructural differentiation from Reye’s syndrome.
Kidney Dis. 1993;21:54-63. Hepatology. 1986;6:1270-1278.
328. Behnke B, Kemper MJ, Kruse HP, Muller-Wiefel DE. Bone min- 351. Taubman B, Hale DE, Kelley RI. Familial Reye-like syndrome:
eral density in children with primary hyperoxaluria type I. Nephrol a presentation of medium-chain acyl coenzyme A dehydrogenase
Dial Transplant. 2001;16:2236-2239. deficiency. Pediatrics. 1987;79:382-385.
329. Detry O, Honore P, DeRoover A, et al. Reversal of oxalosis car- 352. Duran M, Mitchell G, de Klerk JBC, et al. Octanoic acidemia and
diomyopathy after combined liver and kidney transplantation. octanoylcarnitine excretion with dicarboxylic aciduria due to
Transpl Int. 2002;15:50-52. defective oxidation of medium-chain fatty acids. J Pediatr. 1985;
330. Astarcioglu I, Karademir S, Gulay H, et al. Primary hyperoxal- 107:397-404.
uria: Simultaneous combined liver and kidney transplantation 353. Duran M, Hofkamp M, Rhead WJ, et al. Sudden child death and
from living related donor. Liver Transpl. 2003;9:433-436. “healthy” affected family members with medium-chain acyl-
331. Ellis SR, Hulton SA, McKiernan PJ, et al. Combined liver-kidney coenzyme A dehydrogenase deficiency. Pediatrics. 1986;78:
transplantation for primary hyperoxaluria type I in young chil- 1052-1057.
dren. Nephrol Dial Transplant. 2001;16:348-354. 354. Roe CR, Millington DS, Maltby DA, Kinnebrew P. Recognition
332. Watts RWE, Danpure CJ, De Pauw L, et al. Combined liver- of medium-chain acyl-CoA dehydrogenase deficiency in asymp-
kidney and isolated liver transplantations for primary hyperoxal- tomatic siblings of children dying of sudden infant death or Reye-
uria type 1: The European experience. Nephrol Dial Transplant. like syndromes. J Pediatr. 1986;108:13-18.
1991;6:502-511. 355. Greene CL, Blitzer MG, Shapira E. Inborn errors of metabolism
333. Toussaint C, Vienne A, De Pauw L, et al. Combined liver-kidney and Reye syndrome: differential diagnosis. J Pediatr. 1988;113:
transplantation in primary hyperoxaluria type I. Bone histopathol- 156-159.
ogy and oxalate body content. Transplantation. 1995;59:1700-1704. 356. Sokol RJ, Treem WR. Mitochondria and childhood liver disease.
334. McDiarmid S, Anand R, Song C, for the SPLIT Research Group. J Pediatr Gastroenterol Nutr. 1999;28:4-16.
Inferior survival after liver + kidney transplantation for children with 357. Lee WS, Sokol RJ. Liver disease in mitochondrial disorders.
primary hyperoxaluria. Oral presentation at the 2008 Joint Con- Semin Liver Dis. 2007;27(3):259-273.
gress of ILTS, ELITA and LICAGE, Paris. 358. Munnich A, Rotig A, Chretien D, et al. Clinical presentation of
335. Goldfischer S, Grotsky HW, Chang CH, et al. Idiopathic neona- mitochondrial disorders in childhood. J Inherit Metab Dis.
tal iron storage involving the liver, pancreas, heart, and endocrine 1996;19:521-527.
and exocrine glands. Hepatology. 1982;1:58-64. 359. Cormier V, Rustin P, Bonnefont JP, et al. Hepatic failure in disor-
336. Murray KF, Kowdley KV. Neonatal hemochromatosis. Pediatrics. ders of oxidative phosphorylation with neonatal onset. J Pediatr.
2001;108:960-964. 1991;119:951-954.
337. Piccoli DA, Witzleben CA, Watkins JB. Neonatal iron storage dis- 360. Heubi JE, Partin JC, Partin JS, Schubert WK. Reye’s syndrome:
ease. In: Walker WA, Durie PR, Hamilton JR, et al, eds. Pediatric current concepts. Hepatology. 1987;7:155-164.
Gastrointestinal Disease. Philadelphia: BC Decker; 1991:1063-1065. 361. Goncalves I, Hermans D, Chretien D, et al. Mitochondrial respi-
338. Egawa H, Berquist W, Garcia-Kennedy R, et al. Rapid develop- ratory chain defect: a new etiology for neonatal cholestasis and
ment of hepatocellular siderosis after liver transplantation for early liver insufficiency. J Hepatol. 1995;23:290-294.
neonatal hemochromatosis. Transplantation. 1996;62:1511-1513. 362. Dubern B, Broue P, Dubuisson C, et al. Orthotopic liver trans-
339. Sundaram SS, Alonso EM, Narkewicz MR, et al. Characterization plantation for mitochondrial respiratory chain disorders: a study
and outcomes of young infants with acute liver failure. J Pediatr. of 5 children. Transplantation. 2001;71:633-637.
2011;159(5):813-818. 363. Sokal EM, Sokol R, Cormier V, et al. Liver transplantation in
340. Rodrigues F, Kallas M, Nash R, et al. Neonatal hemochromatosis mitochondrial respiratory chain disorders. Eur J Pediatr.
— medical treatment vs. transplantation: the King’s experience. 1999;158:S81-S84.
Liver Transpl. 2005;11(11):1417-1424. 364. Rake JP, van Spronsen FJ, Visser G, et al. End-stage liver disease
341. Whitington PF, Kelly S. Outcome of pregnancies at risk for neo- as the only consequence of a mitochondrial respiratory chain defi-
natal hemochromatosis is improved by treatment with high-dose ciency: no contra-indication for liver transplantation. Eur J Pedi-
intravenous immunoglobulin. Pediatrics. 2008;121:e1615-e1621. atr. 2000;159:523-526.
342. Hayes AM, Jaramillo D, Levy HL, Knisely AS. Neonatal hemo- 365. McKusick VA, Neufeld EF. The mucopolysaccharide storage dis-
chromatosis: diagnosis with MR imaging. AJR Am J Roentgenol. eases. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, et al,
1992;159:623-625. eds. The Metabolic Basis of Inherited Diseases. New York: McGraw-
343. Shamieh I, Kibort PK, Suchy FJ, Freese DK. Antioxidant therapy Hill; 1983:751-777.
for neonatal iron storage disease [abstract]. Pediatr Res. 1993;33:109A. 366. Parfrey MA, Hutchins GM. Hepatic fibrosis in the mucopolysac-
344. Sigurdsson L, Reyes J, Kocoshis SA, et al. Neonatal hemochro- charidoses. Am J Med. 1986;81:825-829.
matosis: outcomes of pharmacologic and surgical therapies. 367. Navarro C, Dominguez C, Costa M, Ortega JJ. Bone marrow
J Pediatr Gastroenterol Nutr. 1998;26:85-89. transplant in a case of mucopolysaccharidosis I Scheie phenotype:
345. Whitington PF, Hibbard JU. High-dose immunoglobulin during Skin ultrastructure before and after transplantation. Acta Neuro-
pregnancy for recurrent neonatal haemochromatosis. Lancet. pathol. 1991;82:33-38.
2004;364:1690-1698. 368. Krivit W, Pierpont ME, Ayaz K, et al. Bone marrow transplanta-
346. Rand E, Karpen S, Kelly S, et al. Treatment of neonatal hemo- tion in Maroteaux-Lamy disease (mucopolysaccharidosis VI):
chromatosis with exchange transfusion and intravenous immuno- Correction of the enzymatic defect. N Engl J Med. 1984;31:
globulin. J Pediatr. 2009;155:566-571. 1606-1611.
347. Muiesan P, Rela M, Kane P, et al. Liver transplantation for neo- 369. Whitley CB, Ramsay NKC, Kersey JH, Krivit W. Bone marrow
natal haemochromatosis. Arch Dis Child Fetal Neonatal Ed. transplantation for Hurler syndrome: assessment of metabolic
1995;73:F178-F180. correction. Birth Defects. 1986;22:7-24.
348. Vohra P, Haller C, Magid M, et al. Neonatal hemochromatosis: 370. McGovern MM, Ludman MD, Short MP, et al. Bone marrow
the importance of early recognition of liver failure. J Pediatr. transplantation in Maroteaux-Lamy syndrome (MPS type 6):
2000;136:537-541. ­status 40 months after BMT. Birth Defects. 1986;22:41-53.
349. Reference deleted during page proof review.
 CHAPTER 28

Transplantation for Hepatic

Malignancy in Children
Jaimie D. Nathan • Frederick C. Ryckman • Maria H. Alonso • Greg Tiao

CHAPTER OUTLINE

TRANSPLANTATION FOR PRIMARY Metabolic Disease

HEPATOCELLULAR NEOPLASMS Hereditary Tyrosinemia
Hepatoblastoma Glycogen Storage Disease
Etiology α1-Antitrypsin Deficiency
Diagnosis TRANSPLANTATION FOR PRIMARY VASCULAR
Staging LESIONS
Treatment Strategy Benign Vascular Lesions
Outcome Arteriovenous Malformations and Infantile
Hepatocellular Carcinoma Hemangiomas
Etiology Malignant Vascular Lesions
Diagnosis Hepatic Epithelioid Hemangioendothelioma
Treatment Angiosarcoma
Outcome
SUMMARY
Hepatic Malignancy Related To Preexisting

Liver transplantation has become an important compo- TRANSPLANTATION FOR PRIMARY

nent of treatment algorithms in children diagnosed with
primary hepatic malignancy. Interestingly, liver trans-
HEPATOCELLULAR NEOPLASMS
plantation for malignancy in the pediatric population has
historic significance. A 3-year old child with biliary atre-
Hepatoblastoma
sia and an incidentally discovered hepatocellular carci- Hepatoblastoma is the most common primary malig-
noma (HCC) underwent transplantation on January 2, nancy found in the liver in childhood with an annual inci-
1970, and that individual is the oldest surviving liver dence of one per million children. The median age at
transplant recipient.1 diagnosis is 1 year, and it is found more frequently in
Hepatoblastoma and HCC are the two most common males. A child who has a hepatoblastoma can present in a
primary hepatic malignancies found in children. Liver variety of fashions ranging from an asymptomatic abdom-
transplantation of a child afflicted with a hepatoblastoma inal mass found by a primary caregiver to an acute abdo-
unresectable by conventional approach results in an men secondary to tumor rupture. On occasion the size of
excellent outcome with multiple institutional and coop- the tumor will be so large as to cause respiratory distress
erative studies reporting survival rates greater than or failure to thrive because of loss of abdominal domain.
80%.2-7 The role of liver transplantation for HCC in the Rarely, a hepatoblastoma may produce β-human chori-
pediatric population remains more controversial. onic gonadotropin (β-HCG) hormone, resulting in the
In this chapter we will discuss the management of chil- paraneoplastic process of precocious puberty.8
dren with primary hepatic malignancy, focusing on recent
developments in the use of liver transplantation. In addi-
Etiology
tion, we will discuss the role of transplantation for vascu-
lar neoplasms of the liver and the evolving role of Hepatoblastomas arise from immature hepatic epithe-
transplantation in patients with preexisting metabolic lium and are classified histologically into epithelial, ana-
disease who are at risk for the development of HCC. plastic, or macrotrabecular cell types. The epithelial cell

346
 28 Transplantation for Hepatic Malignancy in Children 347

type can be further divided into fetal, embryonal, and vein, the presence of extrahepatic spread, and the pres-
small cell undifferentiated variants.9 Children with a hep- ence of metastatic disease are documented. The PRE-
atoblastoma consisting of the fetal cell type have the best TEXT staging system has been shown to be a predictor
prognosis.10 Children with tumors that contain compo- of outcome in multiple clinical trials.16
nents of small cell undifferentiated histological character- In the recent Children’s Oncology Group (COG)-
istics have the worst prognosis.11,12 sponsored trial AHEP 0731, a combination of both PRE-
The cause of a hepatoblastoma remains unknown. As TEXT and the Evans classification, the traditional North
with many malignancies, abnormalities in gene expres- American staging system (Table 28-1), was used to strat-
sion are thought to play a role; however, the specific ify patients. It is anticipated that this combination will be
mechanism by which the tumor develops remains unclear. used in future trial design.
Patients who are afflicted with the genetic conditions of
Beckwith-Wiedemann syndrome, its variant hemihyper- Treatment Strategy
trophy, and familial adenomatous polyposis are found to
have an increased incidence of hepatoblastoma and need Complete surgical resection of the primary liver lesion
close surveillance in childhood.13 Recent studies have remains the most crucial intervention required to achieve
suggested the β-catenin pathway may be aberrantly acti- long-term survival. In children who present with tumor
vated, whereas other studies using genomic sequencing confined to a single lobe of the liver without vascular
have identified profiles that may portend a worse progno- involvement, standard lobectomy followed by adjuvant
sis.14 These studies require validation. chemotherapy is indicated. Historically over 60% of chil-
dren presented with lesions unresectable by conventional
surgery, and the outcome was poor due to residual disease
Diagnosis
after attempted resection. In 1982 Evans et al17 reported
Blood tests obtained from a child with a hepatoblastoma a significant improvement in the outcome of children
will often show anemia, thrombocytosis, and leukocyto- treated with a combination of adjuvant chemotherapy
sis. Hepatocellular transaminase levels are usually within followed by surgical resection. This finding dramatically
normal limits. Serum levels of α-fetoprotein (AFP) are altered the strategy for treatment of children with hepa-
elevated in over 90% of patients with a hepatoblastoma. toblastoma. Over 75% of lesions initially felt to be unre-
On occasion an elevated β-HCG level will be found. sectable will decrease sufficiently in size with neoadjuvant
Radiographic analysis is essential in the diagnosis and chemotherapy to allow conventional resection. The com-
treatment of a child in whom a hepatoblastoma is sus- bination of adjuvant chemotherapy followed by conven-
pected. Cross-sectional imaging of the abdomen using tional resection has improved the prognosis of children
either computed tomography (CT) or magnetic reso- with hepatoblastoma such that 70% to 80% will achieve
nance imaging (MRI) will identify the site from which a long-term survival.18-20 Recent trials have further defined
mass arises and will assist in the determination of the the role of chemotherapy in management, identifying
resectability of the lesion. The proximity of the tumor other active agents, including doxorubicin and irinote-
and the presence of thrombus within the portal vein and can.21,22 These agents have improved treatment algo-
major hepatic veins or inferior vena cava can be deter- rithms with the goal of allowing more conventional
mined by the same imaging modalities or by ultrasonog- resection.
raphy. A CT scan of the chest should be used to rule out In spite of these improvements, some patients after
metastatic lung disease. adjuvant chemotherapy will have tumor that remains
Tissue diagnosis by definitive resection or biopsy unresectable by conventional resection. It is these patients
obtained via a percutaneous, open, or laparoscopic who benefit from total hepatectomy and orthotopic liver
approach is necessary to establish the diagnosis. transplantation. Although initial studies on the outcome
of orthotopic liver transplantation for hepatoblastoma
reported mixed results, multiple studies have documented
Staging
the efficacy of this form of treatment (Table 28-2). Trans-
Over the past 15 years the staging systems for patients plantation can also be used for salvage after attempted
afflicted with hepatoblastoma have evolved significantly. conventional resection in which residual disease remains,
The Pretreatment extent of disease (PRETEXT) staging although some studies suggest that these patients have
system has been accepted by multiple oncology collabor- worse outcome.
ative study groups as the optimal method to classify On occasion the tumor size at the time of presentation
patients. In this system, tumors at the time of diagnosis is so large that it may compromise the respiratory status
are staged by radiographic analysis according to the num- of the patient. The time required for adjuvant chemo-
ber of sectors of the liver in which tumor is present.15,16 therapy to induce tumor shrinkage may leave the patient
The liver is divided into a right anterior, right posterior, ventilator dependent for a prolonged period of time. In
left medial, and left lateral sector. Patients are classified in these patients, early transplantation may be indicated.
four stages: PRETEXT I, tumor in only one sector; The current COG treatment algorithm in the man-
PRETEXT II, tumor involving two adjoining sectors; agement of a child who presents with a hepatoblastoma
PRETEXT III, tumor involving three contiguous sectors uses a combination of conventional resection, chemo-
or in two nonadjoining sectors; PRETEXT IV, tumor in therapy, and transplantation (AHEP 0731; Fig. 28-2).
all four sectors (Fig. 28-1). In addition to the intrahepatic The treatment algorithm is tailored to the individual
extent of disease, the involvement of a hepatic or portal child. In those children who present with unresectable
348 PART III Patient Evaluation: Pediatric

R L

II

III

IV

Invasion (III) Displacement (II)

FIGURE 28-1 n SIOPEL (International Childhood Liver Tumours Strategy Group) pretreatment extent of disease (PRETEXT).

transplantation be warranted, the number of chemother-

TABLE 28-1 T
 raditional North American apy cycles administered while awaiting transplantation is
Staging System (Evans) According limited. If the lesion remains too large to resect after four
to the Extent of Residual Disease cycles of chemotherapy, the patient is listed for trans-
After Surgery at Time of Diagnosis plantation. Chemotherapy is continued while the patient
I Complete resection
is waiting for transplantation. In some of our patients we
II Microscopic residual tumor
have used living related transplantation so as not to pro-
III Gross residual tumor
long the use of chemotherapy while waiting for an appro-
Biopsy without resection priate organ. Ideally, two rounds of chemotherapy are
IV Metastatic disease at diagnosis administered after transplantation.
One area of controversy in the management of hepa-
toblastoma is the role of aggressive conventional resec-
tion (i.e., trisegmentectomy or central liver resection) in
lesions at the time of diagnosis, adjuvant cisplatin-based those children who have bulky tumors despite adjuvant
chemotherapy is administered, and after every two cycles chemotherapy. Surgical radicality as defined by triseg-
of chemotherapy, the patient is restaged radiographically. mentectomy was shown to be a negative predictor of out-
If the lesion has decreased in size to allow for conven- come in the German Cooperative Pediatric Liver Tumor
tional resection, surgery is performed. At least two cycles Study HB 94.28 In contrast, a recent study suggests
of chemotherapy are administered after resection. aggressive conventional resection did not negatively
In children diagnosed with a PRETEXT III or IV affect outcome.29 Even in the patients who had positive
tumor, early referral to an experienced center with liver microscopic margins after resection, none developed
transplantation capacity is recommended so that should local tumor recurrence.19
 28 Transplantation for Hepatic Malignancy in Children 349

TABLE 28-2 Liver Transplantation for Hepatoblastoma

Preoperative Overall
Author No. of Patients Chemotherapy Prior Resection (%) Recurrence (%) Mortality (%) Survival (%)
Penn23 18 No NA 50 NA 50
Koneru et al24 12 No 33 25 25 50
Al-Qabandi 8 Yes 25 25 12 63
et al25
Reyes et al2 12 Yes 8 17 0 83
Srinivasan 13 Yes 8 8 7 93
et al4
Molmenti 9 Yes 33 13 33 63
et al26
Pimpalwar 12 Yes 0 17 8 83
et al3
Tiao et al27 8 Yes 38 0 12 88

NA, Not available.

Patients with extensive hepatic disease not amenable however, are similar to those following conventional
to conventional resection after chemotherapy who also resection. A recent study by Pimpalwar et al3 addressed
had metastatic lung lesions at diagnosis may still be con- this observation. They found that tumor susceptibility to
sidered for transplantation. Although the overall progno- chemotherapy, as manifest by decreasing AFP levels or
sis is worse for this group of patients, there is a subset that reduction in tumor size indicated by cross-sectional imag-
responds well to adjuvant chemotherapy and if complete ing, better predicted outcome than the manner by which
clearance of their lung disease can be achieved, may do the tumor was completely removed. In patients who had a
well following transplant. Thoracoscopic or open resec- poor response to adjuvant chemotherapy, the outcome
tion may be necessary to remove all metastatic lesions. In was worse, regardless of whether the patient underwent
the SIOPEL (International Childhood Liver Tumours conventional resection or transplantation, when compared
Strategy Group) 1 study performed in Europe, there with those who had a good response to chemotherapy
were three patients who presented with metastatic lung before surgery. The number of patients within this study
disease and large lesions that responded well to chemo- was small, and a larger study will be necessary to confirm
therapy and subsequently underwent transplantation who these findings.
were disease free 3 years after transplant.8,30 In our own Close follow-up is essential for all children who have
experience, we performed transplantation in several chil- undergone treatment for a hepatoblastoma. Serial mea-
dren who had lung lesions at the time of diagnosis, all of suring of AFP levels and radiographic evaluation during
whom have done well since transplant. The length of the first 3 years after treatment are important so that
time a patient needs to be free of metastatic disease before early detection of recurrent disease is possible.
transplantation remains uncertain.

Outcome
Hepatocellular Carcinoma
Etiology
Initial reports of liver transplantation for hepatoblastoma
found a 50% survival rate with half of the poor outcomes HCC is seen less frequently in the pediatric population
due to tumor recurrence.23,24 Most patients did not than hepatoblastoma. Affected children present in two
receive adjuvant chemotherapy. More recent studies, in different fashions. Preexisting liver disease such as biliary
which patients received chemotherapy both before and atresia, tyrosinemia, Fanconi anemia, glycogen storage
following transplantation have reported improved out- disorders, progressive familial intrahepatic cholestasis
come after liver transplantation such that the 5-year sur- syndromes and viral hepatitis, all of which cause chronic
vival after transplant ranges from 63% to 93%.2-5,7,27 underlying hepatocellular damage, predisposes a child at
Variables previously thought to be predictors of poor any age to the development of HCC (see later). HCC in
outcome, such as vascular invasion or metastatic disease this population mirrors the disease process that occurs in
at the time of presentation, have not been shown to affect adults.
outcome after transplantation. Transplant-related com- Cases of pediatric HCC that arise de novo occur in
plications were the cause of mortality in less than 10% of older children.31 These children do not have underlying
the patients since 1999. These studies demonstrate the liver disease that predisposes them to hepatocellular car-
efficacy of transplantation in patients who had what was cinogenesis, and their disease process appears biologically
considered unresectable hepatoblastoma. different from HCC that arises in the context of cirrhosis.
Tumor recurrence remains a significant problem fol- The biological differences between de novo HCC and
lowing transplantation, with recurrence rates of up to cirrhosis-related HCC include responsiveness to chemo-
25% in recent series. The outcome is usually poor if recur- therapy and better survival rates after resection. When
rence occurs. Recurrence rates following transplantation, compared to HCC in adults who experience no response
350 PART III Patient Evaluation: Pediatric

Biopsy/resection*

Newly diagnosed
hepatoblastoma

Enrolled on AHEP 0731

Risk stratification

Very low risk Low risk Intermediate risk High risk

Tumor resected Tumor resected Tumor not resected Tumor not resected
at diagnosis at diagnosis at diagnosis at diagnosis

No further Treatment Treatment Treatment

treatment Regimen T Regimen F Regimen W

C5V C5VD 2 cycles of “upfront”

2 adjuvant cycles 4-6 cycles VI window therapy
Surgical resection
after 2 cycles with 2 Responders will then
postoperative cycles receive 6 cycles of
OR C5VD with 1 cycle of
Resection/transplant VI in between each
after 4 cycles with 2 2-cycle block
postoperative cycles Nonresponders will
then receive 6 cycles
Very low risk: Stage I PFH hepatoblastoma of C5VD
Low risk: Stage I non-PFH, non-SCU or stage II non-SCU hepatoblastoma Tumor resection or
Intermediate risk: Stage I SCU, stage II SCU, or stage III hepatoblastoma liver transplant should
High risk: Any stage IV or any stage + initial AFP < 100 ng/mL hepatoblastoma occur after fourth cycle
of C5VD with 2 cycles
C5V: Cisplatin, fluorouracil, vincristine
of C5VD given
VI window: Vincristine, irinotecan
after operation/
C5VD: Cisplatin, fluorouracil, vincristine, doxorubicin (with dexrazoxane)
transplant
*Biopsy or complete tumor resection if deemed feasible at diagnosis
FIGURE 28-2 n Algorithm for the management of a child with hepatoblastoma. AFP, α-Fetoprotein; PFH, pure fetal histological type;
SCU, small cell undifferentiated type.

to chemotherapy, children afflicted with HCC experi- vascular nuclei. The fibrous stroma is characteristically
ence a reported response rate to neoadjuvant chemother- arranged in a lamellar pattern between groups of tumor
apy of 50%.31 Survival rates in children who undergo cells with a surrounding pseudocapsule. It has an indolent
resection are greater than 50%, much higher than the growth pattern, which affords the patient a better chance
rates experienced by adults.31,32 On a molecular level, at primary resection and hence an improved prognosis.
pediatric HCC differs from adult tumors by a lower level
of cyclin D1 and a higher loss of heterozygosity of chro- Diagnosis
mosome 13q.33
Although the biological behavior of HCC that arises The laboratory findings in a child with HCC typically
in children appears different than that encountered in show anemia and a mild elevation in hepatocellular trans-
adults, the histological appearance is similar to that found aminase levels. In 50% of the children, serum levels of
in adults, consisting of the “classic” and fibrolamellar AFP are elevated but not to the same degree as those
subtypes. The fibrolamellar variant is seen most often in found in a child with a hepatoblastoma.
adolescents and young adults. Its distinct histological Cross-sectional imaging of the abdomen using either
appearance consists of polygonal cells with large oval CT or MRI will identify the site from which a mass arises
 28 Transplantation for Hepatic Malignancy in Children 351

TABLE 28-3 Liver Transplantation for Hepatocellular Carcinoma in Children

Preoperative Preexisting Liver Transplant Overall 5-Year
Author No. of Patients Chemotherapy Disease (%) Recurrence (%) Mortality (%) Survival (%)
Tagge et al34 9 Selected NA 45 11 44
Superina and 3 Yes 66 0 0 100
Bilik35
Achilleos et al36 2 Yes 100 50 50 0
Reyes et al2 19 Selected 79 32 10 68

NA, Not available.

and will assist in the determination of the resectability of reported in adults.2 Tumor recurrence with a resulting
the lesion. The patency of the portal vein and hepatic poor outcome was the most common cause of
artery and the proximity of the tumor to major hepatic mortality.
veins can also be determined. Metastatic disease is seen Careful screening must be employed when consider-
more frequently in patients with HCC; therefore a CT ing a child with HCC for liver transplantation. Extensive
scan of the chest is essential. radiographic imaging, including bone scan, should be
Tissue diagnosis by definitive resection or biopsy used to rule out the presence of extrahepatic spread. If
allows differentiation between HCC and hepatoblas- vascular invasion is suspected, arteriography may be nec-
toma, which is essential because the treatment strategies essary to better define vessel integrity. Diagnostic lapa-
are markedly different. The TNM staging system used in roscopy should be considered if hilar lymphadenopathy is
adult HCC population is also applied to children. present to rule out lymphatic spread. A “back-up” recipi-
ent should be identified at the time of transplant so that if
extrahepatic spread is encountered during exploration, an
Treatment
alternate recipient is available.
There are fewer treatment alternatives for a child with
HCC than one who has hepatoblastoma. Adjuvant che- Hepatic Malignancy Related To
motherapy may be helpful in a subset of patients and typi-
cally consists of cisplatin and doxorubicin.
Preexisting Metabolic Disease
Chemoembolization may be used to try to reduce tumor Metabolic liver diseases represent approximately 10% of
size so that definitive resection can be attempted. Com- pediatric liver transplants and are characterized by a
plete surgical resection offers the only opportunity for a defect in an enzyme or transporter that results in an alter-
good outcome; however, recurrence and extrahepatic ation in a metabolic pathway. Such inborn errors of
spread are common even when total resection has been metabolism lead to the accumulation of a “toxic metabo-
achieved. In contrast to children who have a hepatoblas- lite” in the liver and to the development of chronic liver
toma, the prognosis of a child who has HCC is poor, with injury. HCC is the most commonly diagnosed hepatic
5-year survival reaching only 20% to 30%. neoplasm in children with metabolic liver diseases; how-
Total hepatectomy and orthotopic liver transplanta- ever, the presence of cirrhosis is not a prerequisite for the
tion has been used in the treatment of children and ado- development of HCC in metabolic disorders. Although
lescents with HCC. Because of the relative infrequency they are rare diseases, hereditary tyrosinemia, glycogen
of HCC in children, the experience of transplantation storage disease, and α1-antitrypsin (A1AT) deficiency are
in the pediatric population for HCC is limited (Table associated with a high risk for HCC. The use of liver
28-3).2,34-36 transplantation in these diseases provides the option of
planned replacement of the affected liver before the
development of malignancy, or certainly early in the
Outcome
course.
The outcome of liver transplantation for HCC in the
pediatric population has been dependent on the mode Hereditary Tyrosinemia
of presentation. Children with incidental HCC identi-
fied at the time of transplant for other liver disease have Hereditary tyrosinemia is an autosomal recessive disor-
an outcome consistent with their primary disease. der of amino acid metabolism caused by a deficiency of
Recurrence is uncommon. In those patients with preex- fumarylacetoacetate hydrolase, resulting in the accumu-
isting liver disease leading to HCC or in those who lation of abnormal metabolites of tyrosine that are toxic
present with large lesions not amenable to conventional to both the liver and the kidneys.37-39 The consequence
resection, prognosis is dependent on the features of the is variable hepatocellular and renal dysfunction. Two
HCC. In a study from Pittsburgh of children with HCC differing presentations of the disease occur, both of
who have undergone transplantation, variables that pre- which can be seen within a single kindred. Acute tyro-
dicted outcome after liver transplantation, including sinemia presents in infancy, typically at less than 6
extrahepatic spread, vascular invasion, and a tumor size months of age, with fulminant hepatorenal failure asso-
greater than 4 cm, mirrored those predictive variables ciated with fatty degeneration of the liver and hepatic
352 PART III Patient Evaluation: Pediatric

fibrosis. These infants present with rapidly progressive Although liver transplantation has been used as a treat-
hepatosplenomegaly, coagulopathy, ascites, jaundice, ment modality for children with known HCC, its more
failure to thrive, and encephalopathy. The chronic form appropriate role is preventive; transplantation should be
of the disease is more indolent and allows survival into performed before malignancy develops. In the pre-
childhood with slowly progressive cirrhosis. Renal NTBC era several studies detailed the natural history of
involvement is the major manifestation of the chronic tyrosinemia in an effort to identify an appropriate age for
form of tyrosinemia. preemptive transplantation.44 NTBC treatment has sig-
Dietary restriction of phenylalanine and tyrosine is nificantly diminished the need for liver transplantation
partially effective in the chronic form of the disease but for tyrosinemia. However, some children may present at
does not impact the course of infants presenting with such a late stage that treatment will be ineffective. Still
acute liver failure or reduce the risk for HCC. The use of others may develop HCC in spite of NTBC therapy.
2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexane- Therefore children receiving NTBC should be followed
dione (NTBC) inhibits the enzyme 4-hydroxyphenylpy- carefully for the development of progressive liver disease,
ruvate dioxygenase and prevents the formation of the because the potential for carcinogenesis is not completely
toxic metabolites maleylacetoacetate and fumarylacetoac- abolished. Routine screening for HCC in children with
etate.40 Recent studies report that approximately 90% of tyrosinemia involves interval abdominal ultrasonography
patients presenting with acute liver failure experience a and magnetic resonance imaging. A rise in AFP level or a
good clinical response to NTBC with improvement in slower-than-expected decline or lack of return to normal
liver function, whereas liver transplantation is indicated AFP level (after the grossly elevated AFP level that is
in those who do not respond to NTBC.41 Patients with typical at the time of diagnosis of tyrosinemia) should
the chronic form of tyrosinemia inevitably develop nodu- trigger a more extensive evaluation for malignancy.41
lar cirrhosis, but NTBC has shown promise in slowing Liver transplantation should be considered when malig-
the progression of the chronic liver disease. The role of nancy cannot be completely excluded.45
NTBC in improving liver function and portal hyperten-
sion and in inducing regression of nodules in children
Glycogen Storage Disease
with chronic liver disease remains to be completely
defined.42 Glycogen storage disease type I (GSD-I) is an autosomal
The most important complication of tyrosinemia is recessive disorder caused by mutations in the glucose-
the development of HCC, which becomes more likely 6-phosphatase complex, leading to the accumulation of
with increasing age and liver injury. Before the use of glycogen in the liver, kidneys, and intestine. Patients
NTBC the reported incidence of HCC ranged from 18% typically present within the first 6 months of life with
to 37% in those beyond 2 years of age.43 More recent hepatomegaly, hypoglycemia, and failure to thrive.
data from the international NTBC study suggest that the Hepatic adenomas develop in 16% to 75% of patients
incidence of HCC is reduced with early initiation of with GSD-I, and their prevalence increases with age and
NTBC therapy.41 Malignant degeneration is thought to with poor glycemic control.48-50 Most patients with
be related to an inhibition of S-adenosylmethionine by GSD-I develop adenomas by the second or third decade
accumulated fumarylacetoacetate, presumably resulting of life, and these adenomas are typically small, multiple,
in decreased methyl groups available for methylation of and nonencapsulated. The pathogenesis of adenoma for-
DNA and RNA, leading to mutagenesis and abnormal mation has not been elucidated, although it is clear that
protein synthesis.37 In addition, decreased activity of these lesions have the potential to transform into carci-
mixed-function oxidases has also been noted and may noma. In several reports, serial liver biopsies have docu-
contribute to difficulties with the metabolism and excre- mented the development of HCC within previously
tion of hepatotoxins.44 This presumed biochemical benign adenomas.48,51-54 In a review by Coire et al,48 the
mechanism would make all children with tyrosinemia malignant transformation to HCC occurred in 11% of
potentially susceptible to HCC formation secondary to reported cases. Metabolic control has not been demon-
these metabolic abnormalities. However, NTBC treat- strated to decrease the risk for malignancy in patients
ment reduces hepatic injury and seems to decrease the with GSD-I. In a recent study, Kishnani et al55 suggested
risk for development of HCC.45 In addition, it is likely that genetic aberrations involving chromosome 6 may
that the earlier that NTBC treatment is begun, the lower play a role in the malignant transformation of adenomas
the risk for HCC, presumably because the cumulative to HCC in GSD-I. Liver transplantation is appropriate
exposure of the liver to the mutagenic effects of fumaryl- when adenomas are progressively increasing in size
acetoacetate is reduced.41 Although HCC has been despite dietary management and malignant change can-
reported in at least one infant started on NTBC at 5 not be excluded or when patients have failed vigorous
months of age and treated for 1 year before transplanta- medical therapy.48,56-58 In addition to eliminating the
tion, the data do show a diminished need for liver trans- possibility of HCC development and progression, trans-
plantation for liver disease and for HCC in patients plantation offers the advantage of correction of the meta-
started on therapy at less than 2 years of age.46 In patients bolic abnormalities characteristic of GSD-I. Investigation
who are started on NTBC after 2 years of age, the inci- continues regarding approaches to gene therapy for
dence of HCC remains high, and liver transplantation for GSD-I, which may one day offer an alternative to liver
proven or suspected HCC has been reported in 25% of transplantation.59
such patients.47 In addition, the risk for HCC in patients Glycogen storage disease type III (GSD-III) is an
on long-term NTBC therapy requires further study. autosomal recessive disorder caused by a deficiency of
 28 Transplantation for Hepatic Malignancy in Children 353

glycogen debranching enzyme activity, leading to the The risk for HCC in patients with A1AT deficiency
accumulation of glycogen in the liver and muscle. increases with age and most commonly occurs in older
Accounting for 85% of cases, GSD-IIIa is the more com- men; however, HCC can develop in children and has
mon subtype, in which patients have both liver and mus- been reported in a 12-year-old girl with end-stage liver
cle involvement. In GSD-IIIb, patients have isolated disease secondary to PiZZ disease.70 Although liver carci-
liver involvement, because enzyme activity is lacking nogenesis in A1AT deficiency remains poorly under-
only in the liver.60 Adenomas have been reported to stood, it is believed that at least one Z allele is required
occur in 5% to 25% of patients with GSD-III.61,62 Sev- for the development of HCC.71 Recently, using a trans-
eral reports have documented HCC in both types of genic PiZ mouse, Marcus et al72 reported that the accu-
GSD-III in adult patients who developed cirrhosis and mulation of Z-protein resulted in altered expression of
had either an explant or autopsy-proven malignancy.62-64 several genes that are implicated in cell proliferation and
Although the mechanism of tumorigenesis in GSD-III tumorigenesis. Liver transplantation is indicated in A1AT
remains unknown, it appears to involve the development deficiency patients who develop complications of cirrho-
of HCC in a background of cirrhosis, which is distinct sis or early-stage HCC. Graft and patient survival rates
from the adenoma-carcinoma sequence proposed for for liver transplantation for A1AT deficiency are similar
HCC in GSD-I. to outcomes following liver transplantation for other
indications.73 Importantly, serum levels of A1AT nor-
malize in liver transplant recipients, and there is evidence
α1-Antitrypsin Deficiency
that the progression of pulmonary disease is slowed and
A1AT deficiency is an autosomal codominant disease may be prevented following transplantation.74
caused by mutations in a serine protease inhibitor whose
physiological function is the inhibition of neutrophil elas-
tase and other serine proteases released by neutrophils. TRANSPLANTATION FOR PRIMARY
As a result of misfolding of an otherwise functional VASCULAR LESIONS
mutant protein, the protein is retained in the endoplas-
mic reticulum of hepatocytes, causing toxicity, liver The spectrum of hepatic vascular lesions that are seen in
injury, and progressive fibrosis. In addition, in severe dis- children includes benign vascular malformations that pos-
ease the absence of adequate protease inhibitor in the sys- sess no malignant potential but can present with life-
temic circulation allows neutrophil elastase to degrade threatening progressive congestive heart failure or
lung parenchyma, resulting in emphysema during adult- coagulopathy, benign infantile hepatic hemangioma
hood that may ultimately require lung transplantation. (IHH), epithelioid hemangioendothelioma, which is a
A1AT deficiency is the most common inherited meta- lesion of intermediate invasive potential, and rare aggres-
bolic cause for liver transplantation in the pediatric sive malignant lesions such as angiosarcoma. The primary
population.65 therapy for each lesion is dictated by a proper initial histo-
Protease inhibitor Z (PiZ) and protease inhibitor S logical diagnosis, which is often difficult due to the large
(PiS) are the most common alleles associated with clinical size, variable radiological imaging, and complex histologi-
disease, and protease inhibitor M (PiM) is the common cal nature of hepatic vascular lesions. With the use of imag-
nonmutated allele. As both parental A1AT alleles are ing studies and immunophenotyping, the classification of
expressed, the presence of a normal allele (PiM) can pro- hepatic vascular lesions in children has continued to
tect against the effect of the mutated allele. The most undergo critical reassessment over the past decade, and
severe disease develops when the patient expresses two current consensus is that two major groups, malformations
mutated alleles, and liver disease primarily develops with and neoplasms, embrace most, if not all, lesions.75-78
homozygous PiZZ A1AT deficiency.66 However, only
approximately 8% to 15% of PiZZ infants develop severe
liver disease, suggesting that other genetic or environ- Benign Vascular Lesions
mental modifiers play a role in the development of liver
Arteriovenous Malformations and Infantile
injury.67,68 Although the genetic and environmental fac-
Hemangiomas
tors that predispose to the development and the progres-
sion of liver disease require further elucidation, there is Broad characterization of benign vascular lesions of the
evidence that genetic differences in protein degradation liver in infants and children includes congenital hepatic
pathways may be important.67 The initial clinical presen- arteriovenous malformations (AVMs) and IHHs. Liver
tation of liver disease in A1AT deficiency is highly vari- transplantation for either type of benign vascular lesion
able and includes cholestatic jaundice and hepatitis during in pediatric patients is undertaken only when extensive
the neonatal period, hepatomegaly and increased amino- multicentric or diffuse involvement precludes partial
transferase levels during childhood, and rarely, cirrhosis hepatectomy and complications endanger the life of
or acute liver failure. The measurement of serum levels of the child.
A1AT and genotype analysis are both used in the diagno- Congenital hepatic AVMs are rare vascular anoma-
sis of the disease. lies that often present with high-output congestive heart
A1AT deficiency is associated with an increased risk failure during infancy. Additional presenting features
for HCC, and an early Swedish study reported an odds include hepatomegaly, thrombocytopenia, anemia,
ratio of 5.0 for the development of HCC in patients with consumptive coagulopathy, portal hypertension, and
­
A1AT deficiency, compared to the general population.69 persistent pulmonary hypertension of the newborn.79
354 PART III Patient Evaluation: Pediatric

The association of consumptive coagulopathy and their endothelium does not stain positive for GLUT-1
thrombocytopenia with a large vascular lesion is known (a marker of infantile hemangiomas), focal hepatic hem-
as Kasabach-Merritt syndrome, and such clinical presenta- angiomas likely represent the liver equivalent of the cuta-
tions portend very high morbidity and mortality rates. neous rapidly involuting congenital hemangioma,
Initial medical management in infants with large hepatic presenting fully grown at birth and rapidly spontaneously
AVMs includes diuretics and inotropic support for heart regressing by approximately 1 year of age.76,81,82 Focal
failure symptoms. Hepatic AVMs may be successfully hemangiomas may be large enough to cause arteriovenous
managed by transcatheter coil embolization, with shunting, and some may be associated with thrombocyto-
improvement in cardiac function.80 However, more penia. In such patients, as well as in those with progressive
commonly, attempts at embolization are overcome by symptoms, corticosteroid therapy is initiated, and emboli-
the recruitment of preexisting collateral circulation with zation or surgical resection may be necessary.77
recurrence of symptoms. In addition, hepatic necrosis Multifocal IHHs are GLUT-1–positive lesions and may
following embolization can lead to poorly controlled be simple and uncomplicated, remaining asymptomatic.
and tolerated metabolic acidosis, further complicating Asymptomatic patients require observation with interval
subsequent surgical intervention. These procedures are imaging to ensure regression. However, some patients with
occasionally beneficial in decreasing hyperperfusion multifocal IHHs progress to congestive heart failure, con-
before planned surgical resection. Individual experience sumptive coagulopathy, and hypothyroidism. Medical
with this lesion validates transplantation in these infants therapy with corticosteroids is initiated in symptomatic
as the treatment of choice when the clinical manifesta- patients, with response expected to begin within 1 week.83-
tions of arteriovenous shunting are life threatening and 85 In patients who are refractory to steroid therapy, pro-

a conventional surgical resection is not feasible. Recur- pranolol, interferon-α, vincristine or cyclophosphamide
rence or metastasis is not expected with this nonneo- may be used.86-89 If medical therapy fails or in patients ini-
plastic lesion. Histological confirmation is critical so tially presenting with large shunts and heart failure, hepatic
that a vascular neoplasm, possibly of an aggressive type, artery embolization or ligation may be considered. Impor-
can be excluded. tantly, embolization and hepatic artery ligation may not
IHH is a benign endothelial cell neoplasm that is most result in lasting improvement in coagulopathy and throm-
commonly recognized within the first 6 to 12 months of bocytopenia.90 Conventional resection, if feasible, or liver
life, usually caused by hepatomegaly. Cutaneous heman- transplantation must be considered in patients who remain
giomas of similar histological characteristics may be asso- symptomatic after attempts at medical or interventional
ciated in 20 to 40% of patients. Additional clinical management.
presentations of IHHs include congestive heart failure Infants with diffuse IHHs (Fig. 28-3) have near-total
related to arteriovenous shunting, Kasabach-Merritt syn- replacement of their liver parenchyma with hemangiomas
drome, abdominal compartment syndrome, hypothy- and are at greatest risk for life-threatening complications
roidism due to overproduction of type III iodothyronine of heart failure, respiratory failure, Kasabach-Merritt syn-
deiodinase, and failure to thrive.78 IHHs typically drome, abdominal compartment syndrome, acute renal
undergo rapid proliferation and growth postnatally, fol- failure, and acute liver failure. A multidisciplinary approach
lowed by slow regression and involution during child- to the management of patients with diffuse IHHs is criti-
hood. It is likely that most IHHs remain undetected cally important due to the very high risk for morbidity and
because most patients do not become symptomatic, and mortality. Medical management includes optimization of
many other IHHs are identified incidentally on imaging cardiac function, thyroid hormone monitoring and
performed for other indications. However, those who replacement, and combination pharmacotherapy, includ-
present with congestive heart failure, coagulopathy, or ing steroids and propranolol, interferon-α, vincristine, or
abdominal compartment syndrome are at very high risk cyclophosphamide. Multimodal therapy consisting of
for morbidity and mortality. pharmacological and interventional approaches has been
Historically in the literature IHHs have been misclas- reported to be successful in a few patients with diffuse
sified as arteriovenous malformations and hepatic epi- IHHs.91 Nevertheless, early referral for transplant evalua-
thelioid hemangioendotheliomas (HEHs), both of which tion is advised for this patient subgroup, because response
are distinct entities, and IHHs have also previously been to pharmacological therapy is generally poor and emboli-
referred to as hemangioendothelioma, further confusing zation is typically ineffective.76
the nomenclature. With the development of the Infan-
tile Hepatic Hemangioma Registry, our understanding
of IHHs regarding their radiographic features, patho- Malignant Vascular Lesions
logical characteristics, and biological behavior has
Hepatic Epithelioid Hemangioendothelioma
improved substantially.76 Collection of prospective data
via the registry will continue to allow for further refine- HEH is a rare low- to intermediate-grade malignancy of
ment of management strategies. IHHs are currently vascular endothelial origin, which is frequently multicen-
classified into three subtypes: focal, multifocal, and dif- tric in origin, precluding partial hepatectomy. It most
fuse. Importantly, the biological behavior and response commonly occurs in young noncirrhotic adults with
to medical management of an IHH correlate with its female predominance, and its clinical course character-
subtype classification. ized by slow growth and late metastatic potential has
Focal hepatic hemangiomas are discrete, well-defined, made these patients candidates for total hepatectomy and
solitary lesions that usually remain asymptomatic. Because liver transplantation.92-96
 28 Transplantation for Hepatic Malignancy in Children 355

with a natural disease span of 5 to 10 years and a reported

mortality rate of approximately 65%.100 Consistently
effective chemotherapy options do not currently exist for
HEH, and either conventional resection, if feasible, or
liver transplantation offers the only potential manage-
ment strategy. Because most patients have multifocal or
diffuse disease at diagnosis, surgical resection is often not
possible. Because HEH is typically a very slow-growing
tumor, liver transplantation has been proposed for defini-
tive management in patients who are not amenable to
conventional resection.101,102
Very few pediatric cases of HEH have been reported in
the literature, so management of children with this tumor
has been extrapolated from the adult experience. In a report
of 59 HEH patients from the European Liver Transplant
Registry, overall 10-year patient survival and disease-free
survival following transplantation were 72% and 64%,
A respectively.103 The presence of microvascular or combined
macro-microvascular invasion significantly negatively
affected survival, whereas preexisting extrahepatic disease
and lymph node involvement did not affect survival rates. It
has been suggested that liver transplantation be offered
early in the course of the disease and that aggressive treat-
ment of recurrence in the allograft can result in good long-
term survival. In a United Network for Organ Sharing
database review of pediatric liver transplant recipients, 35
patients less than 18 years old underwent transplantation
for HEH between 1987 and 2007.104 The reported 5-year
patient and allograft survival were 61% and 50%, respec-
tively, and in cause-of-death analysis, HEH patients were
least likely to die secondary to recurrence, compared to
patients transplanted for hepatoblastoma and HCC.
Liver transplantation remains the best option for man-
agement of pediatric HEH patients who have unresect-
able disease. Although there has been limited success in
the use of chemotherapeutic modalities for HEH,99 the
B development of effective chemotherapeutic agents, anti-
FIGURE 28-3 n Infant with diffuse infantile hepatic hemangiomas. angiogenic drugs, and rapamycin-based immunosuppres-
A, Axial postcontrast MRI demonstrating peripheral enhancement sion for HEH may result in further improvement in
of lesions on initial arterial phase image. B, Portal venous phase posttransplant outcomes for children with this tumor.
postcontrast MRI demonstrating near-complete filling in of lesions Furthermore, the worldwide registry for liver transplan-
with residual small patchy areas of low signal.
tation in childhood liver tumors (Pediatric Liver Unre-
sectable Tumor Observatory [PLUTO]) will allow the
The clinical presentation is usually that of upper collection of prospective data and the establishment of
abdominal pain, weight loss, and jaundice, although standardized management guidelines.
Budd-Chiari syndrome, portal hypertension, and acute
liver failure have been reported. Imaging characteristics of
Angiosarcoma
HEH most commonly demonstrate a diffuse tumor with
multiple peripheral hepatic lesions. The accurate defini- Angiosarcoma is a rapidly progressive, often multifocal,
tion and diagnosis of this tumor have been facilitated by but rare highly malignant lesion seen in the liver in chil-
the presence of several immunohistochemical markers, dren. Lung metastases are often evident at the time of
including staining for factor VIII–related antigen in the diagnosis, and some hepatic angiosarcoma cases are
tumor, and defined histological criteria.97 The accurate believed to represent malignant transformation of a pre-
immunohistochemical identification of HEH has shown existing IHH.105 In all, fewer than 45 cases of pediatric
that the conventional histopathological variables to grade hepatic angiosarcoma have been reported, with 3 cases in
malignancies, such as necrosis, cytological pleomorphism, the literature having undergone liver transplanta-
and mitotic figures, are not reliable in this tumor.93,98 tion.106-108 In 2 cases, the pretransplant diagnosis was
The clinical course of HEH is unpredictable and “benign hemangioendothelioma,” emphasizing the diffi-
highly variable, although it has been reported to behave culty in identifying the highly malignant component
more aggressively in children, with very rapid growth and within a large hepatic lesion. One patient died of post-
a more malignant behavior.99 Metastasis most often transplantation cytomegalovirus infection 4 months fol-
occurs to the lungs, peritoneum, lymph nodes, and bone, lowing transplantation without residual or metastatic
356 PART III Patient Evaluation: Pediatric

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27. Tiao GM, Bobey N, Allen S, et al. The current management of 52. Limmer J, Fleig WE, Leupold D, et al. Hepatocellular carcinoma
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29. Lautz TB, Ben-Ami T, Tantemsapya N, et al. Successful nontrans- 55. Kishnani PS, Chuang TP, Bali D, et al. Chromosomal and genetic
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30. Perilongo G, Brown J, Shafford E, et al. Hepatoblastoma present- 4781-4790.
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31. Czauderna P, Mackinlay G, Perilongo G, et al. Hepatocellular car- 57. Malatack JJ, Finegold DN, Iwatsuki S, et al. Liver transplantation for
cinoma in children: results of the first prospective study of the type I glycogen storage disease. Lancet. 1983;1(8333):1073-1075.
International Society of Pediatric Oncology group. J Clin Oncol. 58. Reddy SK, Austin SL, Spencer-Manzon M, et al. Liver transplan-
2002;20(12):2798-2804. tation for glycogen storage disease type Ia. J Hepatol. 2009;51(3):
32. Lang H, Sotiropoulos GC, Brokalaki EI, et al. Survival and recur- 483-490.
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33. Kim WR, Krowka MJ, Plevak DJ, et al. Accuracy of Doppler echo- 60. Matern D, Starzl TE, Arnaout W, et al. Liver transplantation for
cardiography in the assessment of pulmonary hypertension in glycogen storage disease types I, III, and IV. Eur J Pediatr.
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34. Tagge EP, Tagge DU, Reyes J, et al. Resection, including 61. Labrune P, Trioche P, Duvaltier I, et al. Hepatocellular adenomas
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noma: impact on survival. J Pediatr Surg. 1992;27(3):292-296. and review of the literature. J Pediatr Gastroenterol Nutr.
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35. Superina R, Bilik R. Results of liver transplantation in children 62. Demo E, Frush D, Gottfried M, et al. Glycogen storage disease
with unresectable liver tumors. J Pediatr Surg. 1996;31(6): type III-hepatocellular carcinoma a long-term complication?
835-839. J Hepatol. 2007;46(3):492-498.
36. Achilleos OA, Buist LJ, Kelly DA, et al. Unresectable hepatic 63. Siciliano M, De Candia E, Ballarin S, et al. Hepatocellular carci-
tumors in childhood and the role of liver transplantation. J Pediatr noma complicating liver cirrhosis in type IIIa glycogen storage
Surg. 1996;31(11):1563-1567. disease. J Clin Gastroenterol. 2000;31(1):80-82.
37. Mieles LA, Esquivel CO, Van Thiel DH, et al. Liver transplanta- 64. Haagsma EB, Smit GP, Niezen-Koning KE, et al. Type IIIb gly-
tion for tyrosinemia. A review of 10 cases from the University of cogen storage disease associated with end-stage cirrhosis and hepa-
Pittsburgh. Dig Dis Sci. 1990;35(1):153-157. tocellular carcinoma. The Liver Transplant Group. Hepatology.
38. Weinberg AG, Mize CE, Worthen HG. The occurrence of hepa- 1997;25(3):537-540.
toma in the chronic form of hereditary tyrosinemia. J Pediatr. 65. Roy A, Finegold MJ. Hepatic neoplasia and metabolic diseases in
1976;88(3):434-438. children. Clin Liver Dis. 2010;14(4):731-746.
39. Scott CR. The genetic tyrosinemias. Am J Med Genet C Semin 66. Fairbanks KD, Tavill AS. Liver disease in alpha 1-antitrypsin
Med Genet. 2006;142C(2):121-126. deficiency: a review. Am J Gastroenterol. 2008;103(8):2136-2141.
40. Lindstedt S, Holme E, Lock EA, et al. Treatment of hereditary quiz 2142.
tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate 67. Wu Y, Whitman I, Molmenti E, et al. A lag in intracellular degra-
dioxygenase. Lancet. 1992;340(8823):813-817. dation of mutant alpha 1-antitrypsin correlates with the liver dis-
41. Santra S, Baumann U. Experience of nitisinone for the pharmaco- ease phenotype in homozygous PiZZ alpha 1-antitrypsin
logical treatment of hereditary tyrosinaemia type 1. Expert Opin deficiency. Proc Natl Acad Sci U S A. 1994;91(19):9014-9018.
Pharmacother. 2008;9(7):1229-1236. 68. Piitulainen E, Carlson J, Ohlsson K, et al. Alpha1-antitrypsin defi-
42. Crone J, Moslinger D, Bodamer OA, et al. Reversibility of cir- ciency in 26-year-old subjects: lung, liver, and protease/protease
rhotic regenerative liver nodules upon NTBC treatment in a child inhibitor studies. Chest. 2005;128(4):2076-2081.
with tyrosinaemia type I. Acta Paediatr. 2003;92(5):625-628. 69. Elzouki AN, Eriksson S. Risk of hepatobiliary disease in adults
43. Russo PA, Mitchell GA, Tanguay RM. Tyrosinemia: a review. with severe alpha 1-antitrypsin deficiency (PiZZ): is chronic viral
Pediatr Dev Pathol. 2001;4(3):212-221. hepatitis B or C an additional risk factor for cirrhosis and hepato-
44. Freese DK, Tuchman M, Schwarzenberg SJ, et al. Early liver cellular carcinoma? Eur J Gastroenterol Hepatol. 1996;8(10):
transplantation is indicated for tyrosinemia type I. J Pediatr Gas- 989-994.
troenterol Nutr. 1991;13(1):10-15. 70. Hadzic N, Quaglia A, Mieli-Vergani G. Hepatocellular carci-
45. Shneider BL. Pediatric liver transplantation in metabolic disease: noma in a 12-year-old child with PiZZ alpha1-antitrypsin defi-
clinical decision making. Pediatr Transplant. 2002;6(1):25-29. ciency. Hepatology. 2006;43(1):194.
46. Mohan N, McKiernan P, Preece MA, et al. Indications and out- 71. Nelson DR, Teckman J, Di Bisceglie AM, et al. Diagnosis and
come of liver transplantation in tyrosinaemia type 1. Eur J Pediatr. management of patients with alpha1-antitrypsin (A1AT) defi-
1999;158(Suppl 2):S49-S54. ciency. Clin Gastroenterol Hepatol. 2012;10(6):575-580.
358 PART III Patient Evaluation: Pediatric

72. Marcus NY, Brunt EM, Blomenkamp K, et al. Characteristics of 91. Draper H, Diamond IR, Temple M, et al. Multimodal manage-
hepatocellular carcinoma in a murine model of alpha-1-antitryp- ment of endangering hepatic hemangioma: impact on transplant
sin deficiency. Hepatol Res. 2010;40(6):641-653. avoidance: a descriptive case series. J Pediatr Surg. 2008;43(1):120-
73. Kemmer N, Kaiser T, Zacharias V, et al. Alpha-1-antitrypsin defi- 125. discussion 126.
ciency: outcomes after liver transplantation. Transplant Proc. 92. Scoazec JY, Lamy P, Degott C, et al. Epithelioid hemangioendo-
2008;40(5):1492-1494. thelioma of the liver. Diagnostic features and role of liver trans-
74. Jain AB, Patil V, Sheikh B, et al. Effect of liver transplant on pul- plantation. Gastroenterology. 1988;94(6):1447-1453.
monary functions in adult patients with alpha 1 antitrypsin defi- 93. Marino IR, Todo S, Tzakis AG, et al. Treatment of hepatic epithe-
ciency: 7 cases. Exp Clin Transplant. 2010;8(1):4-8. lioid hemangioendothelioma with liver transplantation. Cancer.
75. Mo J, Dimashkieh H, Bove K. GLUT1 Endothelial Reactivity 1988;62(10):2079-2084.
Distinguishes Hepatic Infantile hemangioma from Congenital 94. Klompmaker IJ, Sloof MJ, van der Meer J, et al. Orthotopic liver
Hepatic Vascular malformation with Associated Capillary Prolif- transplantation in a patient with a giant cavernous hemangioma of
eration. Hum Pathol. 2004;35(2):200-209. the liver and Kasabach-Merritt syndrome. Transplantation. 1989;
76. Christison-Lagay ER, Burrows PE, Alomari A, et al. Hepatic hem- 48(1):149-151.
angiomas: subtype classification and development of a clinical 95. van de Stadt J, Gelin M, Adler M, et al. Epithelioid hemangioen-
practice algorithm and registry. J Pediatr Surg. 2007;42(1):62-67. dothelioma and liver transplantation. Gastroenterology. 1989;96(1):
discussion 67-68. 275-276.
77. Dickie B, Dasgupta R, Nair R, et al. Spectrum of hepatic heman- 96. Dietze O, Davies SE, Williams R, et al. Malignant epithelioid hae-
giomas: management and outcome. J Pediatr Surg. 2009;44(1): mangioendothelioma of the liver: a clinicopathological and histo-
125-133. chemical study of 12 cases. Histopathology. 1989;15(3):225-237.
78. Bonaccorsi-Riani E, Lerut JP. Liver transplantation and vascular 97. Ishak KG, Sesterhenn IA, Goodman ZD, et al. Epithelioid heman-
tumours. Transpl Int. 2010;23(7):686-691. gioendothelioma of the liver: a clinicopathologic and follow-up
79. Alexander CP, Sood BG, Zilberman MV, et al. Congenital hepatic study of 32 cases. Hum Pathol. 1984;15(9):839-852.
arteriovenous malformation: an unusual cause of neonatal persis- 98. Madariaga JR, Marino IR, Karavias DD, et al. Long-term results
tent pulmonary hypertension. J Perinatol. 2006;26(5):316-318. after liver transplantation for primary hepatic epithelioid heman-
80. Zanjani KS, Mazloumi M, Zeinaloo A, et al. Transcatheter embo- gioendothelioma. Ann Surg Oncol. 1995;2(6):483-487.
lization of congenital hepatic arteriovenous malformation using 99. Sharif K, English M, Ramani P, et al. Management of hepatic epi-
ethylene-vinyl alcohol copolymer (Onyx). Diagn Interv Radiol. thelioid haemangio-endothelioma in children: what option? Br J
2012;18(2):231-235. Cancer. 2004;90(8):1498-1501.
81. Mo JQ, Dimashkieh HH, Bove KE. GLUT1 endothelial reactiv- 100. Mehrabi A, Kashfi A, Fonouni H, et al. Primary malignant hepatic
ity distinguishes hepatic infantile hemangioma from congenital epithelioid hemangioendothelioma: a comprehensive review of
hepatic vascular malformation with associated capillary prolifera- the literature with emphasis on the surgical therapy. Cancer.
tion. Hum Pathol. 2004;35(2):200-209. 2006;107(9):2108-2121.
82. Berenguer B, Mulliken JB, Enjolras O, et al. Rapidly involuting 101. Rodriguez JA, Becker NS, O’Mahony CA, et al. Long-term out-
congenital hemangioma: clinical and histopathologic features. comes following liver transplantation for hepatic hemangioendo-
Pediatr Dev Pathol. 2003;6(6):495-510. thelioma: the UNOS experience from 1987 to 2005. J Gastrointest
83. Meyers RL, Scaife ER. Benign liver and biliary tract masses Surg. 2008;12(1):110-116.
in infants and toddlers. Semin Pediatr Surg. 2000;9(3):146-155. 102. Nudo CG, Yoshida EM, Bain VG, et al. Liver transplantation for
84. Daller JA, Bueno J, Gutierrez J, et al. Hepatic hemangioendothe- hepatic epithelioid hemangioendothelioma: the Canadian multi-
lioma: clinical experience and management strategy. J Pediatr centre experience. Can J Gastroenterol. 2008;22(10):821-824.
Surg. 1999;34(1):98-105. discussion 105-106. 103. Lerut JP, Orlando G, Adam R, et al. The place of liver transplanta-
85. Stanley P, Geer GD, Miller JH, et al. Infantile hepatic hemangio- tion in the treatment of hepatic epitheloid hemangioendotheli-
mas. Clinical features, radiologic investigations, and treatment of oma: report of the European Liver Transplant Registry. Ann
20 patients. Cancer. 1989;64(4):936-949. Surg. 2007;246(6):949-957. discussion 957.
86. Woltering MC, Robben S, Egeler RM. Hepatic hemangioendo- 104. Guiteau JJ, Cotton RT, Karpen SJ, et al. Pediatric liver transplanta-
thelioma of infancy: treatment with interferon alpha. J Pediatr tion for primary malignant liver tumors with a focus on hepatic
Gastroenterol Nutr. 1997;24(3):348-351. epithelioid hemangioendothelioma: the UNOS experience. Pediatr
87. Ezekowitz RA, Mulliken JB, Folkman J. Interferon alfa-2a ther- Transplant. 2010;14(3):326-331.
apy for life-threatening hemangiomas of infancy. N Engl J Med. 105. Kirchner SG, Heller RM, Kasselberg AG, et al. Infantile hepatic
1992;326(22):1456-1463. hemangioendothelioma with subsequent malignant degeneration.
88. Taki M, Ohi C, Yamashita A, et al. Successful treatment with vin- Pediatr Radiol. 1981;11(1):42-45.
cristine of an infant with intractable Kasabach-Merritt syndrome. 106. Awan S, Davenport M, Portmann B, et al. Angiosarcoma of the
Pediatr Int. 2006;48(1):82-84. liver in children. J Pediatr Surg. 1996;31(12):1729-1732.
89. Hurvitz SA, Hurvitz CH, Sloninsky L, et al. Successful treatment 107. Dimashkieh HH, Mo JQ, Wyatt-Ashmead J, et al. Pediatric
with cyclophosphamide of life-threatening diffuse hemangioma- hepatic angiosarcoma: case report and review of the literature.
tosis involving the liver. J Pediatr Hematol Oncol. 2000;22(6): Pediatr Dev Pathol. 2004;7(5):527-532.
527-532. 108. Geramizadeh B, Safari A, Bahador A, et al. Hepatic angiosarcoma
90. Kuroda T, Kumagai M, Nosaka S, et al. Critical infantile hepatic of childhood: a case report and review of literature. J Pediatr Surg.
hemangioma: results of a nationwide survey by the Japanese 2011;46(1):e9-e11.
Infantile Hepatic Hemangioma Study Group. J Pediatr Surg.
2011;46(12):2239-2243.
 CHAPTER 29

Ethical Decisions in
Transplantation
Elisa J. Gordon • Sally E. Jensen • Joel E. Frader

CHAPTER OUTLINE

DONATION AND PROCUREMENT OF ORGANS Insurance Coverage for Liver Transplantation

Deceased Donor Organs Transplanting Foreign Nationals in the United
Definition of Death States, Transplant Tourism, and Payment
for Organs
Family Veto of Organ Donor Cards
Regulated Payment
Required Request and Presumed Consent
Laws ORGAN ALLOCATION AND UNOS POLICIES
Live Liver Donation Expanded or Extended Criteria Donor and
Increased-Risk Donor Livers
SELECTION OF PATIENTS FOR TRANSPLANTATION
Disparities in Access to and Outcomes of
Equitable Selection and Access
Liver Transplantation
Human Immunodeficiency Virus
Resources and the Future of Liver
Patients with End-Stage Alcoholic Liver Transplantation
Disease
Retransplantation CONCLUSIONS
Nonadherence Acknowledgments

DONATION AND PROCUREMENT and economic contexts in which such issues arise. These
OF ORGANS factors help inform us about what is meaningful and con-
tentious about ethical issues and shape public opinions
As a complex, high-technology, lifesaving procedure about the range of ethically acceptable options for diffi-
associated with considerable risks, liver transplantation cult clinical decisions. Accordingly, this chapter provides
often poses numerous ethical dilemmas that require dif- the necessary information to situate ethical issues in their
ficult decisions. These quandaries pertain to patients, appropriate contexts.
their potential donors, and society at large. The underly-
ing ethical principles that guide treatment decision mak- Deceased Donor Organs
ing about ethical dilemmas include the following:
• Respecting the self-determination of patients with The United Network for Organ Sharing (UNOS), the
decision-making capacity (autonomy) organization that administers the U.S. Organ Procure-
• Protecting the patient’s well-being (beneficence) ment and Transplantation Network (OPTN), reported
•  Acting in a manner that promotes fairness and that as of January 6, 2012, more than 16,000 people
equity to all involved (justice) (adults and children) on its national patient list were wait-
This chapter reviews how these principles apply to ing for a liver, and that a total of 6341 liver transplants
liver transplantation with regard to the donation and pro- were performed at 131 U.S. liver transplant programs
curement of organs, the selection of patients for trans- during 2011.1,2 The total number of transplants performed
plantation, and macrolevel considerations about the annually has gradually decreased since 2006, in which 6651
allocation of health care resources and national health liver transplants took place.2
priorities. Addressing complex ethical issues requires a Many end-stage liver disease patients die each year
clear understanding of the scientific data relating to clini- waiting for a transplant, and their numbers appear to be
cal factors to ensure fact-based reasoning, not inadequate increasing each year. Based on the latest data available, of
presuppositions. Thus up-to-date empirical data are pro- those liver patients registered on the UNOS/OPTN
vided throughout, as available. In addition, ethical deci- Transplant Waiting List, 1791 died in 2000, 1894 in
sions must take into account the social, cultural, historical, 2005, and 1468 in 2010, before a liver could be obtained.3

360
 29 Ethical Decisions in Transplantation 361

These deaths occurred despite the generally increasing on ventilator support is different from the death of
number of deceased donor livers obtained from 2000 to patients supported by ventilators who have circulatory
2010: 4595 in 2000, and 6009 in 2010.4 However, many activity and appear to breathe. In brain death neurological
families decline the option to donate their loved one’s (brain) control of breathing and regulation of circulation
organs because of cultural, religious, and other factors, as have been replaced by external mechanisms—the ventila-
well as a lack of public education.5 The number of livers tor and often medications—to support an adequate flow
procured each year therefore cannot meet the current or of blood to maintain the function of vital organs, includ-
future needs in the United States. Because donor livers ing the heart, lungs, kidneys, liver, pancreas, intestines,
are a scarce resource, questions of fairness in their pro- and so forth.
curement and distribution are inevitable. Two streams of thought object to the current defini-
tion of death for transplant procurement purposes:
• Some advocate narrowing the current whole-brain
Definition of Death death criteria to require stricter criteria with pro-
Acceptance of organ procurement and transplantation longed observation and mandatory neurological
depends, in large part, on public confidence that deceased testing.9
donor organs are procured only when people are actually • Others contend that the criteria should be widened
dead, according to the public understanding of that term. to include patients who have been declared dead
Although the determination of death constitutes a medi- by traditional cardiopulmonary criteria (i.e., the
cal decision, the concept of death depends on social, legal, regular dead as contrasted with the brain dead, often
and medical conventions. Fundamentally, transplantation referred to as the cardiac dead)10 or who are alive by
must contend with the fact that the concept of death is current criteria but have been diagnosed with
culturally constructed, informed by religious beliefs, and “permanent loss of consciousness” (i.e., the
situated within a historical context. “higher brain” versus “whole brain” standard).11
The medical criteria for whole-brain death in the In these situations, organ procurement would
United States were authoritatively defined by a U.S. pres- occur after the declaration of death by circulatory
idential commission in 1981. The major principles are as criteria or with the use of "rapid organ recovery"
follows: techniques.12
•  Both cerebral and brainstem functions must be Still others have proposed the elimination of the dead
absent. donor rule (DDR) altogether,13 permitting organ recov-
• The cause or causes of this total lack of brain func- ery before the declaration of death. The DDR provides
tioning should have been identified and determined the moral framework guiding organ procurement from
to be irreversible. However, in actuality the cause of deceased donors, such that vital organs may be removed
death may be unknown. In such cases the proce- only after clinicians confirm the patient’s death. The
dures for determining death by neurological crite- DDR aims to ensure public trust in organ procurement
ria typically involve both a longer period of by preventing premature removal of organs. However,
observation after the first examinations compatible controversy remains over whether donation after circula-
with brain death before confirming the diagnosis, tory determination of death does and should conform to
and greater use of confirmatory tests, such as cere- the DDR.14,15 For some, the circulatory determination of
bral blood flow studies, than would occur when the death does not conform to the DDR because cardiopul-
nature of the brain injury is clearly identified. monary resuscitation could be (re)instituted, meaning
•  The absence of all brain function must have that organs could technically be procured before the indi-
persisted during a period of treatment and
­ vidual’s death. According to Truog and Miller,14 those
observation.6,7 advocating the DDR confuse the dying process with
The Uniform Determination of Death Act (UDDA) death. Donation after cardiac death is a rapidly expanding
(1981) provided the legal framework by stating that “an component of the donor pool that has received increased
individual is dead if there is irreversible cessation of circula- emphasis.16
tory and respiratory functions or if there is irreversible Recently OPTN has proposed revisions to the lan-
cessation of all functions of the entire brain, including the guage describing procurement. To date, organ removal
brain stem.” This means that function will not reverse, following death caused by the permanent and irrevers-
and “irreversible” means that function cannot reverse.8 ible loss of circulatory and respiratory function has
These two criteria evoke much controversy, as described been referred to as donation after cardiac death or DCD.
later. The UDDA statutory definition has been adopted However, OPTN has proposed the term donation after
by most U.S. state legislatures; New York and North circulatory death, to accurately reflect the definition of
Carolina have adopted substantially similar versions. In death determined by cardiopulmonary criteria used in
other states, courts have upheld these brain death criteria the medical community.17 The UNOS/OPTN Pro-
in judicial rulings. posal for Public Comment rationalized the new term as
Despite the UDDA definition, confusion about the follows: “This change is particularly important because
concept of death has persisted. The phrase brain death the heart is not dead (nor are other organs) when the
connotes to some the existence of two types of death, heart stops, but when circulation and oxygenation to
“regular” death and brain death. This distinction is rein- the tissues are irreversibly stopped,” and “the proposed
forced by the perception that the death of patients who changes will help to maximize the number of donors
lose circulatory and respiratory functions and who are not and transplants by identifying the currently unrealized
362 PART IV Special Considerations in Patient Evaluation

donor potential through the clarification and updating signing donor cards may not understand that agreeing
of language.”18 to donate permits premortem interventions to ensure
Public opinion surveys reveal that the public would medical suitability of the organs.28 In addition, the pro-
not welcome a violation of the DDR. However, most of visions of the 2006 law raise questions regarding auton-
those surveyed poorly understood current definitions of omy, by limiting donors’ ability to use designated
brain death.19 For many laypeople, doubts still remain surrogates to communicate preferences related to life-
in light of physical evidence of skin warm to the touch, prolonging interventions.28
a heartbeat, and the breathing process—although they Given the potential conflict between patient prefer-
are machine generated—which to all appearances seem ences regarding life-sustaining interventions and consent
to confirm signs of life.20 To address public misunder- to organ donation, a 2007 amendment to section 21(b) of
standings of brain death, Truog21 contends that either the 2006 law now requires the attending physician to
the definition of death must change or the DDR must resolve any potential conflict with the prospective donor
not be requisite. Although the latter option seems ethi- or his or her health care surrogate.29 However, the
cally defensible, it is not likely to find widespread sup- amendment still mandates the provision of life-sustaining
port. It appears that as the organ demand continues to intervention to ensure medical suitability of the organs
rise, challenges to the DDR will continue to be made. while the conflict is being resolved.29 Education during
The window of time between when clinicians declare advance health care planning and offering the option for
death and when organ procurement begins appears to would-be donors to document their specific preferences
be narrowing, coinciding with efforts to embrace novel for premortem OPO procedures at the time of consent
and broader interpretations of the concepts of irrevers- may mitigate these concerns.28,29
ibility and cessation.22 Indeed, when one center began
to remove infant hearts for transplantation after short Required Request and Presumed
periods (75 to 90 seconds) from the declaration of death,
much outrage appeared, despite the resultant increase in
Consent Laws
available organs.23,24 Given the lack of public comfort Since the mid-1980s a series of required request laws
with and understanding of the definitions of death and were enacted to require hospitals to implement policies
the process of organ procurement, distrust will likely ensuring that the families of all eligible donors receive
accompany proposed changes to the DDR by profes- the opportunity to donate.30 Required request laws were
sionals, especially those associated with the transplanta- followed by routine notification laws, which mandated
tion enterprise. that all hospitals receiving Medicare or Medicaid funds
notify the local OPO of all individuals whose death is
imminent or who have died in the hospital.31 Routine
Family Veto of Organ Donor Cards notification laws were designed to increase OPO involve-
Organ donor cards and designation of willingness to ment in the organ request process, with the underlying
donate on drivers’ licenses constitute a means for would- assumption that health care providers communicated
be donors to express their consent for donation, thereby ineffectively with families about donation.30,32 However,
increasing donation rates. Although signed donor cards research findings suggest that a substantially greater per-
indicate the donor’s intention to donate organs, histori- centage of patients’ families prefer that the treating phy-
cally organ procurement organizations (OPOs) also sician make the initial request for organ donation, given
sought consent from next of kin.25 This practice stemmed that the physician knows the patient’s condition best and
from potential publicity and legal challenges that could has spent the most time with the family.30 Nevertheless,
arise if family members objected to donation.25 This de both of these policies rest on the assumption that increas-
facto family veto stood in contrast to the provisions of the ing the number of eligible donors’ families approached
1968 Uniform Anatomical Gift Act, which authorized for consent would increase organ donation. Although the
gifts by any person older than 18 years of age with deci- number of deceased donor livers has increased nationally
sion-making capacity.26 from 2000 (N = 5199) through 2011 (N = 6685),4 the
In 2006 the Revised Uniform Anatomical Gift Act failure to increase donation sufficient to meet the grow-
(currently adopted by 45 states) strengthened the lan- ing demand for livers and other organs has prompted dis-
guage that bars any individual from “making, amend- cussion about whether eliminating decision making at the
ing, or revoking” the donation of an anatomical gift for time of death may result in greater increases in organ
an individual who previously documented (e.g., via donation rates.
donor card) his or her consent to donate.27 This revi- The U.S. Department of Health and Human Services
sion makes it unlawful for an OPO to allow the family established the Organ Donation Breakthrough Collab-
members to veto donation in the presence of a signed orative,16 a quality improvement initiative designed to
donor card, as long as the donor did not revoke the gift “encourage adoption of ‘best practices’ for identifying
before death.27 However, it also granted OPOs the potential donors and obtaining consent for deceased
authority to require life-sustaining interventions to organ donation.”34 The collaborative set a national goal
preserve organs in individuals with signed donor cards, of a 75% conversion rate (“the number of actual donors
regardless of the donor’s preference for end-of-life divided by the number of potentially medical suitable
care communicated by advance directives or surro- donors”).16 Preliminary evidence of the initiative’s effec-
gates.27 This raises two ethical concerns related to tiveness was documented when the conversion rate for all
informed consent using donor cards. First, individuals organs increased from 52% in March 2004 to 60% in
 29 Ethical Decisions in Transplantation 363

August 2004, before and after implementing the initia- donation rates in places, like the United States, that value
tive, compared to a control group, which remained at patient or family autonomy.41
51%.34 The conversion rate for all organs has ­continued Mandated choice constitutes another strategy for
to grow, reaching 72.6% in 2011,35 although the liver increasing organ donation. Working within the con-
recovery rate was 65.1% in the same year35 (Table 29-1). structs of an “opt-in” model, mandated choice requires
Although well intentioned to help patients in need of life- that individuals explicitly decide “yes” or “no” regarding
saving organs, such efforts presume that prospective whether to be an organ donor, typically as part of a
donors’ deep-seated values and beliefs are “convertible” requirement for obtaining a driver’s license.42 Propo-
and that the decision not to consent is “preventable.”36 nents of mandated choice argue that it preserves auton-
This disposition seems to disregard individuals’ cultural omy relative to presumed consent and also minimizes
and religious attitudes or preferences against donating. families’ decision-making burden at the time of death.
A number of other strategies have been considered to However, questions remain regarding the effectiveness of
increase deceased donation. For example, presumed con- mandated choice policies in increasing organ donation.
sent is an “opt-out” model in which a would-be donor is For example, a mandated choice law was repealed in
presumed to consent to organ donation unless he or she Texas after the majority of individuals refused to desig-
had documented an objection to donation before death. nate themselves as organ donors, resulting in an adverse
The rationale for presumed consent includes the supposi- impact on organ procurement efforts overall.30 More-
tion that the majority of individuals favor donation but over, this approach also raises questions about popula-
never document their consent to donate, as well as the tions in which few people obtain drivers’ licenses.
notion that one should minimize the decision-making Although there is a strong need to identify strategies to
burden on families at the time of a loved one’s death.37 ameliorate the current organ donation shortage, it
Several European countries have adopted presumed con- remains to be seen whether such policies will be imple-
sent laws, and a systematic review reported a 20% to 30% mented in the future.
increase in organ donation with presumed consent.38
However, in their analyses of presumed consent, Rithalia
et al and Healy independently concluded that presumed
Live Liver Donation
consent alone did not likely explain the increases in dona- Prompted by the increasing organ scarcity, live liver
tion rates; rather, the resources that such countries invest donors have emerged as an important source of organs,
in organ donation organization, infrastructure, educa- constituting 4% of all liver transplants in 2011.43 Advances
tion, and procurement staff contributed to the improved in surgical technique within the last decade have demon-
donation rates.39 In addition, a recent qualitative study of strated that living donor liver transplantation (LDLT)
transplant physicians from 13 European countries that confers better graft and patient survival compared to
adopted presumed consent revealed that in all countries deceased donor liver transplantation for both adult and
donation was always discussed with the family at the time pediatric recipients.44,45 In addition, LDLT is often the
of death, and that donation did not proceed if the family only promising source of organs when patients become
objected.40 In light of these findings, it remains unclear too sick to await a deceased donor organ. Thus clinical
whether presumed consent laws would in fact increase and ethical decisions must be made as to whether such
organ donation. Moreover, concern arises regarding a patients should be offered a deceased donor organ.
potential negative impact of presumed consent on organ Although this situation justifies some use of living donors,

TABLE 29-1 Breakthrough Collaborative Statistics

National Statistics (Across 58 Donor Service Areas)
January to December 2011 Total United States Mean Median Minimum Maximum
Number of donors recovered 8,127 140 125 34 442
SCD donors 5,251 91 76 17 299
DCD donors 1,053 18 14 0 82
ECD donors 1,823 31 25 5 127
Percent of donors recovered 100% -- -- -- --
SCD donors 64.6% 65.5% 66.8% 37.8% 84.9%
DCD donors 13.0% 12.7% 11.5% 0.0% 37.8%
ECD donors 22.4% 21.8% 21.0% 7.5% 39.8%
Organs transplanted 24,970 431 376 107 1,259
Organs transplanted per donor 3.07 3.10 3.10 2.28 3.72
Eligible deaths reported 9,018 155 138 34 536
Eligible deaths—consent rate 75.2% 76.0% 75.7% 57.9% 91.0%
Eligible deaths—conversion rate 72.8% 73.4% 73.2% 56.8% 89.1%
Collaborative—conversion rate 76.8% 77.0% 76.6% 62.4% 92.0%

Organ Procurement and Transplantation Network (OPTN) data as of March 9, 2012. Available at http://optn.transplant.hrsa.gov.
DCD, Donation after cardiac death; DSA, donor service area; ECD, extended criteria donor; SCD, standard criteria donor.
364 PART IV Special Considerations in Patient Evaluation

it may also place undue pressure on potential donors (dis- other than payment of reasonable medical expenses and
cussed later). lost income. Many acknowledge, however, that trans-
The use of live donors for liver transplantation remains plant centers have no systematic, reliable means to ensure
highly controversial (see Chapter 60). Briefly, live liver the “donations” remain uncompensated.
donation violates the ethical principal of nonmaleficence: The third category of donors—unrelated or Good
do no harm. LDLT involves placing living donors at risk Samaritan donors—raises other ethical issues. The key
for considerable harm with no direct medical benefit to question is whether it is ever ethically acceptable to allow
themselves. Although these ethical considerations apply unrelated donors to donate to liver transplant candidates
to all living donors, the use of live liver donors raises a because the risk-benefit ratio differs from directed dona-
host of concerns about donor safety, given the magnitude tion. Ethical concerns remain about justifying live liver
of risks to both the donor and recipient from the proce- donation to strangers because nondirected donors do not
dure.46,47 In the National Institutes of Health–Sponsored benefit from helping a known recipient.56 In other words,
Adult-to-Adult Live Donor Liver Transplant Cohort the kinds of psychological benefits obtained by donating
Study (A2ALL) recent report of the first 6-year longitu- to a loved one have traditionally been sufficient to justify
dinal study of live donor complications, 40% of live the harms incurred by directed donation. But it is less
donors experienced a complication (e.g., bile leak, surgi- clear whether the psychological benefits obtained by
cal hernia, infection).48 As a result, the risks and benefits, nondirected donors of having done a good deed suffi-
the adequacy of informed consent procedures, and the ciently outweigh the harms. However, there is a growing
selection of recipients and donors remain under careful acceptance of nondirected donation as long as the psy-
scrutiny.49 Informed consent for live liver donors will chosocial benefits can outweigh the risks incurred to
remain suboptimal until information on their long-term donors.56 Because the risk-benefit considerations differ
outcomes becomes available.50 for nondirected donors, some organ procurement orga-
The type of living donor raises other ethical concerns. nizations have developed programs specifically tailored to
There are three categories of living donors: (1) living evaluating altruistic donors in an effort to support pro-
related donors (such as parents, siblings, or adult ­children) curement from these donors.57 Otherwise, guidelines
who are genetically related to the recipient; (2) living generally exclude almost all living unrelated donors (in
emotionally related donors (such as spouses, significant contrast to living emotionally related donors).
others, and close friends) who are genetically unrelated;
and (3) living unrelated donors who are strangers to the
recipient or nondirected donors. This last category has SELECTION OF PATIENTS FOR
also been referred to altruistic or Good Samaritan donors.
To date there have been only 41 nondirected live liver
TRANSPLANTATION
donor transplants, compared to 1092 nondirected live Equitable Selection and Access
kidney transplants.51
Among all categories of donors, living donation raises The combination of increasing organ scarcity with the
ethical concerns pertaining to voluntariness and its con- absence of viable alternative therapies for patients with
verse—the potential for coercion or undue pressure. end-stage liver disease make candidate selection and
Because of the pressures on potential donors to save a organ allocation of liver transplants ethically challenging
loved one’s life, many donors in the first two categories for patients, families, and clinicians58 (see Chapter 5).
feel internal or self-generated pressures to donate, Balancing justice, utility, and the desire to benefit afflicted
whereas others feel pressures from others, albeit less individuals continues to pose complicated allocation
commonly, to donate.52,53 Liver transplant teams must decisions. The Model for End-Stage Liver Disease
evaluate the motives, capacities, and emotions of pro- (MELD) established objective measures of candidate dis-
spective donors in a variety of factual contexts, while at ease severity, reducing subjective biases in the evaluation
the same time seeking to respect the decisions of prospec- of transplant candidates. Patients no longer receive points
tive donors with decision-making capacity, valuing the based on time spent waiting on the list. Nonetheless, psy-
lifesaving potential of this gift to the recipients and the chosocial and medical criteria are used by transplant
satisfaction of donors. Clinicians have also struggled with teams in their candidate selection process.59
how to effectively communicate risks to potential donors Relatively little is known about the actual structure
to ensure, if possible, an adequate level of informed con- and function of liver transplant committees.60 In a multi-
sent in such situations. site observational study of the decision-making process
For these reasons, various national and international for liver transplant selection, Volk et al60 found that cen-
guidelines have emphasized limiting living donation to ters consistently engaged in inductive logic to find ­reasons
those persons who are either genetically or emotionally to exclude patients from candidacy for liver transplanta-
related to the recipient. Compared to living related tion. Notably, criteria for excluding patients included
donors, whose motives seem largely altruistic, living being too well, too sick, too old, having comorbid condi-
unrelated donors raise concerns among transplant pro- tions unrelated to liver disease, having substance abuse
viders about the possibility of financial compensation for problems, and having psychosocial problems associated
donation and whether nondirected donors can make with the patient’s socioeconomic status.60 Volk et al also
informed decisions with a clear understanding of the risks found that the absence of written center policies under-
and benefits involved.54,55 Guidelines typically require mined effective decision making about patient selection.
that potential donors not receive any economic reward Other studies have documented how transplant teams
 29 Ethical Decisions in Transplantation 365

accord greater weight to medical characteristics over psy- about the implications of common coinfections with hep-
chosocial or financial factors in transplant patient selec- atitis B and C virus in many HIV-infected patients, as
tion decisions.61,62 In addition, there appears to be no well as “the risk of needle stick injury to the surgical
consensus regarding what psychosocial selection criteria team,” though similar risks from hepatitis B virus did not
to use to determine listing within and across transplant routinely deter surgeons. In 2006 Roland and Stock93
centers.63 noted: “The advances in HIV management have made it
Deciding to list patients for liver transplantation often difficult to continue denying solid organ transplantation
includes consideration of medical conditions other than to [the HIV-infected] population based upon futility
the primary liver disease. Criteria that remain highly arguments alone.” They noted that various third-party
debated in the transplant community include advanced payers had begun to reimburse for transplantation ser-
age (greater than 65 years old),64,65 HIV seropositiv- vices for those living with HIV. Two recent papers have
ity,66,67 obesity,68,69 psychiatric diagnoses,70-72 incarcera- examined liver transplantation in HIV-infected patients.
tion,73-75 marijuana use,76-78 mental disability,79,80 One single-center cohort study compared outcomes in
citizenship/residency status,81-83 alcoholic liver disease HIV-infected patients with uninfected recipients trans-
(ALD) without abstinence, and acute alcoholic h ­ epatitis.84 planted between 2004 and 2009.94 There were no statisti-
The literature also contains discussions of whether intel- cally significant differences in patient or graft survival.
lectual disability,85,86 mental illness,87 heart disease, Hepatitis C coinfection did not alter the results. Cooper
chronic infections, and other conditions should influence et al95 in 2011 conducted a comprehensive review of
candidacy for transplantation.84,88 available published data and calculated an 84.4%
Age has become a less important issue, with some 12-month survival after transplant, with favorable out-
arguing that liver transplant patients age 60 to 65 years do comes for those coinfected with hepatitis B virus and no
as well as younger patients and candidates should not be impact of hepatitis C virus (HCV) infection. These sur-
excluded solely on grounds of age.46 Others contend that vival figures for HIV-infected patients are similar to those
in this “youth-oriented society,” organs should go to the reported for HIV-negative patients. Nevertheless,
young on the basis of potential productivity rather than another review by Joshi et al96 in 2011 took a somewhat
to older candidates on the basis of past contribution to more cautious view, especially about HIV-infected
society.47 A survey in 1991 found that two thirds of the patients with hepatitis C coinfection. They concluded by
transplant centers polled had no specific age limit, acknowledging that this latter group “includes the vast
whereas the remaining third excluded patients over a majority of cases and appears to be disadvantaged by the
median age of 70 years.48 Today transplant centers gen- lack of available therapeutic options before and after
erally accept new potential recipients until age 70.89 The transplantation….[and] Allocation issues remain undelin-
number and percentage nationally of liver transplant eated in this era of organ shortages.”
recipients age 65 years and older has steadily increased
from 2000 through 2011 (1821 [7.8%]) versus 4511 Patients with End-Stage Alcoholic
[15.8%] recipients).90 It may be that with greater medical
and surgical acumen, transplant centers are more recep-
Liver Disease
tive to giving transplants to older patients. Alcoholic liver disease (ALD) constitutes one of the most
common indications for liver transplantation in the
United States. Since its acceptance as an indication for
Human Immunodeficiency Virus liver transplantation in the 1980s, research assessing
Among the comorbidities considered, human immuno- posttransplant outcomes demonstrates better outcomes
deficiency virus (HIV) infection has generated consider- among ALD recipients when compared to recipients with
able controversy because acquisition of the virus has been nonalcoholic liver disease.97 Despite this, liver transplan-
associated with socially disfavored behaviors and because tation in ALD engenders significant ethical debate pri-
of concern that graft and patient survival would be dimin- marily because of concerns about the potential impact of
ished in HIV-infected individuals. Tzakis et al91 from relapse on posttransplant outcomes. A recent review of
Pittsburgh first reported successful liver and other solid studies with 30 or more participants reported widely
organ transplantation in an HIV-infected population in varying rates of relapse in the literature, with overall
1990. At a mean of 2.75 years after transplant, 5 of 15 relapse rates ranging from 11% to 53% and rates of heavy
liver recipients were alive, perhaps surprising transplant drinking ranging from 5% to 27% after transplant.98 Sev-
programs around the world. Many transplant profession- eral factors may account for differences in relapse rates
als had refused to consider HIV-infected persons for reported across studies. First, studies vary in how they
transplantation because of the assumption that their operationalize relapse, with some studies defining relapse
underlying retrovirus infection conferred a poor as any consumption of alcohol.99,100 This definition of
­prognosis, one that might actually get worse with the relapse is consistent with the perspective of many 12-step
immunosuppression required to prevent graft rejection. programs that advocate for total abstinence. However,
Even in 2004, despite demonstration that highly active critics argue that relapse to heavy drinking sufficient to
antiretroviral therapy (HAART) generally turned HIV cause liver damage would be a more meaningful outcome
infection into a manageable chronic illness, a review in index,101 and recent findings highlight the importance of
Pediatric Transplantation began: “In general, patients examining the trajectory of alcohol consumption after
infected with HIV are excluded from consideration for transplant to better gauge problematic patterns of alcohol
transplantation worldwide.”92 Concern still lingered use.102 Second, the median length of follow-up ranges
366 PART IV Special Considerations in Patient Evaluation

from 21 to 89 months across studies,98 which may also to cause liver damage and preventable.115 In effect, this
account for variation in reported relapse rates. Third, ret- position rests on an interpretation of fairness whereby
rospective studies constitute the majority of relapse individuals who acquire diseases that they could have pre-
research, and most rely upon documentation of relapse in vented are less deserving of receiving treatment, when
the medical record. This form of documentation typically treatment resources are scarce.115 Opponents of this
assumes that recipients accurately report alcohol con- viewpoint assert that although the behavior of drinking
sumption during follow-up visits. Recipients who wish to alcohol is causally linked to the development of ALD,
present themselves in a favorable light during medical only 15% of individuals who drink excessively develop
visits may avoid disclosing alcohol consumption. Indeed, ALD,116 thus suggesting that other factors also contrib-
the majority of studies relied upon patient self-report and ute to the development of this disease.101 In addition,
family interviews to assess posttransplant alcohol con- assigning lower priority to patients with ALD may jeop-
sumption.97,99 Although family-member proxy reports ardize trust in the patient-physician relationship and
may strengthen the quality of these data, given the per- incentivize patients to withhold information if they know
ception of shame associated with relapse, patients may it would limit their access to treatment, thus weakening
not openly disclose alcohol consumption, thus potentially the physician’s ability to provide adequate care because of
compromising the validity of self-reports.103 lack of important information.117 Finally, the fact that
Even with the rates of reported relapse in this popula- other nonalcoholic liver diseases are often linked to vol-
tion, alcohol relapse is not associated with poorer graft untary health-compromising behaviors, such as risky
survival.104,105 The 5-year posttransplant survival rates do sexual practices or needle sharing, raises further ques-
not differ between relapsed and nonrelapsed ALD tions about whether patients with ALD should receive
patients.105,106 Despite this scientific evidence, relapse lower allocation priority.101
remains an ethical concern because of its potential impact
on adherence and transplant outcomes,107 the implica-
tions for fairness in allocation, and its potential adverse
Retransplantation
effect on organ donation.108 For example, some argue If surgeons, hepatologists, and policy makers have trou-
that a public perception that ALD transplant recipients ble knowing which patients deserve priority for primary
return to problematic alcohol use after transplant might liver transplantation, retransplantation raises even thorn-
negatively affect consent to donate. ier questions. On the one hand, those who have received
In an effort to decrease the likelihood of posttrans- a graft may be perceived as having already had their
plant relapse, by 1997 the majority of transplant centers chance of rescue. Accordingly, graft failure, whether
in the United States adopted a policy requiring individu- because of primary nonfunction, surgical complications,
als with ALD to demonstrate at least 6 months of absti- or other causes, should not constitute an adequate reason
nence before being listed as a candidate for liver to become a (re)transplant candidate. Some versions of
transplantation.109 However, the 6-month abstinence utilitarian ethics would add that the generally less favor-
stipulation was not evidence based, and a review of able outcomes associated with retransplantation strongly
recent research yields equivocal support for the policy’s suggest that the next available liver should go to a never-
correlation with posttransplant relapse.98 Critics assert before-transplanted patient. That approach, however,
that the waiting period may unfairly limit the opportunity ignores the bonds established between members of the
for transplant in individuals with rapidly progressing transplant team and their patients and family members—
­disease, such as alcoholic hepatitis,101 and advocate for an attachment made stronger once the patient has had a
reevaluation of the 6-month abstinence policy, based on first transplant operation. In addition, already trans-
empirically supported predictors of relapse to harmful planted patients who again have liver failure are, in fact,
drinking.98 Thus far, research has identified several sig- persons suffering from serious illness who deserve defini-
nificant predictors of posttransplant relapse, including tive treatment regardless of previous transplantation. As
younger age,99 duration of pretransplant abstinence,108,110 with primary transplantation, retransplantation requires
pretransplant abstinence of less than 6 months,108 history an attempt to balance justice considerations, such as pro-
of psychiatric condition,108,111-113 female sex,108 increased viding equity in access to a transplant in a population
personal stressors,108 lack of social support,111-113 family waiting for an organ, with an attempt to benefit each per-
history of alcoholism,102,114 and prior nonadherence to son in one’s care.
treatment.102,112 The use of evidenced-based predictors In 1993 Ubel et al118 noted that as many as 20% of liv-
of relapse may facilitate identification of those ALD ers went to those undergoing retransplantation, despite
transplant candidates at greatest risk for relapse, which evidence of poorer outcomes compared to those receiv-
may help to guide patient selection and interventions to ing a first graft. Examining liver retransplantation data
prevent relapse. from UNOS, they noted important decrements in sur-
In addition to relapse, ethical debate in liver transplan- vival with successive transplants, even in the centers with
tation for individuals with ALD also centers on the ques- the highest surgical volumes. They concluded that fair-
tion of whether individuals with ALD should be given ness—which they defined as “a system that favored those
lower allocation priority than individuals with nonalco- most likely to benefit from a transplant” —required giv-
holic liver disease. Those who support giving lower ing priority access to scarce organs to those awaiting a
­priority to ALD candidates argue that individuals with first liver and eliminating from the waiting list altogether
ALD are both morally and causally responsible for their those in need of a third or fourth, etc, liver. (They noted
liver failure by engaging in a behavior that is both known multiple retransplants at some centers, a practice that,
 29 Ethical Decisions in Transplantation 367

according to more recent reports, continues. Some papers was older than 55 years, those with high (>27) MELD
report four or more retransplants for some patients [see scores, and those with low serum albumin levels at the
later]). time of retransplantation. Although high intraoperative
Despite the rationale offered by Ubel et al,118 transplant blood loss also predicted poor survival, that measure
teams have continued to feel a strong sense of obligation could not be used to deselect candidates for retransplan-
to their patients with failed grafts. A single-center analy- tation. These authors conclude that for retransplantation
sis from France published in 2002 reviewed their experi- patients “excellent long-term survival can be achieved in
ence with 139 patients undergoing retransplantation highly selective patients” (emphasis added).
between September 1986 and September 1999, during The results of these studies and the ethical conclusions
which time 1038 patients had only one liver transplant.119 their authors draw indicate the ongoing tension between
Their analysis excluded 28 patients who received more normative views. On the one hand, some authors would
than one retransplant. They found a 26.6% 60-day mor- like to maximize utility by excluding patients most likely
tality rate, compared with an 8.9% rate in those receiving to die after retransplantation. On the other hand, other
only one graft. They also noted a 34.7% 60-day mortality authors feel a moral duty to try to rescue their sickest
among retransplanted patients in the European Liver patients, even if the likelihood of success is low. Because
Transplant Registry during the same period. Long-term these contrasting views come from equally dedicated
survival was also significantly decreased for the first- transplant teams, it suggests that mathematical models of
retransplant group. Not surprisingly, both length of hos- outcomes will not entirely solve the moral problem of
pital stay and charges were substantially higher for the who deserves a second (or third, fourth, etc) liver while
retransplanted patients, though those differences did not others must await a first.
exist for those receiving elective, versus urgent, retrans-
plantation. These findings prompted the authors to con-
clude: “Retransplantation is fully justifiable when
Nonadherence
performed electively.” They also stated: “Despite its Nonadherence to the medical regimen (e.g., abstinence
inferior results, hepatic retransplantation cannot be from substance use, posttransplant immunosuppression,
totally abandoned.” Somewhat surprisingly, the authors medical appointments, health monitoring, health
suggest using living related liver transplantation for those ­behavior recommendations) is associated with subopti-
with an urgent need for a replacement organ, without mal outcomes in liver transplantation.127 In light of the
explaining how their own poor outcome data could jus- shortage of transplantable livers, as well as efforts to opti-
tify exposing a healthy donor to the risks of partial liver mize transplant outcomes, adherence has emerged as an
resection. important element in the psychosocial screening of liver
In 2007 Pfitzman et al,120 from Germany, noted trends transplant candidates. A lack of consensus regarding how
in liver retransplantation at their center over 15 years. to accurately assess nonadherence currently exists. That
Their analysis also excluded some patients, including and a lack of consensus about the role that adherence
those under 16 years of age, those receiving a second should play in patient selection and posttransplant care,
retransplantation, those whose first transplant had currently raise ethical concerns that nonadherence can be
involved a split cadaveric liver or a liver segment from a used to deny access unfairly if this psychosocial criterion
living related donor and others with complex surgeries. is used too loosely.
Dividing the results into three time periods over the 15 A paucity of evidence-based guidelines for pretrans-
years, they found no secular trend in survival rates for plant assessment of adherence exists.128 Typically the
retransplanted patients, although they did demonstrate pretransplant psychosocial evaluation includes an assess-
reduced intensive care and hospital stays between the ment of a candidate’s history of adherence behaviors
early and late periods of the study. They concluded that ­(Table 29-2), based upon patient and collateral
their decreasing complication rates amounted to “good (e.g., ­
family members, past medical providers) reports.
clinical results” after retransplantation, despite their The assessment of adherence also encompasses factors
observation that retransplantation “inevitably denies that may adversely affect adherence, such as impaired cog-
organs to first-time recipients who have the same legal nitive functioning and uncontrolled psychiatric illness.129
claim to their first donor organ.” Historically the availability and quality of social sup-
Other studies examining results of retransplantation in port has constituted an important component of the
adults continued to show poorer, though improving, out- adherence assessment, given its potential role in promot-
comes of retransplantation compared to first trans- ing adherence.84 Findings from several recent individual
plants.121-125 Virtually all papers concluded that the studies suggest that social support is associated with post-
results seemed sufficient to justify the practice. A recent transplant adherence.128,130,131 However, a meta-analysis
paper presented a predictive index for long-term survival examining risk factors for nonadherence in solid organ
after retransplantation, based on a 26-year experience.126 transplantation failed to find a strong correlation between
They identified four risk groups, with one group, consti- social support and nonadherence,132 prompting questions
tuting 22% of those undergoing retransplantation, as about the weight that should be placed on social support
having much poorer patient and graft survival. The high- during pretransplant screening for adherence. Using
risk group included those who needed mechanical venti- availability of social support as a criterion for evaluating
lation at the time of retransplantation, those needing a adherence remains ethically questionable, given that
second organ within 1 month of their first transplant, individuals may lack volitional control over their social
those who were over 45 years of age, those whose donor support situation.115
368 PART IV Special Considerations in Patient Evaluation

TABLE 29-2 Adherence Behaviors of Importance Before and After Liver Transplantation
Before Transplant After Transplant
• Adherence to prescription medication regimen (e.g., • Adherence to immunosuppression and other prescription
frequency, dose) medication regimen
• Adherence to relevant health monitoring (e.g., blood • Adherence to relevant health monitoring (e.g., blood
pressure, insulin) pressure, insulin, temperature)
• Adherence to medical appointments and tests • Adherence to medical appointments and tests
• Adherence to health behavior recommendations (e.g., diet, • Adherence to preventive care recommendations (e.g., diet,
exercise) exercise)
• Substance use history • Adherence to health precaution recommendations (e.g.,
avoid prolonged sun exposure, protection against
­opportunistic infections)
• Abstinence from substance use

Modified from Dew M, Dunbar-Jacob J, Switzer G, DiMartini A, Stilley C, Kormos RL, eds. Adherence to the medical regimen in transplanta-
tion. In Rodrigue JR, ed. Biopsychosocial Perspectives on Transplantation. New York: Kluwer Academic/Plenum Publishers; 2001:93-124.

Ethical reservations about pretransplant adherence As with other expensive treatments, insurance may
assessment stem in part from the lack of consensus ­provide only partial payment to hospitals and physi-
regarding the role this information should play in deci- cians/surgeons, based on policy “caps” or discounted
sion making about candidates’ eligibility for transplant. rates the insurer has negotiated with “preferred provid-
For example, some transplant programs use risk for ers” or other considerations. This may leave hospitals
posttransplant medical regimen nonadherence as an with inadequate reimbursement, especially for the most
absolute or relative contraindication to listing for trans- complicated cases, which in turn may lead to cherry-
plant.129 The use of behavioral criteria for establishing picking, whereby programs have an incentive to select
transplant eligibility may threaten the fairness of the the healthiest transplant candidates and avoid clinical
evaluation process by introducing the possibility of innovation. To the extent that there is incomplete
social worth judgments.133 For example, some behav- insurance coverage, including large copayment provi-
ioral criteria with perceived association to less favorable sions, patients or families may have substantial residual
posttransplant outcomes (e.g., engaging in health-com- bills from hospitals, professionals, pharmacies, and oth-
promising behavior such as tobacco use) may also carry a ers. In addition, getting to transplantation often involves
social judgment stigma. The fact that candidates with considerable disruption to family life, including addi-
certain behavioral characteristics may be perceived as tional costs for transportation and for housing near the
“less worthy” could result in unjust decisions that limit transplant center and loss of income for the patient,
patients’ eligibility for transplant. Moreover, inconsis- spouse, or patient’s parents, in the case of candidates
tency across transplant programs in the assessment and who are children. These economic realities, according
application of adherence criteria also poses questions to a 2007 study in the United States, often led to use of
about whether the process is ethically sound.133 For personal/family savings and loans, including credit card
example, a recent study examining reasons for liver debt, need for additional employment by family mem-
transplant ineligibility found that although early referral bers, and even bankruptcy in 5% of those studied.135 As
was the most common reason for ineligibility among the authors understatedly conclude, “It seems impera-
white patients, psychosocial issues constituted the most tive that the pretransplant informed consent process
common reason for ineligibility among African Ameri- include an element pertinent to likely out-of-pocket
can patients.134 Regardless of whether a transplant pro- expenses.”
gram uses predictions of posttransplant adherence in
eligibility decisions, information about adherence can be
useful in implementing specific services and interven- Transplanting Foreign Nationals in the
tions to individuals whose previous adherence history United States, Transplant Tourism, and
suggests they might be at risk for nonadherence before
or after transplant.
Payment for Organs
In the 1980s, press reports suggested that wealthy for-
Insurance Coverage for Liver eigners came to large, high-volume transplant centers in
the United States to obtain organs—especially kidneys
Transplantation and livers—outside of normal channels for organ alloca-
Although no discussion of resource allocation in liver tion. In some cases the press alleged that surgeons and
transplantation can ignore payment for this therapy and others accepted valuable gifts to manipulate organ alloca-
the financial burdens of undertaking a transplant for tion systems and in other case reports accused the hospi-
patients and families, we cannot here provide compre- tals of insufficient scrutiny when potential recipients
hensive insight into this issue. In the United States most arrived at the transplant center with “relatives” willing to
private and government insurance programs now cover serve as kidney or liver segment donors. Although the
liver transplantation for the most common indications. media sensationalism petered out, the unpleasant
 29 Ethical Decisions in Transplantation 369

publicity resulted in policy changes in the United States. reported following transplantation of purchased kidneys.…”
A Department of Health and Human Services task force, There are few data to show that the financial compensa-
with help from the American Society of Transplant Sur- tion received by organ donors in developing countries has
geons in 1986 and UNO, in 1988, established guidelines helped improve their lives. It is common knowledge that
to limit and audit transplants into foreign nationals.136,137 donors are underpaid, and that their postoperative medi-
Nevertheless, a 1998 report noted that despite the then cal care is absent or suboptimal.146 In 2010 a kidney
UNOS guidelines “to limit the proportion of foreign transplant center in Saudi Arabia reported their experi-
nationals receiving liver transplants during a calendar ence with 93 patients who traveled abroad to obtain
year to 10%…at several centers the proportion of foreign transplants. They compared outcomes in the “tourist”
nationals transplanted during the study period exceeded group with 72 patients transplanted at their hospital. The
20%.”138 In addition, foreign nationals waiting at some tourist patients had a higher rate of acute rejection in the
centers received organs more rapidly than any other first year, poorer kidney function at 6 and 12 months, and
group. higher rates of cytomegalovirus and hepatitis C infection,
Current OPTN policy, promulgated in June 2005, though the graft and patient survival at 1 and 2 years was
requires transplant centers to use the same organ alloca- not different.147 A 2011 report from Taiwan found a sig-
tion procedures for foreign nationals as those used for nificantly increased rate of posttransplant malignancies in
“domestic candidates.”139 Moreover, the guidelines pro- Taiwanese patients receiving commercial cadaveric kid-
vide for an Ad Hoc International Relations Committee neys in China, compared to those transplanted in Tai-
“to review the activities of each member transplant center wan.148 However, at least one recent Taiwanese study has
where non-resident alien recipients constitute more than suggested much better outcomes for kidney transplants
5% of recipients of any particular type of deceased done in China in the last several years—negating the
organ.”139 Note that there are no guidelines regarding poor-results argument though not addressing the prob-
living donor transplantation. lems associated with the sources of the organs.149
In the 2000s the more controversial international mat- Others note that a regulated system of organ sales
ter concerns “transplant tourism” associated with organ might prevent many of the poorer outcomes and donor
trafficking.140 Although the origins of the term are some- exploitation observed in transplant tourism. A regulated
what obscure, the phrase refers to the practice of trans- system is perceived by some as a promising option given
plant candidates from the developed world traveling to that the developed world has not done enough to increase
developing countries to obtain organs more quickly and the supply of legitimately obtained deceased donor and
less expensively than would be possible if they waited to living donor organs.150,151 Bramstedt and Xu152 in 2007
obtain them at home. This practice raises ethical con- noted that some insurance programs in the United States,
cerns for several reasons. First, the source of organs, at including private and government-sponsored plans,
least in China, appeared in some cases to have been exe- encourage medical tourism, including that for transplan-
cuted prisoners, including political prisoners.141 Second, tation. They concluded that encouraging transplant tour-
despite the lower costs to recipients, relatively large fees ism “exploits living donors and disregards the needs of
went to organ brokers and relatively small sums to the resident patients in the foreign countries.”
desperately poor individuals from whom the organs were In 2008, following several years of discussion and
removed (“vendors”). Lured by the promise of improved debate in the transplant community, an international
financial, social, and other forms of well-being, organ group of 140 experts met in Istanbul, Turkey, for the
sellers are exploited. Despite organ vendors’ best inten- International Summit on Transplant Tourism and Organ
tions, studies have shown that financial remuneration Trafficking, producing the Declaration of Istanbul.153,154
does not improve their livelihood and even exacerbates Built upon the Universal Declaration of Human Rights,155
suffering.142-144 Although it is illegal in most countries, the document declares that “organ trafficking and trans-
the black market in human organs or organ trafficking plant tourism violate the principles of equity, justice and
has been reported throughout the West, East, Middle respect for human dignity and should be prohibited.”154
East, and Africa.144 A 2004 BBC news report referred to It calls for prohibitions on advertising, soliciting, or bro-
a government inquiry in Punjab the year before that esti- kering for/of organs, the establishment of clear laws and
mated approximately 3500 people in the area had sold regulations for evaluating and obtaining consent from
their kidneys in the 1990s.145 Third, the developing world living donors and for the development of transparent and
“donors” suffered medical complications at high rates. fair mechanisms for obtaining and distributing deceased
Fourth, recipients experienced complications at relatively donor organs. Specifically, the declaration admonishes
high rates. And fifth, having returned home with their transplant commercialization because it exploits the
new—and sometimes poorly functioning—organs, they impoverished and ultimately fosters organ trafficking.156
sought the time and resources of their original transplant In addition, the declaration asks for the means to provide
centers, including urgent need for retransplantation care, including long-term care, for the consequences of
related to poor surgical technique or medical care pro- organ donation and for “comprehensive reimbursement”
vided in the developing world hospitals. of donors, including for lost income and out-of-pocket
Much of the documentation of these problems comes expenses the donor may incur as a result of the
from reports about transplant tourist kidney, not liver, donation.154
transplantation. A 2006 report stated: “Unacceptably Although most U.S. transplant professionals support
high recipient mortality and transmission of infections, the goals articulated in the declaration, the American
including HIV and hepatitis, have been consistently Society of Transplant Surgeons (ASTS) noted some
370 PART IV Special Considerations in Patient Evaluation

practical concerns raised by document, especially for any human organ for valuable consideration for use in
those working in the United States.157 The authors human transplantation,” it does not define “valuable con-
pointed out that the United States lacks a unified insur- sideration.”162 The law does permit reasonable payments
ance program, making some of the declaration’s provi- to living donors for expenses relating to: travel, housing,
sion difficult to enforce. They also noted some legal and lost wages in connection with the donation of an
difficulties with developing a system for reimbursement organ.162 Thus policy makers and transplant profession-
or compensation for organ donation in the United States. als generally support promoting policies removing finan-
Finally, they pointed out that some of the praiseworthy cial disincentives of living donation.
provisions of the declaration, such as the importance of Unlike the illegal practices of organ trafficking, several
international standards for organ recovery and transplan- countries have instituted governmentally regulated sys-
tation, lack any mechanism for development or tems of payment for kidney donation. Iran and the
enforcement. Philippines are cases in point. Iran has witnessed no
­
There is little evidence that the Declaration of Istan- reduction in the number of donated kidneys163 but claims
bul has had much impact. Indeed, in October 2011 a let- to have abolished the kidney transplant waiting list by
ter in The Lancet by ethicists and transplant surgeons 1999.164
called for strong public action.158 The authors suggested Yet many poor Iranian patients still wait for deceased
that Chinese clinicians and officials had not yet developed donors.165 Not surprisingly, the recipients are relatively
“an ethical system for recovering organs.” As a result, rich, and those who sell kidneys are poor and do so for
transplant tourism to China can continue, despite a short- quick money or to repay debts.165 With regard to out-
age of organs for the country’s own citizens. The letter comes, Iran has comparable graft survival rates for recipi-
writers also decried the continued use of organs from ents as kidney recipients in nonmarket countries.163,165
executed prisoners. Because of these ethical lapses, the However, commercial living donors’ outcomes are
authors called for an end to “scientific and medical inter- mixed163; such donors remain impoverished,163 and a
change with China concerning transplantation,” includ- quality-of-life study of 300 donors found that the major-
ing a boycott on accepting papers at meetings, publishing ity developed major psychosocial complications follow-
articles in journals, and cooperating with research. ing removal of a kidney.166 In recognition of the ethical
Schiano and Rhodes159 noted that transplant programs shortcomings of the poorly run system,164 some Iranian
in the developed world will face decisions about what to policy makers contend that the regulated system should
do with patients returning from abroad with a new liver. never have begun.167 Although financial disincentives are
As in the world of kidney transplantation, there may be a experienced by all donors—liver or kidney alike—it is
higher incidence of complications in these patients.160 unknown how financial incentives would affect live liver
Although most programs and individuals recognize an donor rates.
ethical obligation to provide emergency care for post- Several U.S. transplant professionals have advocated
tourism transplant patients, many still debate whether for a regulated system of compensation for organ dona-
they should provide ongoing care, including treatment tion.163,168 They imagine such a system would provide
necessary to prevent or treat rejection, dealing with tech- compensation to donors through the federal government
nical complications of the foreign surgery, treatment of or insurance companies. They assert that a regulated sys-
infections acquired while abroad, and so on. Schiano and tem in the United States would help offset financial disin-
Rhodes159 insist that “a transplant center that provides centives to donation and increase the number of available
ongoing care for patients before their transplantation organs by boosting motivation for living donation.
abroad should not deny the patients post-transplantation According to the proposal, UNOS would apply the same
care.” They feel that turning such patients away fails to algorithm for organ allocation as in current use, and the
uphold professionals’ duties of “beneficence and non- donor evaluation and consent processes would remain the
judgmental regard” and that it simply shifts the burden of same. Compensation options would include either fixed
care to others who will accept the patients. As long as sums, a tax deduction, term life insurance, reimburse-
patients feel the need to seek transplantation abroad, ment for travel/work, long-term health insurance, or cash
despite apparent increased risk, developed world profes- payment.
sionals will have to deal with these “tourists” upon their In recent years the debate over the ethical permissibil-
return. Of note, although Schiano is a hepatologist, his ity of a regulated system has reached high levels of inten-
views do not necessarily reflect those of other liver trans- sity, but policy remains at a standstill.156,169,170 Advocates
plant physicians—some prefer not to provide posttrans- contend that a regulated system would provide effective
plant care to those who obtained organs in the developing incentives to increase organ donation rates, thereby
world.161 reducing the size of the waiting list and time to transplan-
tation, thus saving lives.163,168 Many proponents bolster
support for regulated financial incentives by arguing that
Regulated Payment it would support the commercial living donors’ choices to
Western nations have been quick to condemn such prac- sell organs, respecting their autonomy and ownership
tices of organ trafficking. The National Organ Trans- over their bodies.171 Others argue that a regulated system
plantation Act (NOTA) of 1984 in the United States could improve lives of commercial living donors through
makes the buying and selling of human organs illegal.162 increased income.172 Yet others posit that preventing a
Although NOTA states: “It shall be unlawful for any per- regulated organ market is overly paternalistic.173 Propo-
son to knowingly acquire, receive or otherwise transfer nents also claim that donors can still express altruism
 29 Ethical Decisions in Transplantation 371

while also receiving a financial reward.172 Some also claim equitable opportunities to receive an organ, provide rea-
that it is unfair for physicians, organ procurement organi- sonable chances that the recipient and graft will survive,
zations, and transplant centers to receive financial com- and provide a reasonable likelihood that recipients will
pensation for organ donation/transplantation but not consider their quality of life acceptable before and after
living donors.174 Moreover, other advocates claim that transplantation. Ways to maximize posttransplant life-
there would still be a kidney shortage even if all potential years attempt to satisfy concerns about justice (i.e., the fair
deceased donors in the United States donated.175 use of the scarce resource of available organs).
Opponents of organ selling contend that proponents With the growth of liver transplantation in the United
maintain a flawed conception of autonomy by assuming States in the 1980s and 1990s, allocation of livers
that commercial living donors are free from external depended largely on patients’ access to transplant centers,
pressures and can make autonomous choices. In reality, as well as severity of illness and time waiting for an organ.
those opposing any type of organ market say, commercial Expanding indications for liver transplantation during
living donors have no alternative, no “choice” indepen- this time meant increasing death rates for those on wait-
dent of external factors.176 From this perspective, finan- ing lists and growing public concern about the subjective
cial incentives present “undue pressure” to the poor and nature of the allocation process. Congressional and fed-
vulnerable to donate. Others point out that living unre- eral administrative action led UNOS in 2002 to put in
lated kidney donors in Iran lacked knowledge of long- place an evidence-based system that predicted patient
term complications and the need for regular follow-up death using measures of physiological function, the
care.177 Financial incentives are also believed to be unnec- Model for End-Stage Liver Disease (MELD) (Fig. 29-1)
essary because altruism works, although it insufficiently and the Pediatric End-Stage Liver Disease (PELD) liver
promotes donation in the current system.178 Market allocation systems, supplemented by a notion of urgency
opponents also contend that financial incentives weaken (likelihood of death within 7 days). The intent of MELD/
and divest donation of the virtue of generosity by replac- PELD is to allocate livers first to patients with the great-
ing it with goal of financial gain.179 In addition, the idea est likelihood of dying without a transplant, rather than
of paying for human body parts is perceived by some as according priority to waiting list time and subjective clin-
degrading and offensive to the inherent integrity of ical assessments.182,183 Thus the current UNOS policy
human body.178-180 Some are also concerned that dona- allocates deceased donor livers to the patient with the
tion rates will drop because of a backlash against the sys- highest MELD/PELD score within the donor’s OPO.184
tem with a “crowding out” of altruistic donors. Children receive priority for livers from donors under
Although increased educational programs, new legal age 18.183 The scheme also required distribution of
approaches, or financial or other incentives show some organs first through local OPOs, then to the immediate
promise to increase the supply of deceased donor and liv- geographical region (out of 11 national regions), and
ing donor organs, evidence from Iran suggests that such finally to a national list.
efforts will not succeed in other developing world con- This system improved rates of organ placement and
texts. It is unknown how such a regulated system would did not reduce posttransplant survival but came with sev-
unfold in the U.S. context. eral drawbacks. Specifically, this system does not take
into account all important factors, such as intolerable
symptoms (pruritus) not necessarily associated with
ORGAN ALLOCATION AND UNOS short-term risk for death, nor does it account for long-
POLICIES term risks in some patients, such as those with amyloido-
sis, familial hyperlipidemia, and portopulmonary
Any ethically acceptable system for organ allocation must hypertension. As a result, the system in the United States
balance competing definitions of justice (fairness) that gives special priority to some patients with additional
consider medical, sociomedical, social, personal, and qualifying conditions, such as those just noted.
impartial factors.181 For example, the allocation system for Implementation of MELD internationally has been
liver patients has considered providing organs first to those found to be associated with improved outcomes. One
in greatest need of rescue (i.e., those most likely to die U.S. center’s analysis indicated that using MELD to pri-
while awaiting transplantation); it also strives to ensure oritize which patients receive an organ did not

Lowest Highest
priority priority
MELD  15 MELD  15 MELD  15 MELD  15 Status 1 Status 1
within within OPO within within OPO within within OPO
UNOS UNOS UNOS
region region region

*Time on waiting list is only used as a tiebreaker if competing patients have identical
MELD scores.
FIGURE 29-1 n Model for End-Stage Liver Disease (MELD) allocation system. OPO, Organ procurement organization; UNOS, United
Network for Organ Sharing. (Modified from Coombes J, Trotter J. Development of the allocation system for deceased donor liver transplan-
tation. Clin Med Res. 2005;3[2]:87-92.)
372 PART IV Special Considerations in Patient Evaluation

significantly decrease 1-year posttransplant survival.185 The MELD system’s prioritization of patients with
Higher MELD scores were associated with higher total early-stage hepatocellular carcinoma (HCC) also prompts
hospital costs and “higher MELD score recipients were questions about equity in allocation across disease etiolo-
much more likely to need ongoing rehab care once dis- gies.184 Patients with HCC receive priority in the MELD
charged from the initial inpatient hospitalization.”185 A system because their scores tend to be low and would
recent study from Switzerland reviewed their experience result in excessive waiting list time with the possibiltiy of
with the first 100 liver transplant recipients after the metastasis development, which would eliminate them as
institution of MELD allocation, comparing the outcomes candidates for transplant.184 Prioriy for HCC in the
with those in the last 100 cases transplanted before the MELD system resulted in a substantial increase in the
use of MELD.186 Although, as expected, MELD alloca- number of liver transplants performed for HCC, and
tion decreased the mortality for those awaiting transplan- liver transplants for HCC account for 18% to 20% of all
tation, it also resulted in increased posttransplant liver transplants performed in the United States.190 Yet
morbidity (chiefly kidney failure) and substantially some argue that HCC candidates receive excess priority
increased the costs. These studies illustrate the practical, in which they have a better chance to receive a transplant
as well as moral, tradeoffs generated by any allocation than individuals with non-HCC disease.191 Thus,
system. although a lack of prioritization would result in inequity
Thus all approaches to allocation, even those using in allocation for individuals with HCC, the possibility
mathematical calculations with objective measurements of exists that prioritization may also result in inequity in
organ function, depend on the assumptions used to con- allocation for non-HCC candidates. The poorer survival
struct the formula. For example, in discussing ways to outcomes in HCC recipients when compared to non-
improve allocation policies, Dawwas and Gimson88 in HCC recipients192 also highlight questions about utility
2009 mentioned survival benefit models and noted a study in the context of HCC prioritization. Ongoing debate
by Merion et al186a that found, among other things, “no will likely continue as policies related to prioritization in
absolute MELD score was associated with transplant allocation are reviewed and refined.
futility (>50% mortality).”88 This definition of futility Although rare, intraoperative death of the liver trans-
contrasts sharply with another definition widely used in plant recipient before transplantation of the graft can
the bioethics literature, which depends on whether a ther- result in an “orphan graft” that can no longer be trans-
apy has “less than a 1% chance of success.”187 No objec- planted into the intended recipient. In the case of
tive criteria allow one to choose where to set the “right” deceased donor livers, UNOS policy dictates that the
measure of futility between l% and 50%. Similarly, no orphan graft be returned to the OPO for reallocation.193
universally accepted moral system specifies the superiority However, UNOS policy provides no guidelines for allo-
of maximizing posttransplantation life-years versus maxi- cating orphan grafts from living donors.193 Living donor
mizing the number of desperately ill individuals with liver orphan grafts differ from deceased donor orphan grafts
failure one attempts to rescue with transplantation, recog- because they are a directed donation, in which the donor
nizing many in the latter category may not survive long specifies who will receive the liver. Inherent in donors’
term. No algorithms will resolve the ethical tensions decisions is the assessment of whether the potential ben-
between attempting to provide individual benefit to sick efits associated with helping a loved one outweigh the
patients and attempting to achieve statistical utility within risks of donation. When the intended recipient can no
the population of those with end-stage liver disease. longer receive the living donor liver, the donor may no
Proponents of the MELD/PELD system assert that longer derive the benefits of helping a loved one.194 Sev-
priority allocation to the sickest first improves equity in eral ethically complex decisions emerge in this situation,
allocation. However, transplanting the sickest patients as depicted in Figure 29-1. Consensus among transplant
first may also lead to poorer outcomes, greater need for surgeons supports the reallocation of the graft.195,196
retransplantation, and subsequently fewer livers for dis- General consensus also asserts that informed consent be
tribution.182 This raises the question of whether the obtained from the donor or the donor’s family,195,196 with
MELD/PELD system’s underemphasis of utility might the suggestion that a contingency plan be discussed dur-
negatively affect equity. The imposition of upper and ing the donor evaluation process.196 Finally, ethical ques-
lower MELD/PELD score limits instills a degree of util- tions related to justice versus utility characterize the
ity in the system by eliminating priority in allocation to debate about whether an orphan graft should be given to
patients least likely to have a survival benefit.182 How- the OPO for allocation or whether it should be allocated
ever, several ethical questions remain to be addressed. within the transplant center of origin.194,195 Others argue
First, geographical variation continues to pose a chal- that since the initial donation was a directed donation,
lenge to allocation equity. Evidence demonstrates that the donor or donor’s family should be able to stipulate
smaller OPOs offer transplants to patients with less dis- donor criteria for reallocation.196
ease severity than those in larger OPOs.188 Findings also
reveal geographical variation in PELD scores at the time Expanded or Extended Criteria Donor and
of allocation.189 Challengers argue that deceased donor
livers should be considered a national, not a regional
Increased-Risk Donor Livers
resource, and that the allocation system should be revised To increase the organ supply, some transplant centers
to address the geographial inequities.182 Although such a use extended criteria donor (ECD) or “marginal” livers.
position may enhance equity, it also raises questions Although varying definitions exist, marginal livers gener-
about utility in liver allocation. ally meet relaxed standards in the risks presented to
 29 Ethical Decisions in Transplantation 373

recipients in terms of impaired donor allograft func- Disparities in Access to and Outcomes of
tion.197-199 Based on evidence of increases in recipient
risk, organs that meet marginal criteria include those over
Liver Transplantation
age 60 years, cold ischemia time over 12 hours, hyperna- Because bias in transplant candidate selection appears
tremia, donor hepatic steatosis, split livers, and DCD liv- unavoidable, it is no surprise that social disparities appear
ers, among other factors.197 Generally ECD organs fall in the distribution of liver transplants. Disparities exist
along a continuum of donor quality, rather than simply with respect to geography, race/ethnicity, and gender.
representing a “good” or “bad” organ.198 The advent and Geographical disparities in access to liver transplants
validation of the donor risk index (comparable to the have garnered considerable attention over the past
recipient risk score—MELD) that uses donor and recipi- decade.188,210 The current system allocates organs to
ent variables enables the prediction of outcomes, includ- the sickest patients (MELD of 15 or more) at the local
ing outcomes in transplants using ECD organs.200,201 level, then to the sickest in the surrounding region. If
Another relevant category of organs, which some no eligible patients are found, then livers are allocated
include as marginal but can also be construed as a sepa- to a patient who is not as sick within the region. A major
rate group, is increased-risk donor livers (often referred logistical issue involves the desire to minimize cold
to as CDC high-risk donors). According to the OPTN, ischemic time, thus limiting the distribution (transport)
increased-risk donor livers are livers that have “factors of livers nationally. Because sick patients do not live
associated with increased risk for disease transmission, evenly distributed around the country, the waiting
including blood borne pathogens HIV, Hepatitis B, and times vary from region to region. Thus when Steve
Hepatitis C, if the donor meets the criteria set forth in Jobs, the CEO of Apple computers, traveled to Ten-
the current US Public Health Service (PHS) guid- nessee in 2009 to obtain a liver transplant, his waiting
ance.”202 Increased-risk donors refer to deceased donors time was much shorter than would have been the case
who engaged in risk behaviors associated with an had he stayed in California.211 Although UNOS and
increased risk for disease transmission. transplant centers do not prohibit patients from being
About 9% of all U.S. donor organs (approximately listed at multiple transplant centers, not all patients
2580 organs per year) are from increased-risk donors.203 have the means to travel to or live in another city.
There is significant regional variability (2.3% to 26.1%) There has been public and professional uproar at the
in their use.204-206 A host of factors likely influence trans- geographical inequities in the allocation system,
plant centers’ willingness to use such organs, such as ethi- prompting the Institute of Medicine in 1999 to call for
cal concerns about incurring potential harm to patients “allocation [to] be based on common medical criteria
in light of broader considerations of patient waiting time, and not accidents of geography.”212 The regulatory
transplant center volume, surgeon’s/physician’s philo- Final Rule that emerged in 1998 required greater parity
sophical stance toward marginal organs, and center statis- among OPOs in organ allocation, leading to a more
tics and Centers for Medicare & Medicaid Services standardized approach to assessing disease severity via
(CMS) certification.207 Patients must provide consent to MELD.184 Yet geographical disparities remain, with
accept marginal organs and specific informed consent for patients in smaller regions receiving liver transplants at
increased-risk organs. lower disease severity levels than patients in larger
Therefore the organ distribution system uses a differ- regions.213 Despite the outcry, little has been done to
ent allocation system for ECD and increased-risk livers ameliorate the situation.184
from the system used for standard-risk organs. Instead of Before MELD, African Americans received liver
distribution according to the waiting list priority system, transplants at a disproportionately lower rate compared
patients are asked on a case-by-case basis whether they to whites.214 In an analysis of minority liver transplant
are willing to receive an ECD or increased-risk organ. recipients from 1999 to 2008, Fan et al215 found that
Thus transplant surgeons/physicians undertake a deliber- whites were transplanted at a rate in proportion to their
ate process of matching ECD or increased-risk organs representation on the waiting list. However, African
with specific patients based on the patient’s clinical con- Americans and Asians were transplanted at a dispropor-
dition and treatment preferences. The rationale for using tionately greater rate than their representation on the
ECD or increased-risk donor livers is that the benefits of waiting list. Compared to those for whites and Hispanics/
early transplantation, albeit with increased risk for acquir- Latinos, liver transplantation rates are increasing for
ing an infection or having poorer organ function, out- African Americans and Asians. Yet Hispanics/Latinos
weigh the risks of waiting for an optimal liver. The 2008 received liver transplants at a decreasing rate between
case of simultaneous HIV and HCV transmission from a 2000 and 2008 in relation to their proportion on the wait-
deceased donor to a liver recipient during the “window ing list. Fan et al215 did not adjust these results for patient
period” when typical testing did not reveal the infections characteristics, including MELD scores. However,
generated a call for improved nucleic acid testing, the Mathur et al216 sought to control for geographical and
reconsideration of using increased-risk donor organs, and MELD score differences and found that although African
improvement in patients’ informed consent.208 Nonethe- Americans did not significantly differ from whites with
less, there appears to be growing interest in providing comparable characteristics in deceased donor liver
HIV-positive or HCV-positive liver grafts, given promis- ­transplant rates, subgroups of Hispanic and Asian candi-
ing outcomes, to the increasing number of HIV-positive dates experienced disparities in access to liver transplan-
or HCV-positive liver transplant candidates,198 albeit tation. Thus MELD appears to have been partially
there is much coinfection with these viruses.209 effective in reducing inequities in deceased donor liver
374 PART IV Special Considerations in Patient Evaluation

transplantation.216,217 Similarly, Volk et al218 found that conduct trials of liver cell infusions have to compete for
geographical variation contributed to ethnic/racial the substrate with surgeons using the livers for solid
disparities. organ transplantation. To date, attempts to establish
Inequities also persist in the receipt of LDLTs. The embryonic cell lines grown in laboratories have not suc-
majority of LDLTs in 2011 in the United States went to ceeded, and animal liver cell sources continue to pose
whites (190 [78%]), while the remainder went to Hispan- serious immunological and potentially problematic infec-
ics (30 [12%]), African Americans (15 [6%]), and Asians tion risks, even if they could produce all of the needed
(9 [4%]).219 human proteins.227
Disparities also persist in liver transplant graft and Gene therapy and bioengineered artificial livers have
patient survival rates. Fan et al215 observed that Asian and also not yet progressed to clinical usefulness. Gene ther-
Hispanic/Latino liver transplant recipients had superior apy could have the major advantage of avoiding the need
graft and patient outcomes across 1-, 5-, and 10-year time for immunosuppression; however, as with hepatocyte
frames. For example, in 2010 1- and 5-year graft survival infusions, many efforts in the field have not produced
was 85% and 66%, respectively, for Asians, and 82% and lasting clinical effects.225 Two different extracorporeal
64% for Hispanics, whereas the rates were 82% and 66% dialyzing approaches to removing toxins (molecular
for whites and 79% and 58% for African Americans.215 adsorbent recirculating system, or MARS, and the Pro-
Similarly, Asians and Hispanics had higher 1-year patient metheus system) have had some clinical benefit for some
survival rates at 88% and 87%, respectively, whereas acute liver failure patients. However, the systems cannot
whites and African Americans had rates of 87% and 84%, replicate the metabolic/synthetic functions of healthy
respectively.220 Fan et al found that African Americans liver cells and therefore have limited utility.228 A number
and Asians have increasing access whereas Hispanics/ of bioartificial systems have been used, some in random-
Latinos have decreasing access to liver transplants. These ized clinical trials in acute liver failure. The devices
disparities may reflect a different distribution of liver dis- appear to have some value, especially as a bridge to trans-
eases across ethnic/minority groups or differential listing plantation, although a significant survival benefit has not
practices. yet been demonstrated.228,229
With regard to sex, more men than women consis- Although transplanters have established the clinical
tently received liver transplants from 2000 to 2011. In utility of liver transplantation in many situations, this
2011, 4121 (65%) men, and 2220 (35%) women received form of therapy must demonstrate not only the ability
a liver transplant.221 In an analysis of Scientific Registry to extend lives with adequate quality of life, but also the
of Transplant Recipients data (n = 78,998) consisting of means to do so in ways individuals and society can
adult candidates listed before or after implementation of afford. Liver transplantation is expensive, and although
MELD, females had significantly lower covariate- the expense creates pressure to reduce costs and
adjusted transplant rates in the pre-MELD era (by 9%; improve efficiency, many countervailing factors influ-
P < .0001) and in the MELD era (by 14%; P < .0001).222 ence use of the technology. As surgical and immuno-
Sex-based disparity in liver transplant rates in the MELD suppression techniques improve, the indications for
era was exacerbated in some regions of the United States, using transplantation increase. As large programs suc-
which have witnessed more than a 30% lower covariate- ceed, demand for the s­ervices also increases, and the
adjusted transplant rate for females compared to males.222 trainees and rising stars from the most successful pro-
The factors contributing to these sex disparities remain grams spread to new or expanding programs. Although
unclear. that means people may travel shorter distances to
transplant centers, it also means the limited supply of
Resources and the Future of organs must go to a larger number of transplant cen-
ters, reducing some of the efficiencies—and opportuni-
Liver Transplantation ties to engage in coherent research to improve
For over a decade, those who treat patients with liver fail- outcomes—associated with high surgical volumes.
­
ure have dreamed about alternative approaches to ortho- These forces have been affecting transplantation for
topic solid organ transplantation. These possible many years.230
technologies have included transplantation of liver cells One effect of the drive to balance access, clinical effec-
into the native liver’s “scaffold” via catheter, insertion of tiveness, and economic efficiency has been the demand
missing genes or normal genes (into patients with muta- for programs to demonstrate adequate results using
tions), xenotransplantation, or use of artificial organs. objective outcome measures. In 2007 CMS published
Human liver cell transplantation was first reported in participation conditions for programs receiving Medicare
1992.223 The approach seems attractive in acute liver fail- funding for transplant services. In practical terms, statis-
ure because in theory it could reduce major surgery by tical deviation from the expected patient safety perfor-
delivering new cells to repopulate the dying liver. In addi- mance (e.g., patient deaths or graft failure) could result in
tion, several groups have used the technique experimen- a transplant center’s decertification from the Medicare
tally for partial replacement of the native liver’s missing program.231 A commentary from the ASTS noted that
functions, chiefly in children with metabolic disease.224-226 such a system depended on the assumptions used in the
The function of the transplanted cells has been transient, statistical analysis and might not employ an adequate
presumably because the new cells die because of apopto- risk-adjustment formula, among other problems.231 As a
sis and host rejection. Moreover, unless science can result of the CMS proposal, ASTS worried that some
develop new sources of liver cells, those wishing to programs would change their practices in ways that would
 29 Ethical Decisions in Transplantation 375

protect the center but not necessarily benefit patients transplant centers should provide posttransplant care
(e.g., offer less access to liver transplantation for patients for those who have obtained organs via transplant
at high risk for death without a transplant). In addition, tourism, and so on.
the CMS system could mean programs might have less These thorny issues require sustained and sometimes
tolerance for undertaking innovative approaches and uncomfortable discussions and negotiations with patients,
experimental protocols aimed at improving outcomes.231 live donors, family members, clinical colleagues, organ
This demonstrates the tension between a focus on estab- procurement personnel, and policy makers, among oth-
lishing and maintaining standards and a desire and need ers. Disputes about these matters can generate consider-
to accept risks in the hopes of developing new and able distress, including anger, guilt, and regret. Clinicians
improved standards. may find it useful to avail themselves of institutional
Given an intense push in early 2012 (the time of writ- mechanisms for addressing these problems, such as ethics
ing of this chapter) to reduce at least the escalating growth consultants and/or ethics committees. In each case those
in health care expenditures in the United States, one can- caught up in disagreements should try to listen carefully
not begin to predict what further efforts public agencies, and see the issue from the perspective of those with dif-
such as the CMS, and private insurers may initiate to con- ferent points of view. Most of the time the disputants
trol spending on liver transplantation. On the one hand, share a desire for a peaceful resolution in which each
efforts, such as the Affordable Care Act of 2010, to party feels heard, respected, and in some way understood.
improve access to primary care could eventually reduce Sometimes it helps to remember that disagreements
morbidity associated with many chronic conditions, about ethics cannot be settled by appeals to empirical
including such entities as ALD. In the shorter term, science.
before prevention can work, increased access to care
could also improve access to subspecialty care for those
Acknowledgments
with advancing chronic liver disease, which in turn might
increase evaluation for transplantation and further This research was conducted with support by the
increase the demand for livers, with an expected increase Chicago Transplant Ethics Consortium through the
­
in mortality for those awaiting organs.232 On the other Comprehensive Transplant Center at Northwestern
hand, cost-control efforts might increase the pressure to University. This work was supported in part by Health
stop listing entire groups of patients with the highest risk Resources and Services Administration contract 234-
for posttransplant morbidity and mortality.233 The popu- 2005-370011C. The content is the responsibility of the
lation of the United States has frequently rejected the lat- authors alone and does not necessarily reflect the views
ter kind of health care rationing, but the enormous overall or policies of the Department of Health and Human
costs of medical care could change the political and moral Services, nor does mention of trade names, commercial
equations. products, or organizations imply endorsement by the
U.S. government.

CONCLUSIONS
Ethical controversies in liver transplantation, like most
ethical issues in medicine, do not often lend themselves Pearls and Pitfalls
to resolution by the development of new scientific evi- • Greater coverage of immunosuppressants is provided in
dence. Although good moral reasoning requires rigor- the Affordable Care Act of 2010.
ous logic and frequently depends upon facts, ethical • Recent availability of data on living donor long-term
disputes can involve clashes over matters of faith/belief outcomes may increase support for living donation.
and cultural attitudes or worldviews. This chapter has • Greater attention to outcomes data and ­ cost-benefit
touched on many of the ethical issues and decisions in analyses could increase or decrease priorities for
the clinical arena of liver transplantation over the 30 or recipient subpopulations (e.g., decrease likelihood of
­
more years of practice. It seems likely that a better transplant for those with malignant liver tumors or al-
cohol-associated liver disease, increase priority for those
understanding of pathophysiology of neuronal death
with congenital disorders).
will contribute to the debate about how long after cir- • The spread of international transplant programs will in-
culatory arrest one needs to wait before starting to crease pressure on U.S. programs to increase quality and
remove solid organs. However, science will not tell us decrease costs.
whether former patients are “dead enough” for organ • Recent findings suggest that outcomes for older liver
retrieval following the permanent loss of cortical brain recipients are better than previously thought, leading
function. Similarly, neither legislation nor official pol- to greater acceptability of liver transplant in aging indi-
icy will fully settle the problem of organ donation, viduals.
complete with adequate documentation of the deceased, • Recent liver donor deaths have given transplant centers
when surviving family members object. Nor can we use pause in promoting living donation.
• Disparities in liver transplantation continue or are on
randomized controlled trials to determine (1) how
the rise.
many, if any, repeat transplants are justifiable; (2) • Rationing of health care may increase pressure to
whether, or how, to require that those with alcohol- ­consolidate liver transplantation in “centers of excel-
related liver disease prove that they have overcome lence.”
their substance use; (3) when, if ever, developed-world
376 PART IV Special Considerations in Patient Evaluation

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 CHAPTER 30

Psychiatric Assessment of
Liver Transplant Candidates
Elisa A. Moreno • Sheila Jowsey • Tara McCoy

CHAPTER OUTLINE

THE ROLE OF THE TRANSPLANT PSYCHIATRIST Methadone Maintenance

Liver Transplant Outcomes in Patients on
SPECIAL ISSUES
Methadone Maintenance
Adapting to the Waiting Period
Methadone Maintenance and Psychiatric
Mood Disorders Morbidity
Alcohol Abuse Obesity
Tobacco Obesity and Psychiatric Morbidity
Smoking and Psychiatric Morbidity Food Addiction
Smoking Increases Morbidity in Liver Bariatric Surgery
Transplant Recipients
Living Donor Liver Transplantation
Smoking Exacerbates and Accelerates
Ethical Considerations
Liver Disease
The Living Donor Liver Transplant Psychiatric
Alcohol Use Disorders in Smokers
Evaluation
Smoking as a Contraindication to
Cancer
Transplantation
The Elderly Patient
Marijuana
Considerations in the Liver Transplant
Personality Disorders
Candidate With Hepatitis C
Schizophrenia
Psychiatric Morbidity in Hepatitis C
Special Considerations in the Transplant
Cognitive Impairment in Hepatitis C
Patient With Schizophrenia
Neuropsychiatric Side Effects of Interferon
Ethical and Legal Issues
Treatment
Acetaminophen Toxicity and Acute Liver
Considerations in the Liver Transplant
Failure
Candidate With Human Immunodeficiency
Psychiatric Morbidity and Acetaminophen Virus Infection
Toxicity
Psychiatric Morbidity in Human
Intentional Overdose Immunodeficiency Virus Infection
Unintentional Overdose Neurocognitive Impairment in Human
Ethical Issues in Acetaminophen Immunodeficiency Virus Infection
Overdose Criminality
Chronic Pain and Opioid Abuse in Liver Mental Retardation
Transplant Candidates
Nonadherence
Chronic Pain Syndromes
Mindfulness and Other Innovative
Psychosocial Support Mechanisms

The psychiatric assessment of the transplant candidate is successfully navigate the complexities of transplanta-
a critical component of the transplant evaluation pro- tion.1-5 The second goal is to make recommendations to
cess.1 There is a relatively high degree of psychiatric mitigate these risks.1,2,4 The transplant evaluation is opti-
morbidity in patients being considered for organ trans- mally accomplished by a multidisciplinary team.1,2 Team
plantation.1 However, active psychiatric illness is a modi- members include psychologists, who perform neuropsy-
fiable risk factor.2 The first goal of the psychiatric chiatric testing and can provide counseling for the patient
assessment is to determine the risk for psychiatric com- and family. Social workers assess social support, identify
plications that may compromise a patient’s ability to caregivers, and assist with financial and insurance needs.

381
382 PART IV Special Considerations in Patient Evaluation

Psychiatric Risk Assessment

Psychiatric diathesis Alcohol/substance use Nonadherence Cognitive impairment

Active symptoms Close psychiatric f/u Longstanding use No regular medical Tx Impaired on basic testing
Refractory to treatment well-controlled sx multiple attempts at abstinence self-discontinuing meds altered mental status
Multiple suicide attempts strong social support recidivism poor dental care
Never treated psychiatrically stable ongoing use despite lost to follow-up
Long standing history consequences
Recent use

Higher risk Lower risk Higher risk Higher risk Higher risk

Recommendations Recommendations Recommendations Recommendations Recommendations

Psychiatric tx Ongoing tx 12 step program Extensive education for Treat active delirium
Demonstrated stability inpt v. outpt rehab pt/family baseline brain imaging
Random urine tox screens Close monitoring neuropsychiatric testing
Tx with addictions psychiatrist for adherence -cognitive functioning
-rule out dementia
Psychiatric re-evaluation
FIGURE 30-1 n Psychiatric risk assessment.

A chaplain can provide emotional support to patients and

families. Chemical dependency specialists can help with TABLE 30-1 Transplantation Psychiatric
recommendations regarding substance abuse issues. Interview
Transplant coordinators who have frequent contact with Patient’s reaction to end-stage disease
the patients and families can also offer important collat- Knowledge about transplantation
eral history to the psychiatrist about the patient’s ability History of compliance
to interact effectively with the transplant team. The role Acceptance of posttransplant medical regimen, including
of the transplant psychiatrist is to evaluate the patient need for daily immunosuppressives, and medical
with a view to diagnosis of psychiatric disorders, includ- follow-up
ing substance abuse and neurocognitive impairment; to Family reaction to health
assess coping skills and adherence history; and to make Psychiatric review of systems
treatment recommendations that can improve the Past psychiatric history
patient’s chance of a good medical outcome. Family psychiatric history
Transplant teams are often confronted with ethical Alcohol use history
issues surrounding the allocation of organs because they Illicit substance history
are a scarce resource. They must balance doing what is Prescription drug use history
best for the patient with what is best for all patients who Nicotine use history
need transplants.1 Psychiatric risk assessment is complex Developmental history
and multidimensional and demands a comprehensive Mental status examination
approach (Fig. 30-1). It is best accomplished by a dedi-
cated transplant psychiatrist4,6 who works closely with
the transplant team and is familiar with the gamut of pre- abuse, including drugs and alcohol as well as prescribed
transplant and posttransplant medical, surgical, and psy- opioid medications, is common in patients presenting for
chiatric issues in this special population. liver transplantation. Pain disorders are among the many
medical conditions common in this population as well.
Cognitive impairment due to hepatic encephalopathy
THE ROLE OF THE TRANSPLANT complicates the assessment of the patient presenting for
PSYCHIATRIST liver transplantation. A family history of psychiatric disor-
ders increases the patient’s risk for a psychiatric disorder.
The transplant psychiatrist conducts an extensive clinical A history of nonadherence with medical recommenda-
psychiatric interview (Table 30-1) that encompasses past tions alerts the psychiatrist to the potential for future non-
and present psychiatric history, including outpatient psy- adherence. Maladaptive coping skills are also a risk factor
chiatric treatment, inpatient psychiatric hospitalizations, for a poor medical outcome (Table 30-2).
suicidality, symptomatology, pharmacotherapy, and coun- When the transplant psychiatrist elicits history
seling. A history of depressive disorders, anxiety disorders, that warrants further investigation, such as psychiatric
including posttraumatic stress disorder, and substance diagnostic clarification or neurocognitive assessment, a
 30 Psychiatric Assessment of Liver Transplant Candidates 383

can affect cognition and behavior. Depression is also not

TABLE 30-2 Behavioral Checklist
uncommon. Patients may have fears of death and worry
Noncompliance with follow-up appointments about family members and impending surgery. Patients
Limited support system will often struggle to continue working despite increasing
Family conflict problems with concentration and fatigue. Moreover, fear
Expressed hostility to transplant team of losing insurance coverage can cause distress. Spouses
Idealizing or devaluing members of the transplant team will often need to maintain insurance coverage if their
Expectation of “special treatment” (e.g., rescheduling insurance is the primary one for the patient. This may
appointments repeatedly for insignificant reasons) make it difficult for spouses to accompany patients to
Excessive concern with physical appearance appointments. Some studies report that spouses can expe-
Rigid expectations regarding patient education, medical rience even higher levels of stress than patients do, both
information (e.g., repeated requests for detailed before and after transplant.14 The spouse and other family
information despite reasonable efforts at education) members may benefit from meeting with the transplant
Indifference to medical teaching/instructions team and participating in support groups. Many transplant
Contradictory history provided to different members of the centers offer support groups for patients and their families,
transplant team
to provide information and foster development of skills to
Engaging in high-risk behavior (altercations with police,
little cope with the challenges of the transplant process. Topics
concern about personal safety) discussed include medication, side effects, the healing pro-
Switching transplant centers for unclear reasons cess, and financial issues.15 Patient education may be
Marked ambivalence about transplantation impeded by language barriers, learning disabilities, or
encephalopathy. In these circumstances an interpreter is
recommended. Patients are more likely to remember if
they understand the information and are more likely to be
neuropsychiatric evaluation with psychometric testing adherent if their preferences are considered.16 The doctor-
tools is recommended. Identification of maladaptive per- patient relationship is also an important factor in commu-
sonality traits, occult psychiatric symptoms, and degree nicating information to patients.17
of cognitive impairment can guide further recommenda-
tions. However, these types of assessments are not suffi- Mood Disorders
cient for diagnosis and should be used to complement the
clinical medical evaluation performed by the transplant Mood disorders occur frequently in patients awaiting
psychiatrist. Transplant-specific scales have been created transplantation, and 47% of patients have been reported
to help assist transplant teams in identifying areas of con- to experience depressive symptoms, which were associ-
cern. The Transplant Evaluation Rating Scale7and the ated with a history of alcohol abuse, interpersonal sensi-
Psychosocial Assessment of Candidates for Transplant tivity, and being single.18The presence of depression
scale8 rate the patients on family support and availability, before transplantation may not predict posttransplanta-
past psychiatric history, coping, substance use, adherence tion nonadherence19 but warrants attention because of
history, and knowledge about transplantation. However, the detrimental effects on QOL and ability to manage
the predictive validity of these scales is unclear.8 complex medical regimens. Typically patients experienc-
Historically there has been variability across trans- ing symptoms of depression (which may include reports
plant centers,5 as well as between heart, liver, and kidney of irritability) can be started on low doses of serotonin
programs,9 regarding certain psychiatric selection crite- reuptake inhibitors and gradually titrated upward to
ria. Mental retardation,10 active schizophrenia,11 crimi- address mood symptoms in the pretransplant period.
nality, and methadone maintenance therapy1 have been Although concerns about increased gastrointestinal
and continue to be exclusion criteria in some cases. How- bleeding have been reported, no consensus exists on this
ever, with the advancement of medical knowledge and risk because of conflicting reports about the frequency of
improved treatment options for patients, as well as the this occurrence.20
ethical imperative to consider each case on an individual Following transplantation, depression occurs rela-
basis, the boundaries of what is considered acceptable risk tively frequently and has been reported to occur in up to
are being propelled to new frontiers. 33% to 63% of patients.21,22 It has been reported to
adversely affect QOL23and increase mortality.24,25
Another study reported that pretransplantation depres-
sion predicted posttransplantation depression but not
SPECIAL ISSUES graft rejection, graft failure, infection, or increased
mortality.26Patients with hepatitis C are more likely to
Adapting to the Waiting Period report depression symptoms following transplantation.27
The stress of the waiting period with the associated physi- Antidepressants are well tolerated following transplanta-
cal symptoms that impair quality of life (QOL) can be dif- tion, and citalopram, sertraline, and venlafaxine can be
ficult for the patient. Muscle cramps and pruritus have used at typical dosage ranges if patients have returned to
been found to impair QOL significantly, as have encepha- good hepatic function and generally have few interac-
lopathy, sleep disorders, and refractory ascites.12 Sleep dis- tions with immunosuppressive medications. Mirtazapine
orders of clinical significance occur in approximately 50% be can be a helpful medication for patients with weight
of cirrhotic patients.13 Minimal hepatic encephalopathy loss and poor sleep because of appetite stimulating and
384 PART IV Special Considerations in Patient Evaluation

sedating side effects. Mirtazapine is partially renally

TABLE 30-3 R
 isks for Relapse in Alcoholic Liver
excreted, so dosage may need to be adjusted for patients
Transplantation Patients
with decreased renal function. Debilitated patients may
be undergoing treatment for hepatitis C with interferon Polydrug dependence
(IFN)-α, which is associated with fatigue, cognitive diffi- Lack of stable social support
culties, neurovegetative symptoms, and suicidal ideation, Lack of insight about diagnosis
and may do well with mirtazapine, although they should Personality disorder
be monitored for blood dyscrasias.20 Past inability to maintain abstinence (previous failed
Anxiety has been reported in up to 19% of pretrans- treatment attempts)
plant patients. Patients with autoimmune conditions or Spouse/partner continues to use alcohol/substances
those who were unemployed reported anxiety more fre-
quently and alcoholic patients less frequently.28 Caregiv-
ers of cirrhotic patients reported higher rates of anxiety Risks for relapse include abstinence less than 3 months,
compared to the cirrhotic patients.29 Patients with fulmi- nonacceptance of the diagnosis of alcoholism,37 alcohol
nant hepatic failure tended to report higher rates of post- dependence diagnosis versus abuse diagnosis, family his-
transplantation anxiety.30 Following transplant, patients tory of alcohol dependence, and use of other substances38
with anxiety reported greater depression, financial prob- (Table 30-3). Relapse rates as high as 90% have been
lems, and negative social and emotional functioning. reported, but in detailed, prospective research different
Patients with hepatitis C reported higher degrees of anxi- trajectories of alcohol use have been noted, with 54% hav-
ety.31,32 Psychosocial stress may affect progression of hep- ing no use and of those who resumed drinking, the major-
atitis C because of effects on tumor necrosis factor, ity drank at low levels on occasion.38 The researchers
interleukin (IL)-1 and IL-6.33 Following transplantation, noted that others had patterns of moderate use that dimin-
patients usually can be managed with serotonin reuptake ished over time, later-onset moderate use that increased
inhibitors for persistent anxiety and brief exposure to ben- over time, and early-onset, heavy use that increased.
zodiazepines. Before transplantation, benzodiazepines Higher mortality was noted in the moderate and heavy
can exacerbate symptoms of hepatic encephalopathy. relapsing groups.
Patients with bipolar disorder have been transplanted The role of treatment for patients has been studied,
and may do well if they have had long-standing stability and patients randomly assigned to motivation enhance-
and careful monitoring is available for detection of active ment treatment versus treatment as usual had lower
symptoms of mood instability. Lithium is primarily rates of relapse while on the waiting list, and surpris-
renally excreted and can be used in end-stage liver dis- ingly 25% of the subjects relapsed after randomization
ease, but monitoring of the patient's fluid status is impor- in the study while on the waiting list.39 Most centers
tant because of the risk for toxic levels with volume recommend either attendance at Alcoholics Anony-
depletion. Ongoing assessment following transplantation mous, participation in counseling, or formal treatment
is important because of the risk for manic symptoms in an addictions treatment program, but no standard
emerging while the patient is on higher-dose steroids fol- exists for all centers. In 1997 a consensus conference of
lowing transplant. Psychiatric consultation to assist in the American Association for the Study of Liver Dis-
management of these patients is recommended. eases and the American Society of Transplantation rec-
Patients benefit from nonpharmacological strategies ommended abstinence from alcohol of at least 6 months,
such as support groups to help cope with the fear of the but this is not supported by research that would suggest
unknown, to share common experiences, and to enhance that this length of time is a significant cutoff point pre-
problem-solving strategies. Encouraging exercise, main- dicting abstinence.34
taining social connections, ongoing participation in spiri- In the past, patients with serious alcoholic hepatitis
tual activities, and encouraging an optimistic framework with no response to medical therapy were not consid-
may help decrease the risk for emerging psychiatric ered for transplantation. However, a multicenter study
symptoms in the setting of medical illness. Herbal reme- investigating the role of transplantation for severe alco-
dies should be avoided because of the possible adverse holic hepatitis suggested that patients with strong fam-
effects on the liver. ily support who made a commitment to abstinence and
had no other severe coexisting conditions had better
survival than those who were not transplanted (77%
Alcohol Abuse versus 23%).40
Alcoholic cirrhosis is the second most common diagno-
sis for patients receiving liver transplantation and
accounts for 20% of all liver transplants that were per-
Tobacco
formed between 1988 and 2009.34 Patients transplanted Patients evaluated for liver transplantation have a higher
for alcoholic liver disease have reasonable QOL follow- lifetime history of tobacco use than the general popula-
ing transplantation,34,35 although some reports of tion.41-43 A substantial number of patients evaluated for
decreased physical QOL have been reported with transplantation are active smokers.44 Obtaining a tobacco
increased reports of pain and physical deficits.36 Survival use history is critical for two reasons. First, nicotine
following liver transplantation is comparable to patients dependence has been found to be highly comorbid with
with nonalcoholic liver disease and better than patients other psychiatric disorders45-48 and can herald other areas
with hepatitis C.34,37 of psychiatric history that require deeper exploration.
 30 Psychiatric Assessment of Liver Transplant Candidates 385

Second, studies have demonstrated that smoking is a sig- liver disease,78 and chronic hepatitis C.70,79-81 One study
nificant cause of increased morbidity and mortality in demonstrated a clear hepatotoxic effect on the severity of
liver transplant patients.49,50 histological activity in patients with chronic hepatitis C,
particularly in patients smoking more than 15 cigarettes
per day.82 Moreover, smoking is associated with the
Smoking and Psychiatric Morbidity
development of hepatocellular carcinoma.70,76,79,83-87
Tobacco use is highly comorbid with psychiatric disor- There is also an increased risk for hepatocellular carci-
ders.48,51-53 In a representative U.S. sample, individuals noma in patients with viral hepatitis and simultaneous
who had a lifetime history of two or more psychiatric exposure to alcohol and tobacco, suggesting syner-
diagnoses had higher rates of smoking and smoked more gism.84,88 Recent evidence also indicates that smoking
cigarettes per day.48,52 Heavier smoking may be an indica- increases the risk for recurrent viral hepatitis after liver
tion of nicotine dependence. Nicotine dependence, transplantation.89
defined as an addiction to nicotine,47 is associated with
other axis I psychiatric disorders, including substance use Alcohol Use Disorders in Smokers
disorders.46 Nicotine-dependent individuals have higher
rates of alcohol, marijuana, and cocaine dependence.45 Approximately 90% of patients with alcohol abuse also
Nicotine dependence is also associated with depression smoke tobacco.62,70 A diagnosis of alcohol dependence
and anxiety disorders.45,47,54-58 Mood disorders associated elevates the risk for nicotine dependence.54 The relation-
with nicotine dependence include major depression, dys- ship between alcohol use disorders and nicotine depen-
thymia, and bipolar disorder. Among the anxiety disor- dence is particularly relevant in the liver transplant
ders correlated with nicotine dependence are posttraumatic population, in which a large percentage of patients are
stress disorder, panic disorder, and social phobia.47 Per- transplanted for alcoholic liver disease. Smoking is
sonality disorders have also been associated with nicotine extremely common in patients with alcoholic liver dis-
dependence.46,59 Authors have speculated that patients ease.44 Most liver transplant patients with alcohol abuse
may be self-medicating psychiatric symptoms with nico- or dependence are also nicotine dependent.50 One study
tine,52,60,61 which produces strong positive reinforcing found that liver transplant recipients with alcoholic liver
effects through the release of dopamine and serotonin.47 disease had an average smoking history of 10 more pack-
years than patients with nonalcoholic liver disease.41 Sev-
eral studies have shown increased risk for cancers in
Smoking Increases Morbidity in Liver
patients transplanted for alcoholic liver disease with a his-
Transplant Recipients
tory of tobacco use.41,90-95 Smoking has also been impli-
Smoking has health implications for liver transplant can- cated in increased risk for cardiovascular events and
didates.60 A history of tobacco use is associated with per- increased rates of de novo cancers in patients with recidi-
sistent health risks after liver transplantation.62 Smoking vism to alcohol after liver transplantation.96 Although
at the time of evaluation for liver transplantation is cor- tobacco and alcohol each exert independent effects in the
related with increased morbidity and all-cause mortal- pathogenesis of these cancers, the potential for synergy
ity.63 In particular, a history of smoking in liver transplant has also been suggested.42,66,91,95
patients is associated with increased rates of vascular A high percentage of patients transplanted for alco-
complications, including hepatic artery thrombosis.64,65 holic liver disease resume tobacco use after transplanta-
In patients who are abstinent from tobacco for 2 years tion.62 One study revealed that 61% resumed tobacco use
before liver transplantation, the rate of vascular compli- within 1 year after transplantation. Of those who resumed
cations is reduced by 58%.64 Both active and former smoking, most resumed within 3 months of liver trans-
smokers at the time of liver transplantation are also at plantation, were smoking daily, increased their consump-
increased risk for biliary complications after transplanta- tion over time, and quickly became nicotine dependent.
tion.43 Smoking is also a risk factor for the development Patients who relapsed to alcohol after transplantation had
of de novo malignancies after liver transplantation.66-70 increased tobacco consumption.62 Several other studies
A history of smoking before liver transplantation71-73 also demonstrate an association between alcohol recidi-
and smoking after liver transplantation50,65,74 are associ- vism and tobacco use after liver transplantation.69,97
ated with de novo malignancies. Smoking may also Given the comorbidity of alcohol and tobacco use, recidi-
increase the risk for infection in liver transplant patients. vism to tobacco may be a risk factor for relapse to alcohol
Tobacco is heavily contaminated with fungal spores, after liver transplantation.41
including Aspergillus fumigatus, Fusarium, Acremonium, Given that tobacco use is associated with poorer
Rhizopus, and Scedosporium,75 and may increase the outcome after transplantation, it has been argued that
patient’s risk for infectious disease, especially in the set- explicit advice to discontinue smoking, as well as referral
ting of immunosuppression. to smoking cessation programs, should be a condition
of listing.98 In general, liver transplant patients are in
need of greater access to tobacco cessation programs,
Smoking Exacerbates and Accelerates
particularly those patients with other substance abuse
Liver Disease
issues.65 However, referral to a community tobacco
Several recent studies demonstrate an association between cessation program may not be sufficient. Tobacco use is a
smoking and advanced fibrosis in chronic liver diseases,76 chronic disorder that requires a structured, compr­
including primary biliary cirrhosis,77 nonalcoholic fatty ehensive approach.85 Several studies suggest that liver
386 PART IV Special Considerations in Patient Evaluation

transplant centers should develop programs to address often comorbid with other substance abuse, including
nicotine addiction85 that focus on pretransplant cessation tobacco, benzodiazepines, opioids, amphetamine,
and posttransplant abstinence.41,44 Moreover, the inter- cocaine, and barbiturates.105 Marijuana has significant
vention programs should target not only active user of detrimental effects on motor and cognitive skills, atten-
tobacco but also former users, and participation should tion, performance, and memory,50,105 which may affect
be long term.74 the patient’s ability to comply with a complicated post-
It is important to note that individuals with psychiatric transplantation regimen. This could result in nonad-
conditions are less successful at smoking cessation.51 herence with medications.104 Marijuana use is also
Therefore more-comprehensive services may be neces- associated with respiratory symptoms, including dys-
sary to assist patients with comorbid psychiatric illness pnea and cough, as well as cerebrovascular complica-
and nicotine dependence with smoking cessation.51 tions, including stroke.105 Furthermore, several studies
Incorporation of mental health treatment into tobacco have demonstrated that marijuana use is a risk factor
cessation programs may increase the effectiveness of for fibrosis,106-110 steatosis,106-109,111 and hepatocellular
these programs.47 carcinoma103,109in patients with chronic hepatitis C.
Marijuana smoking in transplant patients has also been
associated with invasive aspergillosis,105,112 which car-
Smoking as a Contraindication
ries a risk for severe complications.50,113
to Transplantation
Abstinence from marijuana use is not necessarily a
Although authors agree that smoking cessation should be requirement for listing in all liver transplant pro-
encouraged in patients undergoing liver transplanta- grams.50,105 However, concerns of comorbid psychiatric
tion,72,99,100 requiring cessation of smoking before liver disorders, including substance abuse, as well as pain
transplantation remains controversial.44 Only a small issues, and the medical morbidity associated with mari-
number of transplant centers consider smoking an abso- juana, including potentially lethal complications from
lute contraindication to liver transplantation.85 Several infection, suggest that cessation of marijuana use may
studies suggest that tobacco cessation may improve long- be advisable. Patients actively smoking marijuana at the
term outcomes in transplant patients.101 The accumulat- time of transplant evaluation may benefit from referral
ing evidence that indicates smoking is deleterious to liver to a 12-step program. The team may wish to obtain ran-
transplant patients has prompted some authors to recom- dom urine toxicological screens to monitor abstinence.
mend that liver transplant programs may do well to initi- Results of a urine toxicological screen may remain posi-
ate smoking cessation policies similar to those for heart tive for several months after discontinuation of mari-
and lung transplant listing,69 making smoking cessation juana. Any initial screen that is positive for cannabinoids
an absolute requirement for liver transplantation.64 Liver should be followed up with quantifications to ensure
transplant programs may need to consider a requirement ongoing abstinence.
of 6 months’ abstinence for tobacco, as is done with alco-
hol and other substances of abuse. A recent paper
addressed the question of whether it is ethical to deny a
Personality Disorders
patient for liver transplantation on the basis of smok- Personality disorders are defined by an enduring pattern
ing.101 Given the substantial literature that underscores of maladaptive traits,11,114 consisting of experiences and
the morbidity and mortality in liver transplant patients behaviors affecting the cognitive and affective realms,
who smoke, the author suggested that it is both ethically interpersonal functioning, or impulse control, which lead
and medically reasonable to use active smoking as a con- to distress or impairment.115,116 Personality disorders are
traindication to transplantation.101 highly comorbid with substance abuse115,117-119 and mood
disorders.117,118,120,121 The presence of a severe personal-
ity disorder is common among patients with severe alco-
Marijuana hol-related liver disease.119 Antisocial personality disorder
There is no standard United Network for Organ Sharing is common in the liver transplant population.122 Antiso-
(UNOS) policy regarding marijuana smoking in patients cial personality disorder is characterized by persistent
being considered for liver transplantation. However, social rule-breaking, deceitfulness, and offending behav-
many transplant centers discourage the use of marijuana ior, with lack of remorse.116 It is associated with criminal-
in liver transplant candidates and require a period of ity, unemployment, homelessness, interpersonal
abstinence before transplantation in active users of difficulties, and substance abuse.123
marijuana. A recent survey indicates that 70% of U.S. Borderline personality disorder is the most prevalent
transplant centers feel marijuana use is an absolute con- personality disorder in the general psychiatric popula-
traindication to liver transplantation.102 tion.122 Patients with borderline personality disorder may
Patients presenting for liver transplantation may present to the hospital after self-harming and may come
state that they are using medical marijuana, obtained to the attention of the liver transplant team in the setting
through a prescription, for nausea, anorexia,50 or of acetaminophen overdose.2 Borderline personality dis-
pain,103 yet there remains concern over the legitimacy order is characterized by affective dysregulation, poor
of medical marijuana use.104 Moreover, whether it is impulse control, disturbed interpersonal relationships,
used for medicinal versus recreational purposes may be and unstable self-image. Hallmarks of the disorder include
irrelevant with respect to liver transplantation.104 First, emotional lability and self-injurious behavior.124-126
marijuana is a substance with abuse liability. Its use is These patients have chronic suicidal tendencies.120,127
 30 Psychiatric Assessment of Liver Transplant Candidates 387

The disorder is highly comorbid with mood and anxiety

disorders, substance abuse,128 and eating disorders.118
Schizophrenia
Although the long-term course of borderline personality A 1993 survey of U.S. transplant centers revealed that
disorder is characterized by symptom remission, impair- active schizophrenia was considered an absolute contra-
ment in social functioning can be severe and persistent.121 indication to liver transplantation in 67% of liver trans-
Transplant patients must cope with challenges, includ- plant programs.9,133,134 Although controlled schizophrenia
ing the extensive evaluation process, waiting for a donor was considered a relative contraindication in 65% of pro-
organ and living with increasing disability, the trauma of grams,9,135 it was still an absolute contraindication in
surgery, recovery, posttransplant maintenance, and over- 15% of programs.9,133,134
all adjustment to daily life after transplantation.129 The Schizophrenia is a chronic illness136 that puts patients
presence of a personality disorder can have an impact on at risk for increased morbidity and mortality.134 The sev-
posttransplant behavior, management, adherence, and eral subtypes of schizophrenia carry different prognoses.
patient satisfaction.115,120 Associated symptoms of person- In the paranoid subtype, delusions and auditory halluci-
ality disorders can surface or become exacerbated when a nations are prominent, but it is associated with greater
patient is under stress.114,120 These patients have ineffec- preservation of cognitive functioning throughout life. In
tive coping skills,120 which may lead to the inability to contrast, the disorganized subtype is characterized by dis-
navigate the complexities and rigors of transplantation.115 organized speech and behavior with relative absence of
Several studies demonstrate that personality disorders hallucinations and delusions. This subtype is associated
are significantly associated with nonadherence after solid with poor premorbid and overall functioning and signifi-
organ transplantation.115,126,130,131 Nonadherence in cant cognitive impairment. The long-term prognosis for
transplant patients with personality disorders is corre- this subtype is poor compared to other subtypes.137 The
lated with poor outcomes.115 Comorbid substance abuse “negative” symptoms of schizophrenia contribute to poor
in patients with personality disorders may increase the functionality and are the primary reason patients with
risk for nonadherence.126 schizophrenia are unable to live independently, maintain
Personality disorders are also associated with poorer employment, establish relationships, and cope with quo-
QOL after transplantation.115,120,131 Patients with antiso- tidian social situations. Negative symptoms are also
cial personality disorder transplanted for alcoholic liver related to the cognitive impairment seen in these
disease endorsed more physical symptoms and functional patients.138 However, patients with negative symptoms
impairment related to pain and reported increased rates are more compliant with immunosuppressants than
of poorer emotional well-being after transplantation.119 patients with the “positive” symptoms of paranoia, audi-
Patients with personality disorders have disturbed inter- tory hallucinations, and delusions.136 Patients with psy-
personal relationships, which may decrease the likelihood chotic symptoms within the year before transplantation
of a strong social support system for the patient.119 They are at risk for suicide attempts.136 A history of noncom-
can exhibit behavioral problems after transplantation pliance before transplantation and living alone or being
reflective of these social and relational difficulties,115 homeless are associated with immunosuppressant nonad-
which may have an impact on the ability of the medical herence in schizophrenic patients.136
team to maintain a therapeutic alliance with the There are few published data on organ transplantation
patient.120,130,132 Behavioral problems may lead to the in patients with psychotic illnesses such as schizophrenia.
patient being labeled as “difficult,” necessitating increased However, case reports of solid organ transplantation in
effort to manage the patient and resulting in a dispropor- schizophrenic patients indicate that despite the chal-
tionate amount of time and attention spent on the lenges, these patients can have successful outcomes after
patient.122 Patients with personality disorders may transplantation.*
devalue members of the medical team, thereby engender- Some protective factors have been identified as con-
ing negative feelings toward the patient.120,130 tributing to good outcomes after transplantation in this
It has been suggested that the presence of a personality population. Expert psychiatric management may facili-
disorder should not be an absolute contraindication to tate the patient's posttransplant course.133,140 It is impor-
transplantation, but rather should pose the opportunity tant to note that in the pretransplant and immediate
for treatment recommendations that may mitigate the posttransplant period, increasing the intensity of psychi-
posttransplantation risks.115 Long-term therapy, before atric treatment may be warranted141 and may improve
and after transplant is recommended. Pharmacological adherence.2
intervention may also be warranted.115 Identifying a Living alone is correlated with nonadherence with
strong social support network is critical. If liver trans- immunosuppressant medications in schizophrenic
plantation is not urgent, the waiting time can be used as patients.136 Strong family support can be a protective fac-
an indicator of the severity of the personality disorder. tor.140 Involved family members who actively participate
Adherence difficulties and interpersonal difficulties with in the patient’s care can have a positive influence on the
family or team members should be monitored. However, patient’s outcome.133 Family members should be particu-
in the setting of acute liver failure, obtaining collateral larly watchful for psychiatric symptoms that herald
history from the family may shed light on the patient’s decompensation and can affect adherence.136 Patient par-
potential to work effectively with the transplant team.2 ticipation in community aftercare programs has been
The transplant team may need to invoke innovative inter- shown to improve outcomes in schizophrenia.133 One
ventions in the posttransplant period to enhance adher-
ence and optimize outcomes.122 *References 2, 6, 133, 134, 139.
388 PART IV Special Considerations in Patient Evaluation

study reported that strong medical staff support and Acetaminophen Toxicity and Acute
attendance in a psychiatric partial hospitalization pro- Liver Failure
gram was effective in improving adherence in a schizo-
phrenic patient who underwent transplantation.141 If Acetaminophen toxicity is the most common cause of
there is time before transplantation, developing a longi- acute liver failure in the United States.144-158
tudinal relationship with the transplant team, which Acute liver failure due to acetaminophen toxicity has a
allows for therapeutic alliance, may also strengthen the distinct course characterized by rapid clinical deteriora-
chance for a good outcome.140 tion to multisystem organ failure and gross encephalopa-
thy.144,149,159,160 In some cases the patient can be lucid
before the onset of encephalopathy and able to provide a
Special Considerations in the Transplant
history.161 Often, however, the patient is already enceph-
Patient With Schizophrenia
alopathic or intubated.162,163 and cannot be interviewed,164
Patients with schizophrenia have a higher pain threshold which limits the ability to obtain a comprehensive psychi-
and may not complain of pain or discomfort until atric history.† Although it is not optimal to obtain the his-
severe.134,142 Medical illness may not be detected until a tory from family, friends, or roommates because they may
later stage. Early detection and workup of medical symp- not know the relevant history or may be reluctant to dis-
toms is imperative after transplantation, because organ close it,147 sometimes it is the only option available.
rejection could be a complication. Therefore these
patients need particularly close medical follow-up from Psychiatric Morbidity and Acetaminophen
both family and medical personnel. Toxicity
Patients with schizophrenia may experience symptoms
in the intensive care unit after transplantation, including There is a high prevalence of psychiatric morbidity in
agitation, delusions, or paranoia. This may be in part due patients with acetaminophen-induced hepatotoxic-
to their underlying psychiatric diathesis but may also be ity.144,145,162,163 Acetaminophen overdose has been associ-
due to medical factors such as delirium.139 There is some ated with mood disorders, including depression145,162;
question as to whether steroids can precipitate psychosis substance abuse, including alcohol abuse144-146,149,153,154;
in patients with psychotic illnesses. Several early papers and chronic pain.145,146,151
report that patients with psychotic illness are no more
susceptible to the neuropsychiatric effects of steroids Intentional Overdose
than patients without psychotic illness.133,134 However, a
2002 survey of psychotic symptoms in patients who Acetaminophen overdose is frequently taken with intent
underwent transplantation indicates that there may be to suicide.163 In one early single-center U.S. series, sin-
valid concerns regarding steroid exacerbation of psycho- gle-time ingestions with suicidal intent constituted 70%
sis in schizophrenia.136 The standard treatment of delir- of all patients admitted to the hospital with acetamino-
ium suffices to control this complication if it occurs.133,134 phen overdose.166 The estimated incidence of intentional
overdose in the United States is 60,000 cases per year.151
An intentional overdose may be an impulsive act.159,167
Ethical and Legal Issues
The patient may express regret and a desire to live before
In a landmark paper, Orentlicher143 outlined the legal the onset of encephalopathy.161 It may be precipitated by
considerations of organ transplantation in patients with a major life crisis such as bereavement or relationship
schizophrenia. He argued that because schizophrenia is a issues.161 Alternatively, intentional overdose can occur in
disability, denying organ transplantation to schizophrenic the setting of long-term psychiatric morbidity, including
patients on the basis of the disability violates the Ameri- drug and alcohol abuse.159 Data from the National Elec-
cans with Disabilities Act (ADA). However, he noted that tronic Injury Surveillance System looking at emergency
when allocating organs for transplantation, it is appropri- department admissions for acetaminophen overdose in
ate to take into consideration and assess whether the dis- the United States between the years 2006 and 2007 reveal
ability will compromise the patient’s ability to receive a higher percentage of intentional acetaminophen over-
benefit from the transplant. If the patient’s schizophrenia dose-related emergency department presentations among
is so severe that he or she would not be able to benefit females.167,168 Notably, most patients younger than 24
from the transplant, denial of transplantation may be jus- years used single-ingredient acetaminophen products,
tified. Assessment of the schizophrenic patient must be whereas patients older than 24 years used acetamino-
performed on an individual basis, and reasonable steps phen-opioid combination products to overdose.167
taken to mitigate the effect of the disability on the patient’s
ability to benefit from transplantation.143 Some patients Unintentional Overdose
with schizophrenia or other psychotic illnesses can do well
after transplantation. Active psychiatric illness is a poten- The results of the Acute Liver Failure Study Group study
tially modifiable risk factor.2 Even patients considered from 2005 reveal that approximately 48% of cases of acet-
high risk may do well with intensive and expert manage- aminophen-induced acute liver failure in the United
ment.140 Factors that may be protective are strong family States are due to unintentional overdose.145,146 Uninten-
support and social network, relative psychiatric stability tional overdose is defined as multiple ingestions without
before transplantation, and ongoing psychiatric treatment
with pharmacological management of symptoms. †References 144, 145, 153, 162, 163, 165.
 30 Psychiatric Assessment of Liver Transplant Candidates 389

suicidal intent, to treat pain or other somatic symptoms.145 pain. Psychiatric morbidity is common in patients with
These ingestions occur over a period of time, usually chronic pain.171-176 Depression is one of the most com-
more than 3 days.153 Patients who unintentionally over- monly reported psychiatric comorbidities.174,177-182 In
dose on acetaminophen are frequently taking multiple patients with chronic pain the severity of the depression
acetaminophen-containing analgesic products and may be is correlated to the pain severity, duration of pain, and
unaware that acetaminophen is an ingredient in these number of pain sites.174,183 Patients with chronic pain are
products.153 The majority of patients (81%) with uninten- also at increased risk for suicidality.171,175,178,184-193
tional overdose in the Acute Liver Failure Study Group Substance use disorders are also highly prevalent in
had acute or chronic pain issues.145,146 Sixty-three percent patients with chronic pain.177,194-202 Patients with chronic
were consuming an opioid-acetaminophen-containing pain are at increased risk for opioid abuse.195,198,199,203-205
product, and 38% were using two or more acetamino- In patients with chronic pain a history of substance abuse
phen-containing preparations.145,146 predicts opioid abuse.202,206,207 Individuals who have been
abstinent even for several years are at increased risk for
relapse when prescribed medications with addiction
Ethical Issues in Acetaminophen Overdose
potential such as opioids, regardless of the previous sub-
The patient in fulminant hepatic failure may be unable to stance of abuse. The initiation of an opioid to patients in
participate in a decision that will have a profound effect recovery from substance abuse may increase risk for
on his or her life.169 The team must rely on surrogates, addiction to opioids or result in relapse to previously
who essentially consent for the patient to the procedure. abused substances.177
However, surrogate decision making can be imperfect, Several chronic pain conditions have been shown
with a reported 68% accuracy in prediction of patient to be significantly associated with suicidality, including
choices.170 migraines,208 back pain, arthritis, and fibromyal-
Patients with acetaminophen overdose are considered gia.171,188,189 Patients with liver disease often have
at risk for psychiatric complications after transplantation. chronic abdominal pain, which is also associated with
Of patients that undergo liver transplantation for acet- suicidality.171
aminophen toxicity, a high percentage have ongoing psy- Liver disease is comorbid in 4% of patients with fibro-
chiatric issues after liver transplantation, and psychiatric myalgia.209 Cirrhosis, biliary tract, and cholestatic disease
follow-up is warranted.144,162,163 Studies have also reported have been reported. It is more prevalent in females,210,211
increased rates of nonadherence after liver transplanta- with a female-to-male ratio of 9:1.212 It is highly comor-
tion in patients with acetaminophen overdose.144,162 bid with depression213-222 and suicidality.189,209,223,224
Patients with intentional overdose are at risk for future Patients with fibromyalgia are frequently treated with
suicide attempts after transplantation.144,147,162 However, opioids. Those on higher doses frequently have a history
a suicide attempt is not necessarily an absolute contrain- of substance abuse.224
dication to transplantation.147 The patient who overdoses Patients with chronic pain issues presenting for liver
with suicidal intent may be suffering untreated depres- transplant evaluation should be closely screened for
sion, which may respond if optimally addressed.162 The comorbid psychiatric conditions, including opioid abuse.
decision to transplant a patient with an intentional over- Risk factors for opioid abuse in patients with chronic pain
dose should be weighed against other considerations, include a history of substance abuse206,207,225; psychiatric
including active substance abuse, lack of social support, morbidity,172 including anxiety and depression226; family
and a history of nonadherence.147 history of substance abuse202,225; history of childhood
In cases of acetaminophen overdose, it is essential to sexual abuse225; and a history of legal problems,202 includ-
determine the cause of the overdose.164 It is critical to ing drug-related convictions.207,225 Opioid use in patients
elicit the precise nature and timing of the overdose with chronic pain should be closely monitored before and
to ascertain whether the overdose was intentional or after transplant. In patients presenting with problematic
unintentional. To that end, what acetaminophen-con- opioid use, referral to a substance abuse program may be
taining products were taken, in what quantities, and over indicated.
what period of time are vital pieces of information that
can help determine intentionality. Whether there are
other substances, including alcohol, in the urine toxico-
Methadone Maintenance
logical results is also instrumental in steering the evalua- A significant proportion of patients with hepatitis C virus
tion toward psychiatric issues, including chronic pain and (HCV) are on methadone maintenance.227,228 Hepatitis
depression, prescription opioid abuse, and alcohol and C is a major cause of morbidity and mortality in patients
illicit substance abuse. Chronic pain issues will need to be on methadone maintenance.229 Consequently there is a
addressed once the patient is medically stable. relatively substantial need for liver transplantation among
this population,227,230 and the number of patients with
HCV on methadone maintenance referred for liver trans-
Chronic Pain and Opioid Abuse in Liver plantation is likely to grow.227,230,231
Transplant Candidates Currently there are no standard guidelines for listing
Chronic Pain Syndromes liver transplant patients on methadone maintenance.
A 2001 survey of 97 transplant programs revealed
Patients presenting for liver transplantation frequently that 56% of programs would consider patients on meth-
have comorbid medical conditions, including chronic adone maintenance for liver transplantation. Thirty-two
390 PART IV Special Considerations in Patient Evaluation

percent of programs required methadone discontinua- Methadone maintenance treatment as part of a com-
tion before transplantation.230-233 Only 10% of the prehensive program can help prevent relapse in greater
programs surveyed had experience transplanting more than 90% of former heroin users.229 Discontinuing
than five patients on methadone maintenance.231 A methadone results in relapse in greater than 80% of
recent survey of U.S. and Canadian transplant centers patients.230,231,233 The most successful programs are
indicates that methadone maintenance is currently not those with maintenance as the goal, rather than absti-
an absolute contraindication to consideration for liver nence from methadone.227 The transplant evaluation
transplantation.234 Seventy percent of U.S. program process is stressful.229 Moreover, patients with end-
respondents indicated that patients could continue stage liver disease struggle with pain.227 Discontinua-
methadone maintenance. However, 30% of respondents tion of methadone in patients waiting for liver transplant
still required discontinuation of methadone before may lead to relapse.227,229,233,234 Several authors dis-
transplantation.234 courage the practice of requiring the discontinuation of
methadone in patients being considered for liver
transplantation.229-231,233
Liver Transplant Outcomes in Patients on
Some authors speculate that patients on methadone
Methadone Maintenance
maintenance have been largely excluded from transplan-
Outcomes data for patients on methadone maintenance tation because of the social stigma surrounding metha-
who undergo liver transplantation are sparse. Small case done use and the perception that these individuals are
series report increased perioperative morbidity, including “addicts.”230,232 Methadone is often perceived as a drug of
longer hospital stay and intensive care stay,230 signifi- abuse rather than a treatment for opiate addiction.229,232
cantly higher intraoperative anesthesia and postoperative It has been argued that methadone should be conceptual-
analgesia requirements,235 and increased methadone ized as a replacement medication.230,239
requirements after transplantation.229 Although one study There is no overwhelming evidence to suggest that
reported a trend toward decreased survival,235 other stud- patients on methadone maintenance should be automat-
ies have reported patient and graft survival comparable to ically excluded from consideration for liver transplanta-
non-methadone-treated transplant recipients.228-231 tion230-232,239 or that discontinuation of methadone
Although there is no conclusive evidence that patients should be a criterion for transplantation.230,233,234,239 It is
with methadone maintenance have poorer medical out- recommended that each patient be evaluated on an indi-
comes after liver transplantation,227 patients on metha- vidual basis.227 When patients are on methadone main-
done maintenance are at increased risk for depression236 tenance, the transplant team should communicate with
and chronic pain issues.237 Patients with chronic pain on the patient’s methadone clinic in the pre transplant and
methadone maintenance for opioid dependence have posttransplant period for continuity of care.231 It is rec-
higher rates of substance abuse than patients without ommended that the patient be kept on the maintenance
chronic pain.172 Substance abuse is prevalent in patients dose while in house awaiting transplantation.235 Pain
on methadone maintenance.238,239 These comorbidities management perioperatively may be challenging. There
increase the risk for psychiatric complications after is a lack of standardized conversions for methadone and
transplantation. short-acting opioids. Patients on methadone mainte-
nance therapy may have altered pain sensitivity, includ-
ing hyperalgesia or allodynia, due to chronic opioid
Methadone Maintenance and Psychiatric
exposure.227Alternatively, the patient may not report
Morbidity
pain but may evidence other symptoms of withdrawal,
Depression is highly prevalent in former heroin users on including restlessness and irritability.235
methadone maintenance.236,240 Depression is more prev-
alent in patients on methadone maintenance with con-
comitant human immunodeficiency virus (HIV), alcohol
Obesity
dependence, and a past history of suicide attempts. Risk Nonalcoholic steatohepatitis (NASH) is increasingly an
factors for depression include enrollment in a methadone indication for liver transplantation.244,245 The percentage
maintenance treatment program, being female, having of liver transplantations performed for NASH has
any axis I diagnosis, taking any psychiatric medications, increased from 1.2% in 1997 to 7.4% in 2010.246 NASH
and benzodiazepine use or abuse.236,241 A high metha- is now the third most common indication for liver trans-
done dose (>120 mg/day) is also significantly associated plantation in the United States and is projected to surpass
with depression236 and may serve as a marker for other hepatitis C as the most common indication over the next
psychiatric risk factors, including chronic pain.236,241 10 to 20 years.244,246
There is a high prevalence of chronic pain in patients
on methadone maintenance for opioid depen- Obesity and Psychiatric Morbidity
dence.237,242,243 Patients with chronic pain tend to be on
higher doses of methadone.237,242,243 One study demon- Obesity is associated with multiple psychiatric disorders.
strated that, in patients with chronic pain, higher metha- Obesity is correlated with mood disorders.247,248 A body
done dose was correlated with duration and severity of mass index (BMI) greater than 30 significantly increases
pain.237 Benzodiazepine use and abuse are also highly the odds of a lifetime mood disorder, specifically major
prevalent in patients on methadone maintenance with depressive disorder and bipolar disorder.249 Obesity is
chronic pain172,237 and depression.241 also associated with anxiety and personality disorders.249
 30 Psychiatric Assessment of Liver Transplant Candidates 391

A history of childhood trauma increases the risk for obe- alcohol for food as a source of pleasure.277 Thus an
sity.250-252 Obesity is also correlated with substance use “addiction transfer” may occur, in which the patient
disorders,247 specifically alcohol abuse.249 A strong asso- exchanges food addiction for alcohol addiction.275 As
ciation between obesity and attention-deficit/hyperactiv- transplant teams strive to encourage ongoing abstinence
ity disorder (ADHD) has been found in community from alcohol in all liver transplant recipients regardless of
samples.253 Of obese patients presenting to a bariatric the cause of their liver disease, they should bear in mind
clinic, nearly 50% met the criteria for ADHD.254,255 The that this particular subset of patients may be at increased
connection between the two clinical entities appears to be risk for problematic alcohol consumption.
the addictive behaviors common to both.254 Obesity also A higher BMI before transplantation is associated
occurs in the context of eating disorders, particularly with the development of obesity after liver transplanta-
binge-eating disorder,247,256 characterized by repeated tion.278-281 In addition, NASH can recur after liver
episodes of compulsive overeating. transplantation.244 Posttransplantation BMI in particu-
lar is associated with the recurrence of fatty liver disease
after liver transplantation.282 Because of the risk for
Food Addiction
recurrent NASH, one goal of improved medical out-
Although obesity has classically been considered a comes after transplantation should include a focus on
medical disorder, recent evidence suggests obesity has modifiable risk factors.244 A careful weight history,
a substantial psychiatric component rooted in the neu- including eating patterns and triggers for weight gain,
robiological substrates of addiction.247 Several studies should be elicited. Pathological behavior, including
suggest that compulsive overeating is sufficiently simi- binging and purging, should be explored. Weight loss
lar to addiction257,258 as to warrant its consideration as history is also important, including a history of diet
a bona fide substance use disorder.259,260 The concept plans and whether they were successful. Patients may
of “food addiction” has been offered as an explanation benefit from a dietary or nutrition consultation and
for the type of compulsive behavior that can lead to referral for programs for diet modification and exercise.
obesity.261,262 The food addiction hypothesis states that Many transplant centers encourage weight loss before
“hyperpalatable” foods, which are rich in sugar, fat, transplantation.278 This has been recommended espe-
and salt, may have addiction potential.258,261,263-266 cially for patients with a BMI greater than 35.278 Regu-
Behaviors in food addiction conform to the criteria for lar exercise has also been recommended.278 Patients
a substance use disorder,260,265 including tolerance, with psychiatric morbidity should be referred for psy-
withdrawal, relapse,263 loss of control, and cravings.254 chiatric treatment. Close follow-up with psychiatry and
Moreover, there are common neurobiological under- nutrition specialists may contribute to improved out-
pinnings of hyperpalatable foods and drugs of addic- comes in this population.
tion.267-269 These foods have reinforcing effects in the
brain and alter neural transmission in ways similar to
drugs of addiction.260,270
Living Donor Liver Transplantation
Despite over a decade of experience with adult-to-adult
living donor liver transplantation (LDLT), the gamut of
Bariatric Surgery
potential risks of donation remains imperfectly character-
In parallel with the rise in obesity and NASH, increas- ized.283 Short-term medical complications, including
ing numbers of patients are presenting for liver trans- biliary complications,283-285 incisional hernia,283,284,286
plant evaluation with a history of bariatric surgery. wound infection, and small bowel obstruction,284-286 have
Recent studies reveal that patients presenting for con- been extensively documented in the literature on LDLT.
sideration of bariatric surgery have high rates of psy- However, the long-term impact on donor health remains
chiatric morbidity, including depression, anxiety, essentially unknown.287,288 Moreover, the social and psy-
binge-eating disorder,250,271,272 and substance use dis- chiatric consequences are poorly understood.289
orders.250 One study reported that 46% to 68% of Several studies have focused on QOL measures in an
patients presenting for bariatric surgery evaluation effort to measure donor outcomes after LDLT. Quality
admitted to at least one binge episode per week in the of life is defined as “an overall sense of well-being, includ-
month before presentation.272 In obese individuals pre- ing aspects of happiness and satisfaction with life as a
senting for bariatric surgery, 40% met the criteria for whole.”290 The majority of living liver donors report
food addiction.264 Though few patients meet the crite- good QOL after donation.291-298 However, studies reveal
ria for active substance abuse at the time of evaluation clinically and statistically significant reductions in physi-
for bariatric surgery, rates of lifetime history of sub- cal function immediately following donation, with the
stance abuse approach 33%.250,273 greatest impact on physical well-being occurring in the
Several reports suggest that patients with a history of first 3 months after surgery.290 Although there are reports
alcohol use disorders are at increased risk for relapse to that donor QOL appears to be unrelated to donor medi-
problematic alcohol consumption after bariatric sur- cal complications,297 other studies report body image
gery.274 There is also some evidence to suggest the emer- concerns related to the surgical scar,299-302 fatigue,298
gence of de novo alcohol use disorders in patients who sleep disturbance, and surgical site “throbbing, itching or
have undergone bariatric surgery.275,276 Authors specu- numbness.”302 Chronic pain issues,298 including abdomi-
late that because of the changes in eating behaviors that nal pain,303 have been reported. Gastrointestinal symp-
their new physiology demands, patients substitute toms have also been reported.294,300,303 Reports of physical
392 PART IV Special Considerations in Patient Evaluation

disability and inability to return to work for several Ethical Considerations

months have also been published.299
Most studies report that generally, mental health LDLT presents an ethical challenge because it is a proce-
domains of QOL remain essentially preserved through- dure that subjects a healthy individual to a major opera-
out the donation process.290,291 Several studies demon- tive procedure from which the patient derives no direct
strate that donors experience above-average QOL in this medical benefit.284,285,287,311 There is significant potential
domain, compared to the general population.290,291,294 risk for morbidity, including the possibility that the donor
Many studies indicate donor satisfaction with the deci- will be left with insufficient liver function288,312 or experi-
sion to donate, with the majority of donors stating that ence biliary complications.283-285 Moreover, the risk for
they would donate again.‡ Some studies report donor sat- mortality is real and substantial.283-285,287,313 Exposing the
isfaction regardless of complications in themselves or the donor to such risks violates the basic tenet of primum non
recipients,291 as well as willingness to donate again despite nocere.284,287,289 In addition, the long-term medical risks
such complications.305 However, other studies report of the procedure remain unknown at this time.285,288,312
decreased donor QOL across mental health domains in Potential unintended consequences include insurance
the context of recipient complications after transplanta- denial, inability to work, and psychiatric complications.289
tion.300,306 Psychological distress, including depression, The ethical dilemma lies in assessing the acceptable level
has been reported in donors who had severe medical of mortality risk to the donor.284 However, the question
complications after donation.299,304 becomes, what mortality rate is an acceptable one?284,287
Some donors have described their overall transplant The medical community has yet to come to a consensus
experience as “stressful.”300 There have also been reports on the point at which the risk for mortality to the donor
of dissatisfaction with follow-up, with donors feeling that is justified.289 Studies reveal that the lay public is willing
their needs after donation were not adequately met, that to accept a mortality rate of 21% for liver donation,
they had insufficient support from the transplant team,299 whereas the actual estimated risk for donor mortality is
or they expressed dismay that the recipient received more less than 2%,311 indicating that people are willing to
attention after the transplant.294 They have also expressed accept high mortality rates to save the life of their loved
concerns regarding unresolved insurance issues300 and anx- one.287 The majority of transplant surgeons feel that
iety over their own health status, including concerns over donor risk poses a moral dilemma. Nearly half of sur-
whether their own liver would regenerate sufficiently.299 In geons admitted difficulty in helping a potential donor
some cases, donors with complications in themselves or comprehend the risks of donating, given the emotional
their recipients state that they would not donate again.304 context of LDLT.314 Furthermore, the donor may
There have been are very few published reports of spe- acknowledge the risks but expect a good outcome and
cific psychiatric outcomes in LDLT. Most data are accept the surgeon’s willingness to perform the surgery as
derived from case reports or transplant center survey tacit reassurance of donor safety.288
data. Because psychiatric complications can occur late in
the postoperative course, these data may not be captured The Living Donor Liver Transplant
by the transplant teams because of lack of adequate long- Psychiatric Evaluation
term follow-up for donors.307 Cases of donor depression
after donation have been reported.291,304 The Adult-to- The criteria for the psychiatric evaluation of potential liv-
Adult Living Donor Liver Transplantation study retro- ing donors are in evolution.315 A recent paper outlining
spectively examined donor psychiatric complications general guidelines for the evaluation of living liver donors
reported at nine U.S. transplant centers between 1998 echoes earlier guidelines proposed for the evaluation of
and 2003. Of the 392 donors, 4.1% had psychiatric com- living kidney donors.316 Potential risk factors for poor
plications after donation, including mood disorders, anxi- outcomes in living donor kidney donation include past or
ety, and substance abuse. Three cases with severe present significant psychiatric morbidity, substance use
psychiatric complications were identified, including sui- disorders, financial instability, lack of health insurance,
cide attempts and suicide completion.307 unrealistic expectations or marked ambivalence, desire
Paradoxical psychiatric syndrome (PPS) has been for secondary gain, being motivated by desire for recog-
reported LDLT recipients and donors.308 The symp- nition or the hope of developing relationships, family
toms are considered paradoxical because they appear stressors and poor social support, coercion, lacking capac-
despite successful medical and surgical outcomes for ity to understand risks and benefits, and medical morbid-
both recipient and donor.308 Manifestations of PPS ity, such as chronic pain issues.317 A strained
include depression, somatization, adjustment disorders, donor-recipient relationship, a history of nonadherence,
and conversion reactions.309 One 3-year follow-up and lack of disclosure to family are considered relative
study of psychiatric complications in Japanese recipi- contraindications in most living kidney donor programs
ents reported a rate of 80% in adult recipients of child- in the United States. Financial incentive is considered an
to-parent living liver donation.309 Psychogenic pain absolute contraindication at the majority of centers.318
disorders, another manifestation of PPS, have been
reported in adult child-to-parent donors.310 Psychiatric History. Living liver donors incur substan-
tial psychiatric risk.316 In addition to screening for depres-
sion and anxiety, in particular, a history of physical,
‡References 291, 293, 294, 296, 304. emotional, or sexual trauma should be explored. Trauma
 30 Psychiatric Assessment of Liver Transplant Candidates 393

is associated with chronic pain and somatic issues and to the decision not to donate. However, in a cohort of
may have an impact on postoperative recovery.319 Body ambivalent donors who proceeded to donation, none had
image disorders, sleep disorders, and needle phobias have regrets and most stated they would donate again.324 In
reportedly been exacerbated after living organ dona- contrast, one study demonstrated that postponing the
tion.319 Substance abuse history should be explored. The decision-making process was correlated with anxiety and
stress of donation could exacerbate substance use or con- may herald poor coping after donation.325 An association
tribute to relapse.319 Most transplant programs require 6 has been demonstrated between a high degree of ambiva-
to 12 months of abstinence before a patient can be con- lence and poor outcomes.322 Yet if donors arrive at the
sidered for living donor donation.318,319 decision to donate spontaneously and seemingly without
deliberation, it may indicate that the donor has made the
Medical History. It may be helpful to learn whether the decision based without thoughtful reflection on the
patient has ever undergone surgery in the past and how issues.322 One study reports that an immediate willing-
they dealt with it. It is also particularly important to assess ness to donate followed by a period of reflection was asso-
the patient’s history of adherence with medical recom- ciated with increased likelihood of good outcome.321 It is
mendations.319 Health insurance status needs to be ascer- recommended that the donor have at least a 2-week
tained. Lack of insurance puts donors at risk for worse period to reflect.316,320
psychosocial outcomes after organ donation.317 Chronic
pain and multiple somatic issues may influence outcome Financial Stability. The donor’s financial circumstances
after donation.319 should be explored. Financial instability puts donors at
high risk for a poor psychosocial outcome.319 There may
Informed Consent. The clinician should establish that be substantial postoperative medical expenses for which
the patient is well informed about the risks and benefits of the donor may be directly liable.287,294 Time lost from
the procedure.284,320 The clinician should assess the employment and loss of income is also a potential real-
patient’s capacity to consent to donation and the extent of ity.291 If the donor is the sole source of income, this may
their understanding of donation and the transplant pro- be a relative contraindication.319 Job loss and future dif-
cess as a whole. Donors who perceived that they had been ficulties obtaining insurance are also a potential reality.319
inadequately informed about the donation process and Financial incentive for donation must be assessed.316
potential complications have reported poor QOL after
donation.319 Also important is eliciting whether the Coping Skills. Donors will be facing a challenging pro-
potential donor has realistic expectations of the experi- cess of recovery and integration of the donation experi-
ence. Unrealistic expectations regarding the donor expe- ence.321 A history of coping skills should be assessed.316
rience have been associated with psychiatric complications Donors require emotional resilience to cope with myriad
after donation.304,320 Of paramount importance is that potential stressors after the surgery.319 Maladaptive cop-
the donor understands that he or she can opt out of the ing styles, such as denial or venting of negative emotions,
process at any time.316 may indicate psychiatric distress.326 Helping potential
donors identify adaptive coping skills may increase the
Decision-Making Process of the Potential Donor. It likelihood of a good outcome.319
is critical to establish that the donor is making an autono-
mous decision.284 A recent study demonstrated that Social Support. It is vital to assess the degree of social
donors who had strong sense of autonomy and did not support for the donation process, including the postdo-
feel coerced, coped better with the postoperative course, nation period. It is important to ascertain whether the
even if they had complications or the recipient outcome donor has discussed the decision to donate with the sig-
was poor.321 Coercion is more likely to occur when the nificant people in his or her life. It is recommended that
expectation for donation is openly expressed by the fam- donors involve significant people in their lives in the deci-
ily to the donor. However, family expectations can be sion-making process. Conflicts between the potential
more subtle and impose an internalized pressure on the donor and these parties should be resolved before pro-
potential donor.319 It is important for clinicians to under- ceeding with donation.319 Recent reports indicate that
stand how donors arrived at the decision to donate, when living liver donors with adequate social support demon-
they learned about the need for donation, how long strate better postdonation adjustment.321 Areas to explore
before they were tested for donation, and how proactive include who will be able to help with activities of daily
they have been in educating themselves about the dona- living, transportation, and caring for other
tion process; this may give an indication of their commit- dependents.319
ment to donation.319
Some living liver donors demonstrate ambivalence in Motivation for Donation. The motivation for donation
the decision-making process.322 Donor ambivalence has should be elaborated.316 Most donors express the wish to
been correlated with fears about the surgical risks.323 help their loved one.320 Motives related to prolonging the
Ambivalent donors are also less likely to anticipate a posi- life or improving the QOL of the recipient are regarded
tive emotional reinforcement from donation and were as positive.319 Strong motivation appears to protect against
concerned about both the immediate postoperative poor psychosocial outcomes after donation, whereas
period and the long-term complications.322 Ambivalence tentative motivation is associated with postdonation
may be part of the decision-making continuum that leads disappointment, negativism, and physical complaints.319
394 PART IV Special Considerations in Patient Evaluation

One study demonstrated that potential living liver donors are no published guidelines or consensus regarding an
tend to exhibit a high degree of volunteerism.322 How- upper age limit for liver transplantation.329,330 Currently
ever, family pressure, a sense of obligation, or expectation 15.9% of patients listed for liver transplantation in the
of some type of benefit may play a role.320 Enhanced self- United States are 65 years or older.331 In 2011, 11.7% of
esteem or self-gain may be a motivating influence.321 liver transplant surgeries performed in the United States
Reported potential benefits to the donor have included a were performed in patients 65 or older.331 U.S. Census
sense of beneficence and an improved relationship with Bureau estimates predict that by 2030, 22% of the U.S.
the loved one.291 Family dynamics may have an impact on population will be over 65 years of age.332 The percentage
the decision to donate. For example, donors considered of elderly patients considered for liver transplantation is
the “black sheep” of the family may see donation as a expected to rise in parallel with the general population
means of redemption.319 A less close relationship with the increase in this age-group.330,333,334
recipient before donation or the perception of being the Some studies of liver transplantation in elderly patients
“black sheep” of the family has been associated with a have reported successful outcomes.333,335-339 Some papers
negative donor experience.288 Some authors have advo- have reported no difference in morbidity and mortality in
cated that the donor should demonstrate a significant, patients over 70 compared to younger cohorts,340,341 with
long-term,286 and vital emotional relationship with the comparable rates of patient and graft survival in this
recipient.316 cohort.330,333
In summary, living liver donors may experience sig- Others have demonstrated decreased survival after
nificant psychiatric morbidity. An extensive psychiatric liver transplantation in patients older than 60.327,342-345
evaluation should be performed before donation. Longi- Although cardiovascular complications, infection, and
tudinal psychiatric follow-up of donors is recommended. malignancy have been identified as concerns in elderly
liver transplant patients,333 little attention has been
directed toward cognitive impairment as a risk factor for
Cancer morbidity and mortality in this population. Though
Patients with cancer face a unique set of stressors in the frank dementia is generally considered an exclusion cri-
context of transplantation, which include grappling with terion for transplantation,5 some degree of cognitive
the diagnosis of cancer and potentially undergoing che- impairment is commonly observed in transplant candi-
motherapy and radiation therapy or other interventions dates.1 Cognitive impairment can be a direct result of
while awaiting transplantation. Qualitative studies suggest organ failure.346 Liver transplantation may improve or
that patients with hepatocellular carcinoma experience reverse to some extent cognitive disturbance due to
anxiety, depression, helplessness, and hopelessness.326a organ failure; however, recovery may be incomplete, and
Patients with hepatocellular carcinoma also report cognitive disability may persist in the posttransplant
decreased QOL compared to patients with liver disease period.346 Cognitive impairment may also herald an irre-
and report great weight loss, loss of appetite, and decreased versible neurodegenerative or dementing process. Com-
ability to function in usual activities.326b Patients with plicating the assessment of cognitive function in an
cholangiocarcinoma had rates of psychiatric disorders elderly liver transplant candidate is the potential for
similar to those of other patients with end-stage liver dis- encephalopathy to confound the presentation. Cognitive
ease but had lower rates of alcohol and drug use impairment may also complicate the capacity assessment,
disorders.326c Patients with neuroendocrine tumors have affecting the patient’s ability to fully understand the
increased symptoms of depression with increased tumor transplant process and to give informed consent for the
burden.326d Patients who smoke and relapse to alcohol use procedure.2
after transplantation are at increased risk for oropharyn- The elderly transplant patient is at risk for delirium in
geal cancers.326e the immediate postoperative period. Delirium occurs in
Careful assessment for depression and assistance with up to 56% of elderly hospitalized patients and is associ-
symptom management for appetite loss should be consid- ated with in-house mortality of up to 33%.347 Vulnerabil-
ered by psychiatrists assisting in the care of transplant ity factors for delirium include baseline cognitive
patients. Mirtazapine has been noted to increase appetite impairment, frailty, medical morbidity,347 and functional
and may play a role in weight stabilization for this popu- impairment,348 all of which may be seen in the elderly
lation of patients. Supportive counseling reinforcing patient presenting for liver transplant evaluation. In the
problem solving and developing strong support networks posttransplant period tacrolimus, which is associated with
can also be considered. Health coaching for patients with significant neurotoxicity,349 may contribute to delirium.
a high symptoms burden can also be considered to help Delirium in elderly patients is associated with substantial
with ongoing symptom management for this highly bur- morbidity, including functional deterioration, loss of
dened population of patients. independence, and placement in a nursing facility.347
Cognitive impairment is one of the most important risk
factors for medication nonadherence in elderly patients.350
The Elderly Patient Studies reveal that impairment in the domains of execu-
Advanced age was previously considered a contraindica- tive function and memory, which are critical to medica-
tion to liver transplantation. Until the 1980s few centers tion management, places elderly patients at risk for
transplanted patients older than 50 years.327 Now nonadherence.350 Cognitive impairment also is associated
advanced age is increasingly common in patients under- with emotional and behavioral disturbances, including
going liver transplant evaluation.327,328 However, there mood lability, depression, impulsivity, and apathy.346
 30 Psychiatric Assessment of Liver Transplant Candidates 395

A mental status examination may alert the clinician to The deficits observed are consistent with executive
the possibility of cognitive impairment. Formal neuro- dysfunction356 and suggest a frontal-subcortical dysfunc-
psychiatric testing is not routinely included as part of the tion comparable to that seen in patients with HIV infec-
cognitive workup of the transplant patient. However, if tion.351,362,364 Some authors have suggested that HCV/
by clinical history and primitive tests of executive func- HIV coinfection may synergistically increase susceptibil-
tion such as the clock-drawing test, there is concern for ity to cognitive impairment in this population.351
some degree of cognitive impairment, referral for formal
neuropsychiatric testing to assess baseline cognitive func- Neuropsychiatric Side Effects of
tioning may be warranted.1 Brain imaging may also con- Interferon Treatment
tribute to formulating a diagnosis. In cases of documented
cognitive impairment the critical care team should be Neuropsychiatric symptoms occur in up to a third of
alerted to the potential for postoperative delirium and patients undergoing IFN-α treatment.353 Depression is
should closely monitor the patient’s mental status. the most common neuropsychiatric sequela of IFN-α.
Patients with concerning symptoms should be referred Symptoms can be severe and have been associated with
for geriatric psychiatry follow-up. Social support, as veri- suicidality.353 Dose reduction is first-line treatment when
fied by the social worker, will be critical to help ensure an depression develops during treatment. Treatment with
optimal outcome in the elderly patient with impaired antidepressants is also standard, with selective serotonin
cognition. reuptake inhibitors commonly prescribed.353 Some
authors have argued that treatment should be discontin-
ued if suicidal ideation occurs.357 Patients for whom IFN
Considerations in the Liver Transplant treatment is being considered should be screened for
Candidate With Hepatitis C depression before initiation of IFN treatment. Patients
Psychiatric Morbidity in Hepatitis C should be monitored for symptoms throughout the course
of the treatment and after the treatment has been com-
Psychiatric morbidity is common, with up to 40% of pleted, because some studies report ongoing symptoms
patients with HCV meeting clinical criteria for an after treatment has stopped. Some authors have suggested
active psychiatric disorder.351 Depression is the most psychiatric treatment may be required for several months
common comorbid psychiatric diagnosis in patients after completion of IFN-α treatment.353,365 Notably, one
with HCV.351-353 One subgroup in particular, HCV study revealed that patients on methadone maintenance
patients on methadone maintenance, have a fivefold required an increase in the daily methadone dose while on
increased risk for depression.354 Refractory depression IFN therapy. The authors speculate that this was related
has been documented in cases of recurrent HCV after to the mood-modulating effects of methadone.353,366
transplantation. In two cases there was evidence of Though less common than depression, mania has been
HCV RNA-negative strands in brain tissue samples, reported in the context of IFN treatment.353,367-370 Case
and the authors speculate that every depression may reports of psychotic symptoms are rare. One study
have a biological substrate in the HCV viral replication reported several patients with chronic HCV who devel-
in the brain.355 Anxiety disorders are also prevalent in oped de novo psychotic symptoms during IFN treatment
patients with HCV351,353,354,356 with rates ranging from that resolved with IFN withdrawal, either spontaneously
18% to 41%.351 HCV is also highly comorbid with sub- or with psychiatric medication.353,371
stance use disorders.353 A high percentage of intrave- Cognitive impairment is also associated with IFN
nous drug users and patients with alcoholic liver disease treatment.351,353 Though IFN-associated cognitive
are HCV positive.357 Psychotic disorders and personal- impairment has been reported to reverse with cessation
ity disorders are also prevalent,351,353 with antisocial of treatment,353 persistent cognitive dysfunction has also
and borderline personality disorders most commonly been reported.351,353
associated.353 A thorough assessment of cognitive functioning in
patients with HCV is recommended. Objective assess-
Cognitive Impairment in Hepatitis C ment of cognitive functioning should be considered in all
HCV-infected patients, even if they do not have subjec-
Up to 50% of patients with hepatitis C have difficulties tive complaints.352
with memory and concentration.352,356 Cognitive dys-
function in HCV has been described as “brain
fog”351,358,359 or mental clouding,358-360 and consists of Considerations in the Liver Transplant
difficulties with attention, memory, and concentration,§ Candidate With Human Immunodeficiency
which can affect daily routine functioning.351
Cognitive impairment in HCV does not appear to
Virus Infection
correlate to the severity of liver disease351,360,363,364 and Up to a third of HIV patients are coinfected with HCV,
cannot be accounted for by hepatic encephalopathy and liver disease is a primary cause of morbidity in HIV-
or substance use.363 Cognitive impairment is described infected individuals.372 In the era of antiretroviral medi-
in HCV patients with even mild or minimal liver cations, there is increasing experience of liver
disease.351,352,359 transplantation in patients with HIV.373The need for
liver transplantation in this population is expected to
§References 351, 352, 359, 361, 362. increase dramatically in the near future.374
396 PART IV Special Considerations in Patient Evaluation

Psychiatric Morbidity in Human for cognitive impairment include the Mini-Mental

Immunodeficiency Virus Infection State Examination; however, this instrument is more
sensitive for cortical dementia seen in Alzheimer’s dis-
Patients with HIV infection have high levels of psychi- ease than the subcortical dementia seen in HIV.385The
atric mordibity.375 Major depression is extremely com- utility of the HIV Dementia Scale in detecting subtler
mon in this population,376-378 with a reported prevalence forms of cognitive impairment in HIV has not been
rate of up to 61%.379 It is associated with cognitive fully elucidated.385 Three simple screening questions
decline380 and leads to decreased medication adherence may help to detect symptomatic neurocognitive impair-
in this population.377,379 Suicide rates are more than ment in HIV patients375,393: (1) Do you experience fre-
three times higher in HIV patients than in the general quent memory loss? (2) Do you feel that you are slower
population.379 when reasoning, planning activities, or solving prob-
Anxiety symptoms are also widely reported.376,377,379 lems? (3) Do you have difficulty paying attention?
Patients with HIV have high rates of generalized anxi- These questions may direct further testing to assess
ety disorder, adjustment disorders, and posttraumatic cognitive functioning in this population before trans-
stress disorder.377 Increased rates of bipolar disorder plantation. Neuropsychiatric testing, cerebrospinal
and secondary mania have been reported.377,378 New- fluid examination, and magnetic resonance imaging of
onset psychosis occurs in 0.2% to 15% of HIV patients, the brain have been suggested as important diagnostic
with the highest incidence occurring in later stages of tests to assist in the evaluation of neurocognitive
HIV-associated dementia.377 Substance abuse is also impairment in HIV.385 Screening for comorbid condi-
common among HIV-infected individuals, with a life- tions that are risk factors for neurocognitive impair-
time prevalence rate as high as 40% to 50%.377 Mari- ment, including depression and substance abuse, is
juana, cocaine, hallucinogen, and amphetamine use are recommended.382
common in patients with HIV infection.377 The preva-
lence of alcohol use disorders ranges from 22%
to 64%.379 There is evidence to suggest that alcohol
Criminality
and substance use in this population increases the risk Whether criminality should be considered a contraindi-
for accelerated and more severe neurocognitive cation for transplantation has long been a subject of
impairment.379 intense debate.394 Some physicians and medical ethicists
argue that a person who has committed a violent offence
Neurocognitive Impairment in Human has relinquished the right to transplantation.394 Authors
Immunodeficiency Virus Infection have suggested that it is inadvisable to transplant, for
instance, someone with a history of predatory sexual
Neurocognitive impairment is common in patients behavior, due to the high rates of recidivism in this popu-
infected with HIV.375 Although the incidence of HIV- lation.395 Others argue that incarcerated individuals are
associated dementia has declined because of combination legally and ethically entitled to transplantation.394,396-398
antiretroviral therapy (cART), the incidence of neuro- A strong intuitive reaction may be evoked, reflecting the
cognitive impairment in HIV-positive individuals thought that patients with a history of criminality are
remains extremely common.375,381-386 Neurocognitive somehow less deserving of this scarce resource than other
deficits in HIV affect executive function and include members of society.399,400 However, using social worth as
memory, attention, concentration, and processing a criterion for transplantation is considered not ethically
speed.382 HIV neurocognitive impairment can have a sig- legitimate.397,400-402An incarcerated individual is consid-
nificant impact on daily functioning375,382 and medication ered to have the same human worth as any other member
adherence.387,388 Cocaine and methamphetamine con- of society.397
tribute to cognitive impairment in HIV patients.382 One Denial of organ transplantation to incarcerated indi-
study revealed that HIV infection and active metham- viduals violates the Eighth Amendment to the U.S. Con-
phetamine dependence increases the risk for neurocogni- stitution, which guarantees necessary and appropriate
tive impairment.375,389 Chronic infection with HIV is a health care to this population.397,399,400,403 This was pred-
risk factor for neurocognitive impairment.390 Older icated on the legal case Estelle v Gamble in 1976, in which
patients with HIV are at higher risk for neurocognitive the Supreme Court ruled that prisoners are constitution-
impairment.375,382,391,392 HIV patients coinfected with ally entitled to receive adequate health care396,404 and that
HCV have higher rates of neurocognitive impairment excluding them from medical care constitutes cruel and
than patients with HIV monoinfection.375 unusual punishment.398,405 Moreover, the UNOS Ethics
Committee has issued a statement that suggests that
Screening for Cognitive Impairment in Human “one’s status as a prisoner should not preclude them from
Immunodeficiency Virus Patients. The European consideration for a transplant…”406
AIDS Clinical Society recommends screening for cog- The number of incarcerated individuals with end-
nitive impairment in asymptomatic HIV patients who stage liver disease who would qualify for liver transplan-
meet any one of the following criteria: patients with tation is expected to increase dramatically in coming
detectable plasma HIV RNA taking antiretroviral years.394 As organ transplantation has evolved to become
medications with limited central nervous system pene- standard of care for patients with end-stage liver dis-
tration; patients with a CD4 nadir less than 200; ease,405 transplant teams may be increasingly called upon
patients with active depression.375 Clinical instruments to consider patients with a criminal history for liver
 30 Psychiatric Assessment of Liver Transplant Candidates 397

transplantation. Historically transplant centers have objection followed the first heart transplantation in an
declined to list incarcerated individuals for transplanta- incarcerated individual in 2002, because of perceived
tion because of medical factors. They cite concerns that injustice.398,441Some authors argue that such perceived
specialized posttransplant management may be difficult injustice will result in a decrease in organ donation.405
in the context of a correctional facility setting.394,404,405 It A recent study on community preferences for allocation
has been argued that exposure to tuberculosis and other of solid organs for transplantation reveals that commu-
infectious diseases, as well as lack of transplant expertise nity members do in fact place weight on the “social
among prison personnel, increases the risk for organ worth” of an individual, make judgments about behav-
loss.404 However, nonmedical factors should be consid- iors and lifestyle choices of individuals considered for
ered if they could have an impact on medical out- transplantation, and believe that individuals with crimi-
come.399,406 Psychiatric and social risk factors, which are nal behavior should be given lower priority for organ
routinely used as selection criteria for the general popula- allocation.442 Community members commonly perceive
tion, apply equally to patients with a history of inequities in the allocation system based on wealth and
criminality.403 fame. Moreover, community members reporting per-
Incarceration is strongly associated with severe ceived inequity in the organ allocation system are less
mental illness.399,407,408 The most commonly reported likely to donate organs.443 It has been argued that medi-
disorders include psychotic illness409-412; substance cal teams need to take public perceptions into account
use disorders413,414; personality disorders415-417; anxiety, when considering candidacy for transplantation.444 As
depression, and suicidality418-420; and posttraumatic the numbers of incarcerated individuals with end-stage
stress disorder.414,421,422 High rates of ADHD have also liver disease increases, these challenging issues will
recently been reported.411,423,424 likely become more salient.
Incarcerated individuals have high rates of lifetime
trauma,425 including physical and sexual abuse.421,422
Moreover, they are at risk for traumatic victimization and
Mental Retardation
sexual abuse during incarceration, increasing their risk In the early 1990s mental retardation was generally
for posttraumatic stress disorder.422 accepted to be an contraindication to transplanta-
Incarcerated individuals also have high rates of trau- tion.10,445,446 A 1992 survey revealed that 69.6% of liver
matic brain injury426-430 and intellectual disability.431-434 transplant centers reported that an IQ between 50 and 70
There are also high rates of homelessness in incar- was a relative contraindication to transplantation, and
cerated individuals.412,435,436 Moreover, incarceration that 45.7% of centers felt an IQ less than 50 was an abso-
increases the risk for homelessness by attenuating fam- lute contraindication to liver transplantation.445 Concern
ily and community links.436 Released prisoners may regarding the patient’s ability to navigate adherence with
have difficulty reintegrating into society after release.437 posttransplant medication regimens has been cited as a
Suicide is common, particularly in the first year after cause for denial of transplantation.445 In a discussion of
release.438 psychosocial criteria for transplantation, Orentlicher
The UNOS Ethics Committee statement concludes commented that although there may be cases in which
that it is the purview of each individual transplant team to mental retardation would be a contraindication to trans-
consider the potential impact of such nonmedical factors plantation because it increases risk for a poor medical
on posttransplant outcome.406 Some argue that each case outcome, each patient must be evaluated on an individual
should be considered individually. Some prisoners may basis. To deny transplantation a priori purely on the basis
be appropriate transplant candidates, whereas others may of mental retardation is a violation of the Americans
not.403 Aside from the traditional role of risk assessment With Disabilities Act.143 Moreover, patients with mental
in the case of an individual with a history of incarceration, retardation may enjoy a good QOL and can be highly
the transplant psychiatrist’s role may extend to educating valued by their family and society.346 Level of social sup-
the transplant team members regarding legal and ethical port and functionality have been cited as useful criteria
issues and consideration of requesting an ethics and legal for assessment of patients with mental retardation.346,445
consultation in such cases. Evaluating each patient on an individual basis has been
Some transplant programs have come under public recommended.445
scrutiny for transplanting incarcerated patients or There are over 50 reported cases of kidney transplan-
patients with a criminal history. Due to the fact that tation in patients with mental retardation. The evidence
organs are a scarce resource, transplant teams are placed suggests that medical outcomes in patients with mental
in the difficult position of balancing medical justice retardation are comparable to outcomes in patients with-
(what is best for the patient) and social justice (what is out.446 A recent review revealed a 3-year survival of 90%,
best for society). The legal and ethical imperatives in comparable to national survival rates.445 Studies in this
treating these patients are sometimes at variance with review reported that strong social support is critical to
community perceptions of social fairness. The poten- medical follow-up and immunosuppressive adher-
tially damaging effect on social attitudes toward dona- ence.445,447 One multicenter study revealed good graft
tion of transplanting an individual convicted of a morally function at 41 months in 25 pediatric kidney transplant
reprehensible crime, has been raised.439 As recent cases recipients with mental retardation, and superior patient
demonstrate, there is widespread belief within the com- survival at 1 and 5 years compared with controls.448 A
munity that an incarcerated individual is not as deserv- more recent study revealed equivalent 5-year graft sur-
ing of transplantation as other individuals.440 A wave of vival in kidney recipients with mental retardation, with an
398 PART IV Special Considerations in Patient Evaluation

adherence rate of 100% compared to 94% among specific recommendations to physicians.456 There is an
controls.449 understandable reluctance on the part of the medical
There are relatively few published cases of heart trans- community to submit patients to a procedure they can-
plantation in patients with mental retardation. The highly not comprehend.457 Although severe mental retardation
publicized case of the first patient with Down’s syndrome may be a relative contraindication to liver transplanta-
to receive a heart transplant revealed that the patient tion due to the patient’s inability to comprehend the
was fully adherent with the immunosuppressant regimen transplant process, including the need for medications,
and medical care after transplantation.450 A child with in select cases social support may mitigate this con-
8p chromosome deletion underwent heart transplanta- cern.458 Limited evidence suggests that patients with
tion at 3 months, and long-term follow-up revealed evi- mental retardation can benefit from transplantation400
dence of ongoing health at 15 years of age.451 In a recent and that transplant outcomes in this population are
case series of five patients with mental retardation who comparable to the general population.445 Decisions
underwent heart transplantation, the median survival regarding organ allocation should take into account
was greater than 12 years, and nonadherence with individual differences and the total circumstance of the
immunosuppression was clinically significant in only patient.136,143,450
one case, in which the patient’s caregiver decompen-
sated. Although they acknowledge that the literature is
sparse, the authors conclude that this population can
Nonadherence
receive substantial long-term benefit from heart trans- It is critical for liver transplant recipients to remain
plantation with adequate social support, and that mental adherent to immunosuppressant medications and medi-
retardation should not be considered a contraindication cal recommendations. Adherence encompasses not only
to transplantation.446 the correct taking of medicines, but also consistency in
There is a paucity of literature on liver transplanta- attending clinic appointments, laboratory draws,
tion in patients with mental retardation. Two case stud- promptly alerting appropriate transplant team members
ies on liver transplantation in patients with COACH regarding concerns or changes in medical status,459 self-
(cerebellar vermis hypoplasia, oligophrenia, ataxia, col- monitoring (e.g., blood pressure and blood glucose lev-
oboma, and hepatic fibrosis) syndrome report successful els), exercise, and abstinence from substances.460 In the
long-term outcome. In one study a patient with “mini- context of transplantation, adherence to medications
mal mental retardation” underwent liver transplantation includes not only immunosuppressants, but a host of
at the age of 8 years. It was reported that the patient’s antivirals, antifungals, antibiotics, and commonly, dia-
family was dedicated to lifelong supervision of medica- betic medications, antihypertensives, and cholesterol-
tion adherence. The patient had a good long-term lowering medications.459
medical outcome, with ongoing psychomotor and intel- Nonadherence with immunosuppressant medications
lectual development, matriculation into school, and places liver transplant recipients at risk for graft rejection
ultimately graduation from high school.452 A more and loss.459-465 Nonadherence with immunosuppressant
recent study reported a successful long-term outcome medication accounts for up to 25% of deaths after solid
for combined liver and kidney transplantation for organ transplantation.460-462 In liver transplant patients,
COACH in a 28-year old woman with significant men- nonadherence with immunosuppressant medications has
tal retardation. The authors reported good QOL with been demonstrated to correlate with a high incidence of
no neurological deterioration at 5-year follow-up. late acute rejection.459,461,462,466-469
Strong social support was cited as a critical factor in the Several risk factors for nonadherence in transplant
successful outcome.453 recipients have been identified. A history of nonadher-
The American Society of Transplantation guidelines ence is a risk factor for nonadherence after liver trans-
for renal transplant candidates recommends a primary plantation.126,460,462 In particular, a history of medication
support person who can ensure adherence with medical nonadherence is an independent predictor of immuno-
follow-up and medication adherence for patients with suppressant nonadherence after liver transplantation.19
mental retardation.446,454 Current clinical practice Psychiatric disorders are a risk factor for nonadher-
guidelines for kidney transplantation state that “some ence after liver transplantation.459,466 Depression and
individuals with irreversible cognitive impairment, anxiety are associated with nonadherence after liver
although unable to give informed consent, may never- transplantation.126 Depression, in particular, has been
theless benefit from transplantation.”446,454 The current correlated with acute rejection in liver transplant
guidelines for the International Society for Heart and patients.26 Personality disorders are also associated
Lung Transplantation state that mental retardation with nonadherence in liver transplant patients.126 In
may be considered a relative contraindication to trans- particular, borderline personality disorder, with its
plantation but offers no further details apart from a defining feature of unstable emotions and relation-
statement that “psychosocial factors predictive of out- ships, is a risk factor for nonadherence2,126,130 and is
come should not be confused with judgments of an indi- correlated with nonadherence in liver transplant
vidual’s social worth.”446,455 The American Association recipients. Personality attributes, such as an avoidant
for the Study of Liver Diseases practice guidelines for coping style470 and lower “conscientiousness,”19,459 are
liver transplantation state that mental retardation poses also predictive of nonadherence after liver trans­
a significant ethical and logistical challenge but offer no plantation. Cognitive impairment is also associated
 30 Psychiatric Assessment of Liver Transplant Candidates 399

with nonadherence after organ transplantation.460,462 A To address stress management and resilience skills,
history of substance abuse predicts nonadherence with there is some research that shows mindfulness-based
abstinence after transplantation.317 In two early studies stress reduction to be effective in reducing stress and
a history of any substance use was correlated with alco- improving QOL in both transplant patients and their
hol use after liver transplantation.471,472 Relapse to caregivers.480 Mindfulness-based stress reduction
alcohol after liver transplantation is associated with (MBSR) programs generally consist of eight weekly 2.5
medication nonadherence.460 hour classes, originally developed for chronic pain
Patient beliefs that their medications are harmful and patients by Jon Kabat-Zinn. MBSR is designed to facili-
concerns about the side effects of their medications can tate adaptation to the stressors associated with chronic
lead to nonadherence after liver transplanta- illness by emphasizing mindful awareness and meditation
tion.459,462,466,473 Liver transplant patients have reported to reduce symptom distress and improve well-being.480 A
perceived distress due to side effects, including fatigue, randomized controlled trial among solid organ transplant
body image, hypertrichosis, and hyperphagia.466 patients found that within the MBSR group anxiety,
Lack of social support is associated with posttransplant depression, and sleep symptoms decreased and QOL
nonadherence.19,317,461,474 measures improved by 8 weeks and the benefits were
Nonadherence is complex and informed by myriad retained at 1 year.480
factors. Moreover, there is a cumulative relationship Another stress reduction and resilience-building inter-
between the predictive factors; the more risk factors there vention that is being researched in the transplant care-
are, the greater the risk for nonadherence.2 Patient edu- giver population is the Stress Management and Resilience
cation and establishing a therapeutic relationship with Training (SMART) Program, which was adapted from
health care providers may improve adherence.466 Recent Attention and Interpretation Therapy (AIT). AIT was
studies suggest that patient education on immunosup- developed at the Mayo Clinic to decrease stress and
pressant medications is associated with increased medica- enhance resilience. It generally consists of two 90-minute
tion adherence after liver transplantation.459,475 group training sessions and four follow-up teleconfer-
ences, where participants learn to train their attention, to
Mindfulness and Other Innovative delay judgment, and to pay greater attention to novelty in
the world rather than contents of the mind, while also
Psychosocial Support Mechanisms cultivating skills such as gratitude, compassion, accep-
It is well documented that psychosocial factors influence tance, forgiveness, and higher meaning and purpose. The
transplant outcomes, and thus it is important that trans- intervention is currently being researched in transplant
plant centers actively support patient psychosocial needs caregivers and has already been shown to improve resil-
through a variety of mechanisms. Transplantation is ience, perceived stress, anxiety, and overall QOL in
stressful for even the most resilient patient. The stress patients diagnosed with breast cancer.481 One studied
inherent in waiting for an organ, undergoing invasive found music therapy to be effective in liver transplant
surgery, postoperative recovery, and the complex medical patients, leading to an increase in positive affect and a
regimen required to maintain the graft can lead to reduction in pain.482
increased stress and anxiety. If not properly addressed, The support group model has been widely used in
stress can negatively affect health outcomes, increase transplant centers. In addition, many centers are using
maladaptive coping behaviors, and increase mental health peer mentoring programs for patients and caregivers to
risks.476 Ideally some form of psychosocial support must gain additional support and information throughout the
be available for all transplant patients regardless of psy- transplant process, which can improve the patient experi-
chiatric background or diagnosis. ence.483 Increased use of the Internet and social media
In addition to patient support, attention must also be capabilities offers innovative ways to connect patients to
given to supporting the caregiver because high levels of each other, and online mentoring forums and support
caregiver burden and stress are associated with liver communities are now options.
transplant.477 Liver transplant caregivers report more An additional upcoming strategy to further support
mood disturbance, lower life satisfaction, and less social transplant patients is health coaching. A health coach
intimacy with the patient.478 A study of both liver and could provide assistance with coping and health behav-
kidney transplant caregivers found that 19% reported iors during the stages of transplantation, which could
symptoms of clinical depression.479 Caregiver needs are help improve health outcomes and graft survival.
often overlooked but are integral to successful transplan- Health coaches provide patients with self-management
tation and can affect patient outcomes. There currently is tools and coping strategies and assist in self-activation
a lack of research into which strategies best support to master complex medical regimens. Health coaching
patients and caregivers in coping and adapting through- has been used successfully in a variety of chronically ill
out transplantation. Many transplant centers are address- populations, including those with diabetes, asthma,
ing this by using innovative and complementary and hypertension, cancer pain, obesity, and more.484 As
alternative strategies to provide more psychosocial sup- with other strategies, patients can now be easily
port for their patients. The following are examples of coached telephonically or via the Internet using Skype
some of the current strategies being researched and used or other technologies, making it a more feasible strat-
in the transplant community to support patient and care- egy for patients to use regardless of geographical
giver psychosocial needs. constraints.
400 PART IV Special Considerations in Patient Evaluation

Pearls and Pitfalls

• Mood and anxiety disorders are common before and after • Obesity is highly comorbid with psychiatric disorders, in-
transplant. Even patients with mild symptoms may benefit cluding mood and anxiety disorders, and substance abuse.
from pharmacological management and close psychiatric A nutrition consultation, weight loss and exercise program,
follow-up. and referral for psychiatric treatment may be indicated.
• Alcohol abuse is chronic medical disorder with a relaps- • Living donor liver transplantation is associated with psy-
ing and remitting course. Patients with a history of alcohol chiatric morbidity in donors. Psychiatric history, motiva-
abuse and relatively recent abstinence may benefit from tion for donation, and coping history are key features of the
12-step attendance or a structured formal chemical depen- evaluation. A donor advocate team should be established to
dency program. support the donor before and after transplantation.
• Tobacco use is associated with increased morbidity and • Elderly transplant candidates may have cognitive impair-
mortality after liver transplantation. Patients who are ac- ment, which could compromise their ability to manage
tively smoking should be referred to a tobacco cessation the complex medication regimen that transplantation re-
program. Active marijuana use is considered a contraindi- quires. Elderly patients are also at risk for postoperative
cation at most U.S. transplant centers. delirium, particularly in the context of immunosuppres-
• Patients with personality disorders are at risk for non- sion. Neuropsychiatric testing to assess baseline cogni-
adherence and pose a challenge to the development of a tive functioning should be considered for patients with
therapeutic relationship with the transplant team. A multi- advanced age.
faceted and intensive approach may be required to ensure • Hepatitis C virus (HCV) and human immunodeficiency virus
an optimal medical outcome. (HIV) infection are associated with depression, anxiety, and
• Schizophrenia is a chronic mental illness that places pa- cognitive impairment. Patients with HCV and HIV should
tients at risk for psychiatric complications after liver trans- be screened for these neuropsychiatric disorders.
plantation. However, strong social support and optimal • The transplantation of incarcerated individuals or patients
psychiatric treatment can result in successful transplant with a history of criminality may pose an ethical challenge
outcomes. for the transplant team. However, some individuals may
• Acetaminophen toxicity is an increasingly common cause be considered appropriate candidates. Incarceration is
of acute liver failure. The circumstances of the overdose strongly associated with psychiatric morbidity, traumatic
(unintentional versus intentional) should be established, brain injury, and homelessness. Social support may be cru-
along with a history of analgesic use. Collateral history cial to ensuring an optimal outcome.
from family, friends, and treating physicians is critical in • Patients with mental retardation may benefit from trans-
cases in which the patient is unable to provide a history. plantation and should be evaluated on an individual ba-
• Chronic pain and opioid abuse are common in patients sis, taking into account all aspects of their circumstance.
presenting for liver transplant evaluation and are highly co- Strong social support may mitigate the risk for nonadher-
morbid with psychiatric disorders. A history of the pain syn- ence after transplantation.
drome and analgesic use patterns is essential. Patients with • A history of nonadherence is associated with posttransplant
chronic pain may benefit from referral to a pain specialist. nonadherence. Depression, substance abuse, and poor so-
• Methadone maintenance treatment is not necessarily an cial support are associated with nonadherence. Patients
absolute contraindication to liver transplantation. There is with these risk factors should be monitored closely for ad-
no evidence to support discontinuation before transplanta- herence with medical recommendations.
tion. However, this treatment is correlated with depression • Mindfulness and stress reduction strategies may be helpful
and chronic pain issues, which should be addressed.    to patients and their families.

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ronmental correlates and predictors of early adherence and out- ients. J Music Ther. 2011;48(4):463-485.
comes after liver transplantation. Prog Transplant. Mar 483. Wright L, Pennington JJ, Abbey S, et al. Evaluation of a mentor-
2010;20(1):58-66. quiz 67. ship program for heart transplant patients. J Heart Lung Trans-
471. DiMartini A, Weinrieb R, Fireman M. Liver transplantation in plant. 2001;20(9):1030-1033.
patients with alcohol and other substance use disorders. Psychiatr 484. Newnham-Kansas C, Gorczynski P, Morrow D, Irwin JD. Anno-
Clin North Am. Mar 2002;25(1):195-209. tated Bibliography of Life Coaching and Health Research. Inter-
472. Foster PF, Fabrega F, Karademir S, et al. Prediction of abstinence national Journal of Evidence Based Coaching and Mentoring.
from ethanol in alcoholic recipients following liver transplanta- 2009;7(1):39.
tion. Hepatology. Jun 1997;25(6):1469-1477.
473. Kung M, Koschwanez HE, Painter L, et al. Immunosuppressant
nonadherence in heart, liver, and lung transplant patients: associ-
ations with medication beliefs and illness perceptions. Transplan-
tation. May 15 2012;93(9):958-963.
 CHAPTER 31

Pretransplantation
Evaluation: Cardiac
Michelle M. Kittleson

CHAPTER OUTLINE

CARDIAC CONDITIONS Stress Testing

Coronary Artery Disease Coronary Angiography
Heart Failure Right Heart Catheterization
Arrhythmias ROLE OF THE CARDIOLOGY CONSULTANT
EVALUATION ONGOING EVALUATION
History and Physical Examination
SUMMARY
Electrocardiography
Echocardiography

Liver transplantation is now offered to a larger popula- induce cardiac dysfunction or rhythm abnormalities.4
tion of patients because of the growth and experience of Postreperfusion syndrome has been attributed to acute
transplant centers and the improvements in technology acidosis, hyperkalemia, and hypothermia following reper-
and technique. For example, coronary artery disease fusion of the transplanted liver. The resulting cardio-
(CAD), left ventricular dysfunction, and arrhythmias vascular collapse, characterized by hypotension, myo­cardial
were once considered absolute contraindications to liver depression, and rhythm irregularities dramatically increases
transplantation.1,2 However, currently patients with these work placed on the heart.5 Left and right ventricular
cardiac issues may be considered for liver transplanta- dysfunction can occur during liver transplantation. The
tion.3 This chapter examines the incidence, risk factors, resulting hypotension may be multifactorial but can
management, and contraindications for these cardiac be poorly tolerated in patients with compromised coro-
conditions and the role of cardiac testing, including echo- nary perfusion, heart failure, valvular heart disease, or
cardiography, stress testing, and cardiac catheterization, cardiac arrhythmias. Anticipation of these stresses during
in the evaluation process. liver transplantation necessitates full cardiac evaluation
preoperatively.
Thus adequate myocardial reserve is vital to the suc-
CARDIAC CONDITIONS cess of liver transplantation, and the goal of the preop-
erative evaluation of cardiac function is to optimize
As liver transplantation has become more successful in myocardial function and minimize perioperative com-
the treatment of patients with end-stage liver disease, plications by identifying those patients who are at risk
patients of advancing age and patients with extrahepatic for myocardial infarction, heart failure, and arrhythmias.
organ dysfunction are being considered. However, the An overview of these cardiac conditions is provided in
heart of a patient undergoing liver transplantation must Table 31-1.
endure many stressors. Preload reduction may occur
from systemic hypotension related to blood loss or from
clamping of the inferior vena cava during resection of the
Coronary Artery Disease
native liver. The hemodynamic stress is greatest after Patients with cirrhosis were once considered to be at
reperfusion. Release of the inferior vena cava and portal low risk for CAD because of the associated low blood
vein clamps at reperfusion in the absence of venovenous pressure, low cholesterol levels, and coagulopathic state.
bypass will rapidly increase preload at the moment that However, improvements in donor organ management,
contractility is most impaired. Furthermore, aortic cross- surgical techniques, and immunosuppression have
clamping may be required to place an arterial graft and improved patients’ survival, and cardiac complications
thus abruptly increase afterload. Ionized hypocalcemia have emerged as a prominent cause of morbidity and
from citrate complexing during blood transfusions may mortality early6-8 and late9-13 after liver transplantation.

411
412 PART IV Special Considerations in Patient Evaluation

TABLE 31-1 Cardiac Conditions in Liver Transplant Candidates

Risk Factors Treatment Contraindications
Coronary Men > 45 years, women > 55 years Aspirin Disease not amenable to
artery Hypertension Statin revascularization
disease Cigarette smoking β-blockers Inability to tolerate
Elevated cholesterol levels ACE inhibitors antiplatelet therapy
Family history of premature coronary Revascularization (stents or surgical) (required for stents)
artery disease Inability to tolerate
Diabetes surgery (Child-Turcotte-
Nonalcoholic steatohepatitis Pugh class B or C)
Heart failure Coronary artery disease Diuretics Ejection fraction ≤ 40%
Atrial fibrillation ACE inhibitors
Valvular disease β-blockers
Cardiotoxins (cocaine, methamphet- Aldosterone antagonists
amine, alcohol, doxorubicin)
Infiltrative disease (sarcoidosis,
amyloidosis, or hemochromatosis)
Hypertrophic cardiomyopathy
Cirrhotic cardiomyopathy
Valvular Not seen more commonly in patients Surgical repair or replacement as Inability to tolerate
heart with liver disease indicated in patients without liver surgery (Child-Turcotte-
disease disease Pugh class B or C)
Arrhythmias Atrial fibrillation Atrial fibrillation: Would not contraindicate
Other supraventricular tachycardias Chemical or electrical cardioversion liver transplantation
Prolonged QT interval Rate control (β-blockers, calcium
channel blockers, digoxin)
Supraventricular tachycardias:
Rate control (β-blockers, calcium
channel blockers, digoxin)
Prolonged QT interval:
Correct hypokalemia, hypomagnesemia,
hypocalcemia, and avoid medica-
tions that cause QT prolongation

Traditional risk factors for CAD in the general popula- surgery27 but may be feasible in liver transplant
tion include men above 45 years of age, women above candidates.28-32
55 years of age, hypertension, cigarette smoking, ele- There are also no clear guidelines to determine when
vated cholesterol levels, family history of premature CAD is an absolute contraindication to liver transplanta-
CAD, and diabetes.14 In liver transplant candidates, dia- tion. At most centers, CAD not amenable to percutane-
betes, age above 50 years, and cirrhosis caused by non- ous or surgical revascularization would preclude liver
alcoholic steatohepatitis are predictive of postoperative transplantation. Similarly, patients who cannot tolerate
ischemic complications.15-19 Hypertension and hyper- percutaneous coronary intervention with its required
lipidemia are also associated with worse outcomes after antiplatelet therapy because of thrombocytopenia, coag-
transplantation.20 ulopathy, or significant risk for bleeding esophageal vari-
Although the exact incidence of significant CAD in ces would be denied liver transplantation. Liver transplant
patients undergoing liver transplantation is not clear, candidates requiring surgical revascularization with coro-
studies indicate that anywhere from 2.5% to 27% of nary artery bypass grafting who have Child-Turcotte-
asymptomatic patients with cirrhosis have CAD.7,17,21,22 Pugh class B or C cirrhosis may also be denied given the
Furthermore, there are clearly poor outcomes in patients high perioperative mortality from cardiac surgery,33
with preexisting CAD who undergo liver transplantation. although revascularization at the time of liver transplan-
In a study of 32 patients the 3-year cardiovascular mortal- tation is an option that is now being considered at some
ity was 50%,21 although more recent studies indicate centers.28,30
lower 3- and 5-year mortality rates of 22% to 26%, per-
haps related to better patient selection and postoperative
management.23,24
Heart Failure
What is not clear, however, is how treatment of CAD The most common cause of left ventricular systolic dys-
affects outcomes after liver transplantation. Medication function is CAD. Other common causes include atrial
optimization is essential, with aspirin, statin, β-blocker, fibrillation, aortic stenosis, illicit cardiotoxic drugs
and angiotensin-converting enzyme (ACE) inhibitor (cocaine, methamphetamine), medical cardiotoxic drugs
therapy as tolerated based on the patient’s platelet count, (doxorubicin [Adriamycin]), as well as primary myocar-
transaminase levels, blood pressure, and renal function.25 dial disorders such as myocarditis or peripartum cardio-
As for coronary revascularization, this does not confer myopathy. Heart failure can also occur in the setting of
benefit in the general population of patients with chronic normal left ventricular function. In this case the cause is
stable angina26 or in patients undergoing noncardiac most often long-standing hypertension and diabetes
 31 Pretransplantation Evaluation: Cardiac 413

mellitus but can be a result of infiltrative (such as sarcoid- age, hypertension, and CAD. Management strategies
osis, amyloidosis, or hemochromatosis), hypertrophic, or include rhythm control to maintain normal sinus rhythm
constrictive cardiomyopathies. There are causes of heart or rate control to prevent rapid ventricular response and
failure specifically related to liver disease. Alcohol has a anticoagulation to prevent stroke. Other supraventricular
direct myocardial depressant effect and may cause a tachycardias, such as regular narrow-complex tachycardia
dilated cardiomyopathy, which can be reversible on ces- with reentrant electrical pathways often involving the
sation of alcohol use.34 Hemochromatosis not only results atrioventricular node, may also be present in patients
in cirrhosis from hepatic iron deposition but may cause with end-stage liver disease. These tachycardias are par-
an infiltrative cardiomyopathy as well.35 oxysmal and usually well controlled with atrioventricular-
There is also an entity termed cirrhotic cardiomyopathy. nodal blocking agents such as β-blockers, calcium channel
In this condition patients have normal cardiac function blockers, or digoxin or radiofrequency ablation.
on resting echocardiogram because cardiac workload is QT prolongation is often seen in patients with cirrho-
reduced by the peripheral vasodilation related to liver sis,48,49 most often associated with advanced age, alco-
failure,36 but when subjected to stress, these patients will holic cirrhosis, and higher Child-Turcotte-Pugh class. A
develop heart failure and reduced left ventricular systolic prolonged QT interval places patients at increased risk
function. There are specific abnormalities that may be for ventricular arrhythmias, although there is no associa-
detected in asymptomatic liver transplant candidates, tion between a prolonged QT interval and mortality.50
including baseline increased cardiac output, a diminished Management includes correction of reversible causes,
contractile response to stress, impaired diastolic relax- including hypokalemia, hypomagnesemia, and hypocal-
ation, and electrophysiological abnormalities such as a cemia; and avoidance of medications that prolong the
prolonged QT interval and chronotropic incompe- QT interval, including many antiarrhythmics, antipsy-
tence.37,38 However, there is no single diagnostic test to chotics, macrolide and fluoroquinolone antibiotics, and
identify cirrhotic cardiomyopathy, and the entity is most azole antifungal medications.
helpful in retrospect because it provides insight into why Preexisting dysrhythmias such as atrial fibrillation or
some patients develop evidence of heart failure after supraventricular tachycardia may be aggravated by the
transplant.39 Studies indicate that patients who survive increased adrenergic state present after surgery. This is
the initial posttransplant period will have normalization further aggravated by perioperative volume, electrolyte,
of cardiac function over the ensuing months,40 and thus and acid-base imbalances. These circumstances could
efforts should be directed at postoperative stabilization of lead to hypotension, making postoperative management
blood pressure and volume status. more difficult. Patients with preexisting prolonged QT
The incidence of heart failure in liver transplant recip- interval may be at particular risk for polypharmacy, and
ients in retrospective studies ranges from 7% to 31%.41-43 the electrocardiogram (ECG) should be closely moni-
However, identifying which patients may be at risk and tored postoperatively. In general, atrial fibrillation should
identifying what level of pretransplant left ventricular be treated with rate control as the blood pressure allows,
dysfunction should preclude liver transplantation are not and intravenous amiodarone may be particularly useful in
clear. For liver transplant candidates with known left ven- cardioversion to normal sinus rhythm (as long as the QT
tricular dysfunction, optimization of medical therapy interval remains acceptable). Electrical cardioversion is
with diuretics, ACE inhibitors, β-blockers, and aldoste- reserved for patients with hemodynamic instability,
rone antagonists44 is essential, as long as tolerated based because patients may simply revert back to atrial fibrilla-
on renal function and blood pressure. A general recom- tion because of the ongoing postoperative stress driving
mendation is to avoid liver transplantation in patients the arrhythmia.
with an ejection fraction on echocardiogram at or below
40%.45 In extreme cases, heart-liver transplantation may
be performed in patients with end-stage heart and liver EVALUATION
disease and has been successful in case reports.46
The preoperative cardiac evaluation of liver transplant
candidates is far more stringent than that recommended
Arrhythmias by the American Heart Association and American College
Patients with preexisting arrhythmias are generally not of Cardiology for the evaluation of patients undergoing
precluded from liver transplantation. The most common noncardiac surgery.51 According to these guidelines, non-
arrhythmias that occur in candidates for and recipients of invasive risk stratification may be considered (but is not
liver transplantation are atrial fibrillation, other supra- mandated) for asymptomatic patients (1) with functional
ventricular tachycardias, and QT prolongation. Atrial capacity less than 4 metabolic equivalents (comparable to
fibrillation is an irregular narrow-complex tachycardia walking at 3.5 mph); (2) undergoing vascular surgery; and
that may be paroxysmal (spontaneous return to normal (3) who have three or more risk factors (a known history
sinus rhythm), persistent (return to normal sinus rhythm of CAD, cerebrovascular disease, heart failure, diabetes,
after chemical or electrical cardioversion), or chronic or renal insufficiency). For intermediate-risk surgeries,
(chemical or electrical cardioversion is unsuccessful).47 including solid organ transplantation, noninvasive risk
Patients may have no symptoms or feel palpitations, chest stratification is not recommended.
discomfort, shortness of breath, and light-headedness Despite this, the preoperative cardiac evaluation of
related to the rapid and irregular ventricular response. potential liver transplant recipients includes echocar-
The most common causes of atrial fibrillation are older diography and stress testing for essentially all candidates
414 PART IV Special Considerations in Patient Evaluation

Liver transplant candidate

History/physical examination
Electrocardiogram
Echocardiogram

Normal evaluation Abnormal electrocardiogram Abnormal history/physical Abnormal echocardiogram

Age > 40 yr Q waves, ST-T changes, Age > 60 yr EF ≤ 40% RVSP > 40 mm Hg
Risk factors for CAD LVH, BBB Diabetes > 5 yr Wall motion
Symptoms of ischemia abnormalities
History of CAD

No Yes Stress test

Normal Abnormal

No further testing Coronary angiogram Right heart catheterization

FIGURE 31-1 n Suggested strategy for preoperative cardiac assessment of liver transplant candidates. See text for details. BBB, Bundle
branch block; CAD, coronary artery disease; EF, ejection fraction; LVH, left ventricular hypertrophy; RVSP, right ventricular systolic
pressure.

and coronary angiography for high-risk patients. This elevated jugular venous pressure, the presence of ascites,
more intensive approach is justified by the higher acuity edema, and murmurs. However, these findings can be
of potential transplant recipients and because surgery unreliable, because the symptoms and signs of advanced
involves the use of a scarce resource that should be liver disease can mimic those of heart failure. Patients
reserved for patients who will survive the surgery.52 The with cirrhosis may experience fatigue and shortness of
process is summarized in Figure 31-1. breath with minimal exertion, ascites, and edema. In
addition, the debilitated state of these patients may limit
History and Physical Examination their exercise capacity such that they do not exercise to
the point of angina. Thus symptoms and signs are unreli-
Assessment of cardiac risk for liver transplantation able, and the lack of angina does not rule out the presence
begins with a detailed history with careful attention to of CAD or preclude the need for ischemic evaluation.
the presence of cardiac risk factors and symptoms sug-
gestive of coronary ischemia or significant valvular heart
disease. Traditional risk factors for CAD in the general
Electrocardiography
population include men above 45 years of age, women All patients undergoing evaluation for liver transplanta-
above 55 years of age, hypertension, cigarette smoking, tion should receive an ECG. Although an ECG does not
elevated cholesterol levels, family history of premature suffice for evaluation, there may be findings that suggest
CAD, and diabetes.14 A history of tobacco use should be the presence of underlying cardiac disease. Findings that
sought, particularly in patients with alcohol-related liver warrant further investigation with stress testing include
disease. Hyperlipidemia may occur in patients with pri- Q-wave and ST-segment or T-wave abnormalities sug-
mary biliary cirrhosis. Diabetes is a risk factor for nonal- gestive of CAD, left ventricular hypertrophy suggestive
coholic steatohepatitis and may be secondarily present in of hypertension, and right or left bundle branch block
patients with hemochromatosis. Patients with a history suggestive of underlying structural heart disease. The
of hypertension may present with normal or decreased presence of right axis deviation, right atrial enlargement,
blood pressure caused by vasodilation from advanced or right ventricular hypertrophy indicates possible pul-
liver disease but are still at risk for developing coronary monary hypertension and would merit close attention to
disease. the echocardiogram and possibly right heart catheteriza-
The presence of cardiac symptoms should be assessed tion to assess pulmonary artery pressures. Prolongation
in all patients undergoing liver transplant evaluation, of the QT interval, as noted earlier, requires correction
including exertional chest discomfort, exertional dys- of reversible causes, including hypokalemia, hypomag-
pnea, palpitations, light-headedness, and syncopal epi- nesemia, and hypocalcemia; and avoidance of medica-
sodes. Pertinent physical examination findings include tions that prolong the QT interval, including many
 31 Pretransplantation Evaluation: Cardiac 415

antiarrhythmics, antipsychotics, macrolide and fluoro- resulting in hypoxemia. Visualization of bubbles in the
quinolone antibiotics, and azole antifungal medications. left ventricle late after administration of intravenous
Any rhythm abnormalities identified should be con- saline contrast (after the fourth or fifth cardiac cycle) sug-
trolled before transplantation. gests the presence of intrapulmonary shunting. Intrapul-
monary shunting is common in liver disease, and when it
Echocardiography is associated with hypoxemia (Pao2 < 60 mm Hg in room
air), the diagnosis of hepatopulmonary syndrome is sug-
Echocardiography with Doppler should also be per- gested. The intravenous saline contrast should be given
formed on all patients undergoing evaluation for liver both with and without a Valsalva maneuver, because
transplantation. Two-dimensional echocardiography right-to-left shunting may be present only when the right
assesses left ventricular systolic function and the presence atrial pressure is increased, as demonstrated by the Val-
of wall motion abnormalities. Abnormal left ventricular salva maneuver.
function with an ejection fraction of 45% or less or the
presence of wall motion abnormalities will merit coro-
nary angiography to determine if untreated CAD is the
Stress Testing
cause of abnormal left ventricular function. However, a Patients older than 40 years or those with risk factors
general contraindication to liver transplantation is an for CAD (hypertension, cigarette smoking, dyslipid-
ejection fraction on echocardiogram at or below 40% emia, family history of premature CAD, and diabetes)14
because these patients likely lack the cardiac reserve to should undergo stress testing. In addition, those patients
withstand surgery.45 In extreme cases, heart-liver trans- with abnormal findings on ECG as outlined earlier may
plantation may be performed in patients with end-stage also require a stress test. Patients with end-stage liver
heart, and liver disease and has been successful in case disease are frequently debilitated and may not develop
reports.46 angina, because they are unable to exert themselves to
Doppler evaluation of the cardiac valves detects the extent that the myocardial oxygen demand exceeds
whether significant valvular disease is present, which may the decreased supply caused by the presence of CAD.
have an adverse effect on the perioperative risk for car- The debilitated state of these patients also precludes
diovascular complications. The management of valvular them from performing a valid exercise stress test using a
heart disease in a liver transplant candidate is guided by treadmill or a bicycle, because they are unlikely to be
the guidelines for management of valvular heart disease able to exert themselves to the extent that they reach
in patients without liver disease.53 Valvular abnormalities 85% of predicted maximal heart rate with physical exer-
are not more common in patients with end-stage liver tion. Pharmacological stress testing has been used suc-
disease, and usually such abnormalities will not preclude cessfully in a strategy to detect the presence of CAD as
transplantation. However, if a patient has a severe, symp- part of a comprehensive cardiovascular evaluation for
tomatic valvular lesion meriting surgery and has Child- noncardiac surgery in those who cannot perform a max-
Turcotte-Pugh class B or C cirrhosis, he or she may be imal exercise stress test.51
denied because of prohibitive operative risk.33 Pharmacological stress testing involves a pharmaco-
Doppler evaluation of the tricuspid valve is used to logical stress and an imaging modality. The stress may be
estimate right ventricular systolic pressure, which in the dobutamine, which augments heart rate and contractility,
absence of pulmonic stenosis is an accurate estimate of or a vasodilator such as dipyridamole or adenosine, which
the systolic pulmonary artery pressure. Elevation of pul- augments coronary perfusion. The imaging modality may
monary artery pressure suggests the presence of porto- be echocardiogram or myocardial perfusion scintigraphy
pulmonary hypertension. If the estimated right ventricular with thallium 201 or Tc 99m sestamibi. The two most
systolic pressure is above 40 mm Hg, the patient will common modalities are dobutamine stress echocardiog-
require right heart catheterization with a balloon-tipped raphy and vasodilator myocardial perfusion scintigraphy.
pulmonary artery catheter to confirm the presence of There are advantages and disadvantages to each modality
pulmonary hypertension. in patients with end-stage liver disease. β-blockers admin-
Although not a standard part of the evaluation, intra- istered to end-stage liver disease patients for portal hyper-
venous saline contrast can be given to detect the presence tension may interfere with the ability to achieve 85% of
of right-to-left shunting while undergoing echocardiog- predicted maximum heart rate with dobutamine, thus
raphy. This is most commonly performed in patients in reducing the sensitivity of dobutamine stress echocar-
whom an intracardiac or intrapulmonary shunt is sus- diography.54 However, because patients with end-stage
pected on the basis of unexplained hypoxia, unexplained liver disease are often maximally vasodilated with low
right ventricular enlargement, the suggestion of a patent blood pressure and low systemic vascular resistance, they
foramen ovale (PFO) on two-dimensional echocardio- may not achieve the necessary increase in coronary blood
gram, or the suggestion of interatrial shunting on Dop- flow in response to a vasodilator stress test.39
pler echocardiogram. Bubbles from the intravenous In the general population, echocardiography is less
saline contrast crossing the atrial septum seen within the sensitive but more specific than myocardial perfusion
first or second cardiac cycle suggest the presence of a scintigraphy in detecting ischemia,55 and dobutamine is
PFO, which would assist in fluid management preopera- better than vasodilators in inducing ischemia.56 This has
tively, perioperatively, and postoperatively. As preload also been confirmed in patients with liver disease, in
increases, the right atrial pressure will increase and exac- whom dobutamine myocardial perfusion scintigraphy is
erbate right-to-left shunting across the PFO, possibly more sensitive than dobutamine stress echocardiogram
416 PART IV Special Considerations in Patient Evaluation

for detecting myocardial ischemia.57 Multiple studies performed via an internal jugular, subclavian, or femoral
confirm the low sensitivity and low positive predictive vein approach guided by pressure tracings or fluoroscopy.
value, but high negative predictive value, of dobutamine This procedure documents right atrial, right ventricular,
stress echocardiography for obstructive CAD and for pulmonary artery, and pulmonary capillary wedge pres-
postoperative cardiac events.7,54,58,59 The lower specific- sures and also measures cardiac output. Right heart cath-
ity of myocardial perfusion scintigraphy may be due to eterization is required in any patient with suspected
attenuation artifacts from ascites, which mimic ischemia pulmonary hypertension, including those with estimated
or infarction. However, like dobutamine stress echocar- right ventricular systolic pressure above 40 mm Hg on
diogram, normal results of a pharmacological myocardial echocardiogram. The procedure can also assess the
perfusion study do have excellent negative predictive degree of compensation for patients with reduced left
value.23 ventricular function who may be considered for liver
Although there is no consensus on the best stress test- transplantation.
ing modality in liver transplant candidates, it is likely Severe, irreversible pulmonary hypertension noted on
most prudent to opt for whichever modality is considered right heart catheterization would preclude liver trans-
to have the best accuracy at a given center. In any case a plantation. A detailed discussion of the mechanisms, inci-
high pretest probability of CAD or any evidence of isch- dence, risks, and treatment of portopulmonary
emia on stress testing should prompt further evaluation hypertension is covered in Chapter 39. In addition, evi-
with coronary angiography to define the extent of dis- dence of decompensated heart failure on right heart cath-
ease, establish options for treatment, and determine if the eterization, with elevated filling pressures and a reduced
patient remains an acceptable candidate for liver cardiac output in conjunction with an ejection fraction
transplantation. below 45% would contraindicate liver transplantation.

Coronary Angiography ROLE OF THE CARDIOLOGY

Coronary angiography is an invasive approach requiring CONSULTANT
arterial access that provides the gold-standard assessment
of CAD. Coronary angiography is recommended for any At some centers all potential liver transplant candidates
patient with abnormal stress test results. Furthermore, are evaluated by a cardiologist. At the very least, any
any patient with a history of prior CAD treated with per- patient with concerning findings on screening history,
cutaneous coronary intervention or surgical revascular- physical examination, and testing should be seen by a
ization should have a coronary angiogram for risk cardiologist. For example, any patient with exertional
stratification as part of the evaluation for liver transplan- chest discomfort, shortness of breath, palpitations, light-
tation if it has been more than 2 years since the revascu- headedness, or fainting spells may require cardiology
larization procedure.51 Other indications to proceed consultation unless a clear noncardiac cause is estab-
directly with coronary angiography without abnormal lished. Furthermore, patients with a history of CAD,
stress test results include symptoms highly suggestive of heart failure, valvular heart disease, or arrhythmias, even
ischemia, an echocardiogram showing reduced left ven- if currently asymptomatic, should see a cardiologist.
tricular function, patients with long-standing diabetes Patients with findings of heart failure or murmurs on
(usually for over 5 years or with end-organ damage such physical examination should also be also evaluated.
as retinopathy, neuropathy, or nephropathy), and those Finally, if abnormalities are detected in the screening
above 60 years of age. ECG, echocardiogram, or stress test, evaluation by a car-
There are also no clear guidelines to determine what diovascular specialist would be helpful to further deter-
findings on coronary angiography would be an absolute mine the risk for adverse cardiovascular events and to
contraindication to liver transplantation. At most centers identify treatment strategies that would assist in lowering
CAD not amenable to percutaneous or surgical revascu- the risk to an acceptable level. It is also very helpful to
larization would preclude liver transplantation. Similarly, have a cardiologist present at the selection committee
patients who cannot tolerate percutaneous coronary meetings where liver transplant candidates are discussed.
intervention with its required antiplatelet therapy because The cardiologist can discuss patient issues in a clearer
of thrombocytopenia, coagulopathy, or significant risk and more efficient fashion than that provided by review-
for bleeding esophageal varices would be denied liver ing consultation notes and can also provide advice on
transplantation. Liver transplant candidates requiring issues that arise in the course of discussion.
surgical revascularization with coronary artery bypass
grafting who have Child-Turcotte-Pugh class B or C cir-
rhosis may also be denied, given the high perioperative ONGOING EVALUATION
mortality from cardiac surgery,33 although revasculariza-
tion at the time of liver transplantation is an option that is Liver transplant candidates may remain on the waiting
now being considered at some centers.30 list for over a year. In this situation, ongoing evaluation is
essential to confirm their continued acceptability for
transplantation. In a low-risk patient with normal ECG,
Right Heart Catheterization echocardiogram, and stress test results, repeat testing
Right heart catheterization, also known as pulmonary should be performed every 2 years. In patients with
artery catheterization or Swan-Ganz catheterization, is established CAD or long-standing diabetes, cardiology
 31 Pretransplantation Evaluation: Cardiac 417

consultation with stress testing should be performed on Pearls and Pitfalls—Cont’d

an annual basis.
• Coronary angiography is required for any patient with
abnormal stress test results, a history of prior CAD,
SUMMARY symptoms highly suggestive of ischemia, an echocar-
diogram showing reduced left ventricular function,
Liver transplant surgery involves hemodynamic instabil- long-standing diabetes, or over 60 years of age.
ity that can be poorly tolerated in patients with preexist- • Right heart catheterization is required in any patient
ing cardiac disease. Identification of ischemia, heart with suspected pulmonary hypertension, including
those with estimated right ventricular systolic pressure
failure, valvular heart disease, and arrhythmias preopera- above 40 mm Hg on echocardiogram. The procedure
tively is essential to optimizing cardiac status and reduc- can also assess the degree of compensation for patients
ing perioperative morbidity and mortality. Ultimately, with reduced left ventricular function who may be
the cardiac evaluation is a team effort combining the considered for liver transplantation.
expertise of the hepatologist, liver transplant surgeon, • Any patient with concerning findings on screening
and cardiologist to assess the risks and benefits for each history, physical examination, and testing should be
individual patient. seen by a cardiologist, and ideally a cardiologist will be
   present at the selection committee meeting.

Pearls and Pitfalls

• Liver transplant surgery involves hemodynamic insta- REFERENCES
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surgical revascularization because of Child-Turcotte- obesity in adult liver transplant recipients. Transplant Proc.
2003;35:1909-1910.
Pugh class B or C cirrhosis would be denied. 10. Pruthi J, Medkiff KA, Esrason KT, et al. Analysis of causes of death
• An ejection fraction on echocardiogram at or below in liver transplant recipients who survived more than 3 years. Liver
40% would contraindicate liver transplantation. Transpl. 2001;7:811-815.
• Patients with preexisting arrhythmias are generally not 11. Kashyap R, Jain A, Reyes J, et al. Causes of death after liver trans-
precluded from liver transplantation. The most com- plantation in 4000 consecutive patients: 2 to 19 year follow-up.
mon arrhythmias that occur in candidates for and recip- Transplant Proc. 2001;33:1482-1483.
ients of liver transplantation are atrial fibrillation, other 12. Appleton CP, Hurst RT, Lee KS, et al. Long-term cardiovascular
supraventricular tachycardias, and QT prolongation. risk in the orthotopic liver transplant population. Liver Transpl.
• Assessment of cardiac risk for liver transplantation 2006;12:352-355.
13. Guckelberger O, Byram A, Klupp J, et al. Coronary event rates in
begins with a detailed history with careful attention liver transplant recipients reflect the increased prevalence of car-
to the presence of cardiac risk factors and symptoms diovascular risk-factors. Transpl Int. 2005;18:967-974.
suggestive of coronary ischemia or significant valvular 14. Executive Summary of the Third Report of The National Choles-
heart disease. terol Education Program (NCEP) Expert Panel on Detection,
• Signs and symptoms can be unreliable: debilitated pa- Evaluation, and Treatment of High Blood Cholesterol in Adults
tients may not be able to exercise to the point of angi- (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
na, and advanced liver disease can mimic heart failure. 15. Plotkin JS, Johnson LB, Rustgi V, et al. Coronary artery disease and
• All patients undergoing evaluation for liver transplan- liver transplantation: the state of the art. Liver Transpl. 2000;S53-S56.
tation should receive an electrocardiogram (ECG) and 16. Appleton CP, Hurst RT. Reducing coronary artery disease events
in liver transplant patients: moving toward identifying the vulner-
echocardiogram. able patient. Liver Transpl. 2008;14:1691-1693.
• Pharmacological stress testing is required for patients 17. Carey WD, Dumot JA, Pimentel RR, et al. The prevalence of cor-
older than 40 years, those with risk factors for CAD onary artery disease in liver transplant candidates over age 50.
(hypertension, cigarette smoking, dyslipidemia, family Transplantation. 1995;59:859-864.
history of premature CAD, and diabetes), and those 18. Kryzhanovski VA, Beller GA. Usefulness of preoperative noninva-
with abnormal findings on ECG or echocardiogram. sive radionuclide testing for detecting coronary artery disease in
candidates for liver transplantation. Am J Cardiol. 1997;79:986-988.
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19. Munoz SJ. Hyperlipidemia and other coronary risk factors after 44. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update
orthotopic liver transplantation: pathogenesis, diagnosis, and man- incorporated into the ACC/AHA 2005 Guidelines for the Diagno-
agement. Liver Transpl Surg. 1995;1:29-38. sis and Management of Heart Failure in Adults: a report of the
20. Johnston SD, Morris JK, Cramb R, et al. Cardiovascular morbidity American College of Cardiology Foundation/American Heart
and mortality after orthotopic liver transplantation. Transplanta- Association Task Force on Practice Guidelines: developed in col-
tion. 2002;73:901-906. laboration with the International Society for Heart and Lung
21. Plotkin JS, Scott VL, Pinna A, et al. Morbidity and mortality in Transplantation. Circulation. 2009;119:e391-479.
patients with coronary artery disease undergoing orthotopic liver 45. Lavi R, Lavi S, Daghini E, et al. New frontiers in the evaluation of
transplantation. Liver Transpl Surg. 1996;2:426-430. cardiac patients for noncardiac surgery. Anesthesiology. 2007;107:
22. Tiukinhoy-Laing SD, Rossi JS, Bayram M, et al. Cardiac hemody- 1018-1028.
namic and coronary angiographic characteristics of patients being 46. Hennessey T, Backman SB, Cecere R, et al. Combined heart and
evaluated for liver transplantation. Am J Cardiol. 2006;98:178-181. liver transplantation on cardiopulmonary bypass: report of four
23. Zoghbi GJ, Patel AD, Ershadi RE, et al. Usefulness of preoperative cases. Can J Anaesth. 2010;57:355-360.
stress perfusion imaging in predicting prognosis after liver trans- 47. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006
plantation. Am J Cardiol. 2003;92:1066-1071. Guidelines for the Management of Patients With Atrial Fibrillation—
24. Diedrich DA, Findlay JY, Harrison BA, et al. Influence of coronary Executive Summary: A Report of the American College of Cardiol-
artery disease on outcomes after liver transplantation. Transplant ogy/American Heart Association Task Force on Practice Guidelines
Proc. 2008;40:3554-3557. and the European Society of Cardiology Committee for Practice
25. Smith Jr SC, Benjamin EJ, Bonow RO, et al. AHA/ACCF second- Guidelines (Writing Committee to Revise the 2001 Guidelines for
ary prevention and risk reduction therapy for patients with coro- the Management of Patients With Atrial Fibrillation) Developed in
nary and other atherosclerotic vascular disease: 2011 update: a Collaboration With the European Heart Rhythm Association and the
guideline from the American Heart Association and American Col- Heart Rhythm Society. J Am Coll Cardiol. 2006;48:854-906.
lege of Cardiology Foundation endorsed by the World Heart Fed- 48. Garcia Gonzalez M, Hernandez-Madrid A, Lopez-Sanroman A,
eration and the Preventive Cardiovascular Nurses Association. J et al. Reversal of QT interval electrocardiographic alterations in
Am Coll Cardiol. 2011;58:2432-2446. cirrhotic patients undergoing liver transplantation. Transplant Proc.
26. Boden WE, O'Rourke RA, Teo KK, et al. Optimal Medical Ther- 1999;31:2366-2367.
apy with or without PCI for stable coronary disease. N Engl J Med. 49. Zurick 3rd AO, Spier BJ, Teelin TC, et al. Alterations in corrected
2007;356:1503-1516. QT interval following liver transplant in patients with end-stage
27. McFalls EO, Ward HB, Moritz TE, et al. Coronary-artery revas- liver disease. Clin Cardiol. 2010;33:672-677.
cularization before elective major vascular surgery. N Engl J Med. 50. Bal JS, Thuluvath PJ. Prolongation of QTc interval: relationship
2004;351:2795-2804. with etiology and severity of liver disease, mortality and liver trans-
28. Lima B, Nowicki ER, Miller CM, et al. Outcomes of simultaneous plantation. Liver Int. 2003;23:243-248.
liver transplantation and elective cardiac surgical procedures. Ann 51. Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007
Thorac Surg. 2011;92:1580-1584. guidelines on perioperative cardiovascular evaluation and care for
29. Axelrod D, Koffron A, Dewolf A, et al. Safety and efficacy of com- noncardiac surgery: a report of the American College of Cardiol-
bined orthotopic liver transplantation and coronary artery bypass ogy/American Heart Association Task Force on Practice Guide-
grafting. Liver Transpl. 2004;10:1386-1390. lines (Writing Committee to Revise the 2002 Guidelines on
30. Benedetti E, Massad MG, Chami Y, et al. Is the presence of surgi- Perioperative Cardiovascular Evaluation for Noncardiac Surgery):
cally treatable coronary artery disease a contraindication to liver developed in collaboration with the American Society of Echocar-
transplantation? Clin Transplant. 1999;13:59-61. diography, American Society of Nuclear Cardiology, Heart
31. Ehtisham J, Altieri M, Salame E, et al. Coronary artery disease in Rhythm Society, Society of Cardiovascular Anesthesiologists,
orthotopic liver transplantation: pretransplant assessment and Society for Cardiovascular Angiography and Interventions, Society
management. Liver Transpl. 2010;16:550-557. for Vascular Medicine and Biology, and Society for Vascular Sur-
32. Azarbal B, Poommipanit P, Arbit B, et al. Feasibility and safety of gery. Circulation. 2007;116:e418-499.
percutaneous coronary intervention in patients with end-stage 52. Raval Z, Harinstein ME, Skaro AI, et al. Cardiovascular risk assess-
liver disease referred for liver transplantation. Liver Transpl. ment of the liver transplant candidate. J Am Coll Cardiol. 2011;58:
2011;17:809-813. 223-231.
33. Filsoufi F, Salzberg SP, Rahmanian PB, et al. Early and late out- 53. Bonow RO, Carabello BA, Chatterjee K, et al. 2008 Focused
come of cardiac surgery in patients with liver cirrhosis. Liver update incorporated into the ACC/AHA 2006 guidelines for the
Transpl. 2007;13:990-995. management of patients with valvular heart disease: a report of the
34. Urbano-Marquez A, Estruch R, Navarro-Lopez F, et al. The American College of Cardiology/American Heart Association
effects of alcoholism on skeletal and cardiac muscle. N Engl J Med. Task Force on Practice Guidelines (Writing Committee to Revise
1989;320:409-415. the 1998 Guidelines for the Management of Patients With Valvu-
35. Dabestani A, Child JS, Henze E, et al. Primary hemochromatosis: lar Heart Disease): endorsed by the Society of Cardiovascular
anatomic and physiologic characteristics of the cardiac ventricles Anesthesiologists, Society for Cardiovascular Angiography and
and their response to phlebotomy. Am J Cardiol. 1984;54:153-159. Interventions, and Society of Thoracic Surgeons. Circulation.
36. Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of 2008;118:e523-661.
chronic liver diseases: from the patient to the molecule. Hepatology. 54. Williams K, Lewis JF, Davis G, et al. Dobutamine stress echocar-
2006;43:S121-S131. diography in patients undergoing liver transplantation evaluation.
37. Wong F. Cirrhotic cardiomyopathy. Hepatol Int. 2009;3:294-304. Transplantation. 2000;69:2354-2356.
38. Zardi EM, Abbate A, Zardi DM, et al. Cirrhotic cardiomyopathy. 55. Geleijnse ML, Krenning BJ, Nemes A, et al. Diagnostic value of
J Am Coll Cardiol. 2010;56:539-549. dobutamine stress echocardiography in patients with normal wall
39. Martinez-Palli G, Cardenas A. Preoperative cardiopulmonary motion at rest. Echocardiography. 2007;24:553-557.
assessment of the liver transplant candidate. Ann Hepatol. 56. Paetsch I, Jahnke C, Wahl A, et al. Comparison of dobutamine
2011;10:421-433. stress magnetic resonance, adenosine stress magnetic resonance,
40. Torregrosa M, Aguade S, Dos L, et al. Cardiac alterations in cir- and adenosine stress magnetic resonance perfusion. Circulation.
rhosis: reversibility after liver transplantation. J Hepatol. 2004;110:835-842.
2005;42:68-74. 57. Tsutsui JM, Mukherjee S, Elhendy A, et al. Value of dobutamine
41. Fouad TR, Abdel-Razek WM, Burak KW, et al. Prediction of car- stress myocardial contrast perfusion echocardiography in patients
diac complications after liver transplantation. Transplantation. with advanced liver disease. Liver Transpl. 2006;12:592-599.
2009;87:763-770. 58. Harinstein ME, Flaherty JD, Ansari AH, et al. Predictive value of
42. Eimer MJ, Wright JM, Wang EC, et al. Frequency and signifi- dobutamine stress echocardiography for coronary artery disease
cance of acute heart failure following liver transplantation. Am J detection in liver transplant candidates. Am J Transplant.
Cardiol. 2008;101:242-244. 2008;8:1523-1528.
43. Ripoll C, Catalina MV, Yotti R, et al. Cardiac dysfunction during 59. Safadi A, Homsi M, Maskoun W, et al. Perioperative risk predic-
liver transplantation: incidence and preoperative predictors. Trans- tors of cardiac outcomes in patients undergoing liver transplanta-
plantation. 2008;85:1766-1772. tion surgery. Circulation. 2009;120:1189-1194.
 CHAPTER 32

Pretransplantation
Evaluation: Renal
Martin L. Mai • Hani M. Wadei

CHAPTER OUTLINE

ACID-BASE DISTURBANCES Adrenal Insufficiency

ELECTROLYTE ABNORMALITIES Abnormal Renal Autoregulation and
Precipitating Factors
Sodium Disturbances
Diagnosis
Potassium Disturbances
Treatment
ASSESSING RENAL FUNCTION General Management
Creatinine/Cystatin C Vasoconstrictor Therapy
Estimation Equations Transjugular Intrahepatic Portosystemic Shunt
Glomerular Filtration Rate Measurement Combination (Sequential) Therapy
HEPATORENAL DISORDERS Renal Replacement Therapy
Acute Kidney Injury: Prerenal Liver and Liver-Kidney Transplantation
Acute Kidney Injury: Hepatorenal Syndrome Acute Kidney Injury: Parenchymal/Intrinsic
Criteria Acute Kidney Injury: Postrenal/Obstructive
Epidemiology Chronic Kidney Disease
Natural History and Prognosis Acute on Chronic Kidney Disease
Pathophysiology Hepatorenal Disorders and Dialysis Support
Arterial Vasodilatation EVALUATION
Renal Prostaglandins Operative Planning
Role of Sympathetic Nervous System Immunosuppression Planning
Myocardial Dysfunction
SUMMARY

Kidney-related complications are common sequelae of Knowledge of the effects of liver disease on the kidney
hepatic failure. These complications include electrolyte enables proper preoperative evaluation of liver transplant
and acid-base abnormalities in addition to alterations in candidates.
renal function from hemodynamic changes and paren-
chymal disease. Since the introduction of the Model for
End-Stage Liver Disease (MELD) score in 2002, there ACID-BASE DISTURBANCES
has been a rise in the average serum creatinine level, per-
centage of renal replacement therapy (RRT), and use of Many metabolic abnormalities occur in the setting of
combination liver-kidney transplant in liver transplant hepatic failure, including disturbances in acid-base bal-
recipients.1,2 Proper assessment is critical for the patient ance. Respiratory alkalosis is the most frequent acid-base
undergoing evaluation for liver transplantation because abnormality, and the degree of alkalosis directly corre-
these kidney-related changes influence preoperative and lates with the severity of liver disease.19-21 The cause is
postoperative morbidity and mortality.3-13 Correcting uncertain, with progesterone22 and retained amines20
metabolic abnormalities, accurately assessing renal func- implicated as possible causes. The degree of respiratory
tion, appropriately using preoperative or intraoperative alkalosis does not appear to be associated with ammonia
dialysis, and listing for combined liver-kidney transplant (NH3) production or the development of hypoxemia.22
are valuable tools that may reduce perioperative risks.* Metabolic alkalosis may develop, most commonly as a
consequence of diuretic therapy or hypoalbuminemia.19,20
*References 3, 6, 7, 10, 11, 14–18. Metabolic alkalosis stimulates an increased formation of

419
420 PART IV Special Considerations in Patient Evaluation

NH3 from NH4+, which then more easily enters the Hyponatremia is an independent predictor of mortality
blood-brain barrier and increases the risk for hepatic before and after transplant in most,5,7,11,41-43 but not all
encephalopathy.20 Metabolic acidosis can occur in the studies,13,44 being a more discriminating factor at low
form of hyperchloremic and dilutional acidemia in addi- MELD scores. Whether correction of hyponatremia
tion to lactate and renal tubular acidosis. Dilutional and preoperatively improves outcomes after transplant is
hyperchloremic acidosis is a consequence of water reten- not clear, with one study showing liver transplant recip-
tion because of high antidiuretic hormone levels or fluid ients with "resolved" or corrected hyponatremia more
resuscitation with excess water or chloride-containing likely to be discharged at 3 weeks than uncorrected
solutions.3,19,23 Lactic acidosis develops in acute and patients, although there were no differences in mortal-
chronic forms of liver disease when insufficient hepatic ity at 180 days or other complications.34,44,45 A safe cut-
tissue remains to metabolize lactate or from overproduc- off for preoperative sodium concentration has not been
tion of lactate caused by complications of infection, gas- established. One opinion suggests deferring liver trans-
trointestinal bleeding, or hypotension.24,25 Distal (type 1) plant surgery in patients with high surgical risk and a
renal tubular acidosis has been reported in primary bili- serum sodium concentration of less than 120 mmol/L.46
ary cirrhosis, autoimmune hepatitis, alcoholic liver dis- Preoperative management of hyponatremia includes
ease, and cryptogenic cirrhosis.24,26 Proximal (type 2) fluid restriction, use of loop diuretics (to counteract uri-
renal tubular acidosis is associated with Wilson’s disease, nary concentration allowing free water excretion), and
often creating a true Fanconi syndrome.27 Forms of vasopressin-2 receptor blockers (vaptans) as the corner-
hyperchloremic metabolic acidosis may develop with the stones of therapy.† Intraoperative use of fluids to avoid
use of spironolactone, lactulose, or cholestyramine.28-30 overcorrecting hyponatremia is described, including
Renal dysfunction may be a source of metabolic acidosis use of tris-hydroxymethyl aminomethane (THAM) in
with advanced liver disease, and in both anion gap and lieu of sodium bicarbonate.48
nonanion gap forms.3,24 Acid-base disturbances do not Hypernatremia may develop as a consequence of treat-
present a contraindication to liver transplantation, and it ment with lactulose due to free water losses through the
is not known if correction improves outcomes, but recog- stool.30 Preoperative hypernatremia is associated with
nition is important for providing appropriate periopera- higher postoperative liver transplant mortality than
tive support.3,23,24 Mixed acid-base disturbances are hyponatremia but occurs much less frequently.41
common in patients with cirrhosis, and proper assess-
ment requires measurement of levels of electrolytes
(sodium, potassium, chloride, bicarbonate), serum albu-
Potassium Disturbances
min, and arterial blood gas at a minimum.3,19,31 Potassium changes also occur in patients with advanced
liver disease. Hypokalemia is most commonly caused by
diuretic use, gastrointestinal losses associated with lactu-
lose, and, rarely, magnesium deficiency.24 Hypokalemia is
ELECTROLYTE ABNORMALITIES a confounding factor in the development and maintenance
Sodium Disturbances of metabolic alkalosis and, as mentioned earlier, may
therefore increase the risk for hepatic encephalopathy.
Other metabolic abnormalities that occur in the setting Potassium supplementation and the use of potassium-
of hepatic failure are electrolyte changes. Hyponatre- sparing diuretics are effective therapies to correct hypoka-
mia is common in patients with advanced cirrhosis, with lemia. Renal dysfunction, β-blockers (used to prevent
31% to 49% having a serum sodium concentration of variceal bleeding), potassium-sparing diuretics, nonsteroi-
less than 135 mmol/L, 22% less than 130 mmol/L, and dal antiinflammatory drugs (NSAIDs), and the use of
2.5 % to 5.7% less than 125 mmol/L.7,32 Occasionally angiotensin-converting enzyme inhibitor and angiotensin
hypovolemia (most commonly associated with diuretic receptor blocker medication may singly or in combination
use) produces hyponatremia, but most often it is caused produce hyperkalemia.49,50 Monitoring potassium levels,
by hemodynamic changes occurring with hepatic fail- particularly in patients with renal dysfunction and con-
ure in the presence of ascites, representing a dilutional comitant use of these drugs, is important to prevent life-
or hypervolemic state.24,33,34 Splanchnic vasodilation threatening hyperkalemia. Preoperative hyperkalemia
leads to a decrease in effective arterial blood volume increases operative and mortality risks for the recipient.
stimulating baroreceptors, which in turn signal nonos- Preoperative hyperkalemia, defined as a potassium level of
motic production of antidiuretic hormone forcing the 4.5 mmol/L or higher, is associated with higher 1-year
kidneys to retain free water, diluting the serum sodium mortality when compared to those with a potassium level
concentration.6,34-36 Side effects of hyponatremia of less than 3.5 mmol/L.51 Higher preoperative potassium
include serious central nervous system symptoms of level is a risk factor for hyperkalemia during reperfusion.52
nausea, vomiting, lethargy, seizures, delirium, and It is recommended that perioperative dialysis be consid-
coma.35 The central nervous system signs of hyponatre- ered for any patient with a potassium level greater than 5.5
mia may mimic those of hepatic encephalopathy, and mEq/L, particularly patients with renal dysfunction.46,53
indeed hyponatremia is recognized as a precipitating To reduce the risk for reperfusion hyperkalemia during
factor for hepatic encephalopathy.34,37-39 Injudicious surgery, options include the use of insulin, β-agonists,
correction of hyponatremia may produce devastating albumin washout, and dialysis.46,53-56
demyelinating complications of the brain (central pon-
tine myelinolysis) before and after transplant.13,35,40 †References 6, 34, 45, 47, 48.
 32 Pretransplantation Evaluation: Renal 421

ASSESSING RENAL FUNCTION with the MDRD-6 achieved only 66% of estimates within
30% of GFR measured by 125I-iothalamate.76 The
Creatinine/Cystatin C Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) equation77 performs better at measuring
Clinical evaluation of renal dysfunction in patients with higher GFRs than the MDRD in a recent review of 12
advanced hepatic disease is challenging. Defining renal studies, most of which did not include patients with cir-
function remains important in establishing operative risk rhosis.78 When studied in patients with liver disease,
and candidacy for transplantation and may influence CKD-EPI offered no advantage when compared to
perioperative care, including postoperative immunosup- MDRD.79,80 Cystatin C formulas have been proposed to
pression. Creatinine is normally a useful marker of renal estimate GFR better than creatinine-based equations81,82;
function, but in this patient population it has been found however, when studied in patients with cirrhosis, mixed
to be unreliable for several reasons. Creatine, a precursor results were reported.69,83 Although no equation esti-
of creatinine, is primarily synthesized by the liver and is mated GFR acceptably, a work group of members of the
produced at rates that are half that of healthy volun- Acute Dialysis Quality Initiative and the International
teers.57 This decreases the substrate available for use by Ascites Club (IAC) recommended using the MDRD-6
the muscles and other tissue to produce creatinine. In formula to establish a diagnosis of chronic kidney disease
addition, malnourishment and decreased muscle mass with estimated GFR of less than 60 mL/min.84
lead to decreased production of creatinine, with blood
levels lower than one would expect for a particular given
glomerular filtration rate (GFR).58 Increased renal tubular
Glomerular Filtration Rate Measurement
secretion of creatinine may further reduce blood concentra- Determining GFR by direct measurements is possible
tions, particularly in a setting of renal dysfunction.59,60 with several tools. As mentioned before, inulin clearance
Analytic methods to determine creatinine concentration is recognized as the gold standard, but the scarcity of
should be traceable to isotope dilution mass spectrometry product, limited number of trained personnel, duration
creatinine reference measurement for standardization of of the study, and the expense limit its use to research set-
different assays, although even this correction still leads tings.64 A 24-hour urine collection for measuring creati-
to interlaboratory variations.61,62 Some analytical meth- nine clearance is a common means of determining GFR.
ods of determining crea­tinine concentration may under- Unfortunately, measured creatinine clearance in cir-
estimate true serum concentration in the presence of rhotic patients overestimates GFR by 13% when inulin
hyperbilirubinemia or protein-related interferences, clearance is greater than 70 mL/min, and by 96% when
although this appears to be laboratory dependent.63,64 In inulin clearance is less than 70 mL/min.57 These findings
cirrhotic patients with normal serum creatinine levels, were confirmed in a subsequent meta-analysis.85 None-
37% of patients are reported to have a GFR of less than theless, measured creatinine clearance, as an estimate of
50 mL/min, and 31% have a GFR between 50 and 80 GFR, is superior to creatinine or calculated creatinine
mL/min.65 This is one of several studies confirming the clearance.57,64 Other options for determining GFR
poor relationship between creatinine level and GFR.64 include use of isotope markers such as 125I-iothalamate,
Cystatin C has been proposed as an alternative marker to 99mTc-DTPA, and 51Cr-EDTA, and nonisotopes like
creatinine in estimating GFR. Production occurs in all cold iothalamate and iohexol.86-89 These techniques are
nucleated cells, and it is eliminated by glomerular filtra- not widely available, and none has been validated in cir-
tion with blood levels not influenced by age, sex, muscle rhotic patients to determine GFR, although they may be
mass, or bilirubin.14,66-69 Several studies have shown that helpful.57,64,67,85 Current expert opinion recommends
cystatin C better reflects GFR than creatinine.68,70-75 It using serum creatinine as the marker for renal dysfunc-
has not become widely used because of concerns of avail- tion, although it is flawed, because of its use in MELD
ability, cost, and assay variations resulting from infection determination and the fact that estimation equations and
and drugs such as corticosteroids or calcineurin direct measurement of GFR have not proved to be supe-
inhibitors.14 rior in assessment of renal function.90 In the future the
validation of new estimation equations or the isotope and
Estimation Equations nonisotope markers for GFR listed previously in addi-
tion to integrating imaging testing and biomarkers will
Equations estimating GFR are commonly used to assess make the determination of renal function more precise
renal function. These formulas contain varying combina- and improve selection and care of liver transplant
tions of a patient’s age, sex, weight, ethnicity, serum cre- candidates.90
atinine level, serum urea nitrogen level, and serum
albumin level to predict GFR. The popular Cockcroft-
Gault equation when compared to inulin clearance (the HEPATORENAL DISORDERS
gold standard for measuring GFR) in patients with
advanced liver disease is found to overestimate GFR, par- Establishing a diagnosis of renal disease is predicated on
ticularly in patients with inulin clearances less than finding a decreased GFR or proteinuria or abnormal uri-
70 mL/min.57,72,76 The Modification of Diet in Renal nary sediment. In the general population, definitions exist
Disease (MDRD) equation with four, five, and six for acute kidney injury (AKI)91 and chronic kidney disease
(MDRD-6) variables and the Nankivell equation were (CKD).92 Although a definition for hepatorenal syndrome
evaluated before liver transplant, and the best correlation (HRS) was amended in 2007 (Table 32-1),93 defining AKI
422 PART IV Special Considerations in Patient Evaluation

TABLE 32-1 International Ascites Club Criteria Acute Kidney Injury: Prerenal
for Hepatorenal Syndrome
AKI is the most common presentation of renal disease in
Diagnosis
patients with cirrhosis and comes in many forms.98-101
Cirrhosis with ascites Diseases are categorized as prerenal (hypoperfusion),
Serum creatinine >1.5 mg/dL renal (parenchymal/intrinsic), and postrenal injuries. Pre-
No improvement of serum creatinine (a decrease in serum renal injury is the most common form of AKI, mechanisti-
creatinine <1.5 mg/dL) after 2 days off diuretics and cally developing from reduced renal blood flow, loss of
volume expansion with albumin (1 g/kg body weight up renal perfusion maintenance, and a hyperdynamic circula-
to a maximum of 100 g/day) tion that makes the kidney more susceptible to hypoperfu-
Absence of shock sion changes and has been summarized in several
No current or recent treatment with nephrotoxic drugs reviews.84,99,102-110 In advanced form this prerenal physiol-
Absence of signs of parenchymal renal disease, as sug- ogy leads to HRS. The two disorders are differentiated by
gested by proteinuria (>500 mg/day) or hematuria (>50
red blood cells per high-power field) and/or abnormal prerenal disease responding to volume expansion. Diuretic
renal ultrasonography therapy, paracentesis, diarrhea secondary to lactulose, and
gastrointestinal bleeding may produce volume depletion
Modified from Salerno F, Gerbes A, Gines P, et al. Diagnosis, and adversely affect renal function. Although these com-
prevention and treatment of hepatorenal syndrome in cirrhosis.
Gut. 2007;56(9):1310-1318.
plications are risk factors for more severe prerenal injury
leading to HRS, in this setting the effect tends to be mild
and transient, responding to therapy. Prevention of vol-
TABLE 32-2 W
 orking Party Proposal for ume depletion in cirrhotic patients is important in main-
Classifying Renal Disease in taining renal health. Diuretic use for ascites should be
Cirrhosis limited to a maximal dose of 400 mg of spironolactone
and/or 160 mg of furosemide daily in divided doses.111
AKI Rise in Cr ≧ 0.3 mg/dL in <48 hr or rise Diuretics should be used cautiously in the setting of no
of >50% from baseline edema or ascites and urine losses resulting from diuretics
Type 1 HRS regarded as a specific form
of AKI
may exceed resorption of ascites, creating intravascular
CKD GFR <60 mL/min for >3 mo using
volume depletion.102,112 Potassium, blood urea nitrogen
MDRD-6 estimation equation (BUN), and creatinine levels should be monitored on this
Acute on CKD Rise in Cr ≧ 0.3 mg/dL in <48 hr or rise therapy. The furosemide natriuresis test may help identify
of >50% from baseline in a patient diuretic responders in advanced liver disease and avoid
with cirrhosis whose baseline GFR complications of diuretic use in nonresponders.113,114
<60 mL/min for >3 mo using MDRD-6 Hypovolemia after large-volume paracentesis may be pre-
estimation equation
vented by albumin infusion after treatment, and some
Modified from Wong F, Nadim MK, Kellum JA, et al. Working Party studies have suggested that concomitant use of nonselec-
proposal for a revised classification system of renal dysfunction tive β-blockers may increase the risk for paracentesis-
in patients with cirrhosis. Gut. 2011;60(5):702-709. induced circulatory dysfunction.102,115,116 Lactulose-induced
AKI, Acute kidney injury; CKD, chronic kidney disease; GFR, diarrhea used to treat hepatic encephalopathy may pro-
glomerular filtration rate; HRS, hepatorenal syndrome; MDRD,
Modification of Diet in Renal Disease. duce volume depletion, particularly if the patient does not
ingest adequate fluid because of confusion. Gastrointesti-
nal bleeding that produces hypotension must be aggres-
or CKD in patients with cirrhosis simply required a creati- sively treated to limit detrimental effects on renal function.
nine level of 1.5 mg/dL or higher.93-97 This lack of stan- Patients with subacute bacterial peritonitis should receive
dardization has slowed advances in the study of renal intravenous albumin to decrease the risk for kidney
disease in cirrhosis. Fortunately, new proposals have come injury.111,117 Other factors that may induce prerenal injury
forth defining these entities under the umbrella of hepa- resulting from exacerbation of vasoconstriction are
torenal disorders.84,90 Table 32-2 shows the proposed defi- NSAIDs and contrast. NSAIDs should be avoided in
nitions for AKI, CKD, and acute on chronic kidney disease patients with advanced cirrhosis, and the benefit of contrast
in cirrhosis. Validation of these proposals to determine use for imaging must be balanced against the risk for kidney
their role in predicting outcomes such as mortality before injury, particularly in those patients with creati-
and after liver transplant along with kidney function after nine94,99,102,118-120 level of 1.5 mg/dL or higher.
transplant is ongoing. In one study Belcher et al98 demon-
strated the value of the AKI definition in evaluating hospi- Acute Kidney Injury: Hepatorenal
talized patients with cirrhosis by showing that mortality Syndrome
rises as the stage of AKI increases and with the progression
of the AKI stage. Using these proposed definitions may HRS is a prerenal or functional form of AKI that devel-
more accurately determine the level of dysfunction (GFR) ops in patients with advanced cirrhosis or fulminant
in addition to the chronicity of disease, facilitating predic- hepatic failure. The hallmark of HRS is intense renal
tion of renal reserve (and reversibility of dysfunction) in vasoconstriction. Renal vasoconstriction starts early in
the setting of liver transplant. The other hope is that rec- the course of the liver disease, many months before renal
ognition of renal disease may promote earlier treatment, dysfunction is clinically evident, and gradually progresses
thereby improving outcomes. to reach its maximum intensity in HRS patients.
 32 Pretransplantation Evaluation: Renal 423

TABLE 32-3 Characteristics of Type 1 and Type 2 Hepatorenal Syndrome

History of Diuretic-Resistant
Course Precipitating Event Ascites Prognosis
Type 1 HRS Precipitous doubling of Present in 50%-70% May or may not be present Without therapy,
serum creatinine in of cases 90-day survival
<2 wk of 10%
Type 2 HRS Gradually progressive Absent Always present Median survival, 6 mo

HRS, Hepatorenal syndrome.

This explains why cirrhotic patients with normal kidney be misclassified as having CKD despite the absence of
function and Doppler ultrasound evidence of renal vaso- other CKD features such as proteinuria or hematuria.
constriction are more prone to develop HRS.121,122 Lastly, HRS is a form of AKI; nevertheless the IAC crite-
ria deviate from the Acute Kidney Injury Network defini-
Criteria tion of AKI in the general population as an absolute
increase in serum creatinine level by 0.3 mg/dL within a
There are two types of HRS. Type 1 HRS is defined as 48-hour period or urine output below 0.5 mL/kg/hr for 6
doubling of serum creatinine to a level greater than hours.128 Cirrhotic patients who develop AKI and HRS
2.5 mg/dL in less than 2 weeks, whereas in type 2 HRS with a rise in serum creatinine level by more than 0.3 mg/
there is a gradual rise in the serum creatinine level to dL in less than 48 hours and whose creatinine level does
greater than 1.5 mg/dL. There are notable differences not exceed 1.5 mg/dL cannot be labeled as having HRS
between type 1 and type 2 HRS that are summarized in according to the IAC criteria. This scenario is common in
Table 32-3. Type 1 HRS is more acute, commonly associ- cirrhotic patients because of their low muscle mass. A
ated with multiorgan failure, has a very grim prognosis, working party proposal suggested defining AKI in cir-
and can be confused with other causes of AKI, especially rhotic patients as a rise in serum creatinine level by 0.3
acute tubular necrosis (ATN). In type 1 HRS a precipitat- mg/dL or more within a 48-hour period or an absolute
ing event is identified in 50% to 70% of cases, and more 50% rise in serum creatinine level.84 Once AKI is diag-
than one event can occur in a single patient.123-126 Type 2 nosed, all efforts should be made to differentiate organic
HRS is the genuine form of renal failure in cirrhotic AKI from functional HRS. Overall, the current available
patients as it represents the extreme expression of cirrho- criteria for HRS diagnosis still need modification to align
sis-induced circulatory failure and is heralded by refractory HRS diagnosis with the current AKI staging system and
ascites. Renal failure in type 2 HRS is slowly progressive to clearly separate type 2 HRS from CKD.
and parallels the degree of deterioration of liver function.
The new IAC criteria for type 1 HRS diagnosis are Epidemiology
summarized in Table 32-1. The main points of difference
between the old and new criteria for HRS are as follows: Gines et al129 had previously estimated the 1- and 5-year
Creatinine clearance is no longer incorporated in the probability of HRS at 18% and 39%, respectively. How-
diagnosis. ever, a recent study that included 263 cirrhotic patients
Ongoing bacterial infection does not exclude the diag- followed for 41 ± 3 months estimated the incidence of
nosis of HRS, provided septic shock is not present. type-1 and type-2 HRS at 2.6% and 5%, respectively.10
Albumin is preferred to saline for plasma volume In this study the cumulative 5-year probability of HRS
expansion. Up to 100 g/day of albumin might need development was only 11.4%.10 This indicates that the
to be infused before diagnosing HRS. prevalence of HRS declined over the last 2 decades,
Nonessential minor diagnostic criteria, including low probably reflecting better management of cirrhotic
fractional excretion of sodium and oliguria, have patients and the wide use of prophylactic antibiotics for
been omitted. spontaneous bacterial peritonitis (SBP) prevention. The
The IAC criteria, however, have been recently chal- prevalence of HRS increases with the progression of
lenged for multiple reasons. First, these criteria are diffi- liver disease, and in patients with advanced cirrhosis
cult to implement in clinical practice. A recent multicenter waiting for liver transplantation the prevalence of HRS
study examined the applicability of these diagnostic crite- is as high as 48%.130 Almost 50% of cirrhotic patients
ria in daily clinical practice. Of the 116 patients diagnosed with ascites will develop AKI during the course of their
with HRS, only 64% met all diagnostic criteria as out- illness.131 HRS, however, constitutes a small fraction of
lined by the IAC while the remaining 36% with acute all AKI cases that develop in cirrhotic patients. In one
deterioration of serum creatinine level to above 1.5 mg/ study HRS was responsible for the deterioration of kid-
dL could not meet one or more of the diagnostic criteria ney function in only 7.6% of all 129 cirrhotic patients
because of anuria, hematuria, or proteinuria.127 Second, with ascites and AKI.131 In another multicenter retro-
the criteria for type 2 HRS diagnosis overlap with the spective study that included 423 patients with cirrhosis
definition of CKD. CKD is defined as low GFR of less and AKI, the most common cause of AKI was either
than 60 mL/min for more than 3 months' duration. ATN (35%) or prerenal failure (32%), whereas type 1
Therefore patients with type 2 HRS with a progressive and type 2 HRS were the cause of AKI in 20% and 6.6%
rise in serum creatinine level over 3 months or more can of cases, respectively.132
424 PART IV Special Considerations in Patient Evaluation

1.0
Natural History and Prognosis
HRS carries a grim prognosis. Gines and others have pre- 0.8
viously reported a 2-week mortality rate as high as 80%
in untreated type 1 HRS patients, with only 10% of

Probability
0.6
patients surviving for 3 months.94,129 Prognosis of type 2
HRS patients is slightly better, with a median survival of
6 months.133 In recent years, however, there has been a 0.4
trend toward a slight improvement in HRS prognosis.
For example, in a multicenter study by Salerno et al127 0.2
that included 116 HRS patients, some of them did receive
vasoconstrictor therapy; the 3-month survival was 20% 0.0
and 40% for type 1 and type 2 HRS, respectively. Another 0 2 4 6 8 10
study showed a 38% 1-year survival for type 2 HRS A Weeks
patients and a mean survival of only 7 days for type 1
HRS.10 Figure 32-1 outlines the historical and most
recent survival rates for patients with type 1 and type 2 1.0
HRS. It is noteworthy that HRS carries the worst survival
among all causes of AKI in cirrhotic patients. In a study
that included 562 cirrhotic patients with AKI, 3-month 0.8
survival for HRS patients was 15% compared to 31% for
patients with infection-induced AKI, 46% for hypovole-

Cumulative survival
mia-induced AKI, and 73% for AKI associated with evi-
dence of parenchymal renal disease (e.g., proteinuria or 0.6
hematuria; P < .0005).134 Therefore determining the
cause of AKI in cirrhotic patients not only determines the
treatment plan but also foretells the prognosis in these 0.4
patients.

Pathophysiology 0.2
HRS constitutes the most advanced stage of hemody-
namic dysfunction that starts early in the course of liver
disease even before ascites is clinically detectable. 0.0
These hemodynamic changes continue to progress as
cirrhotic patients progress from the preascitic stage to 0 30 60 90
diuretic-sensitive then diuretic-resistant ascites and B Time (days)
finally HRS. These hemodynamic changes are charac- FIGURE 32-1 n Probability of survival of patients with hepatorenal
terized by (1) splanchnic vasodilatation, (2) reduced syndrome (HRS) in two separate time periods. A, Survival of
effective arterial blood volume, (3) hyperdynamic cir- historical cohort of 56 patients who were diagnosed with HRS
before 1995. B, Survival of a recent cohort of 116 patients who
culation with increased cardiac output (CO), (4) reduced either developed type 1 (solid line) or type 2 (dashed line) HRS
systemic vascular resistance, (5) vasoconstriction of between April 2007 and February 2009. There is a trend toward
various extrasplanchnic vascular beds, including the improved 3-month survival in type 1 HRS in the recent cohort.
renal and cerebral circulations, and (6) increased activ- (Modified with permission from Gines A, Escorsell A, Gines P, et al.
Incidence, predictive factors, and prognosis of the hepatorenal syn-
ity of the renin-angiotensin-aldosterone system drome in cirrhosis with ascites. Gastroenterology. 1993;105[1]:
(RAAS), the sympathetic nervous system (SNS), and 229-236; and Salerno F, Cazzaniga M, Merli M, et al. Diagnosis,
nonosmotic release of vasopressin. Figure 32-2 sche- treatment and survival of patients with hepatorenal syndrome: a sur-
matically summarizes the progression of these hemody- vey on daily medical practice. J Hepatol. 2011;55[6]:1241-1248.)
namic changes from the preascitic stage to type 2 HRS.
In type 1 HRS similar pathophysiological changes
occur, albeit at a faster pace than in type 2 HRS. Increased inducible NOS activity has also been docu-
mented.137 Other vasodilator substances such as calcito-
Arterial Vasodilatation nin gene–related peptide (CGRP), substance P, carbon
monoxide, endocannabinoids, and adrenomedullin might
The key pathophysiological change in cirrhotic patients also be involved in the splanchnic vasodilatation.138-142
with HRS is splanchnic vasodilatation. Arterial vasodila- Bacterial translocation plays a central role in splanchnic
tation is mediated by the release of potent vasodilators, vasodilatation in decompensated cirrhosis, and the circu-
the most important of which is nitric oxide (NO).108 NO lating level of bacterial DNA (a marker of bacterial trans-
production is increased in the splanchnic circulation in location) is associated with lower systemic vascular
cirrhotic patients because of shear stress–induced upreg- resistance in cirrhotic patients compared to patients who
ulation of endothelial NO synthase (eNOS) activity, as do not have increased expression of this marker.143
well as endotoxin-mediated eNOS activation.135,136 Intense vascular neoformation in the liver and in the
 32 Pretransplantation Evaluation: Renal 425

Cardiac output

Normal
effective Effective arterial Splanchnic arterial
arterial hypovolemia
vasodilation
blood
volume
Systemic vascular
Changes resistance
Extra splanchnic
vasoconstriction
Degree of activation of
RAAS, SNS, and ADH

Compensated Time
cirrhosis Ascites
Hyponatremia
Type 2 HRS
FIGURE 32-2 n Hemodynamic changes occurring in cirrhotic patients starting from the preascitic phase to hepatorenal syndrome
(HRS). ADH, Antidiuretic hormone; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system. (Modified with
permission from Arroyo V, Fernandez J, Gines P. Pathogenesis and treatment of hepatorenal syndrome. Semin Liver Dis. 2008;28[1]:81-95.)

splanchnic circulation also develop because of the pres-

TABLE 32-4 H
 emodynamic Changes That
ence of high levels of proangiogenic substances such as
Occur in Liver Cirrhosis
vascular endothelial growth factor and platelet-derived
growth factor, which are also involved in the formation of Hepatic and the splanchnic circulation
an extensive network of portosystemic collaterals.144,145 Splanchnic vasodilatation
The end result is a reduction in systemic vascular resis- Hepatic vascular neoformation
tance and a decrease in effective blood volume despite an Increased portal pressure with portosystemic collateral
overall increase in total plasma and blood volumes. formation
Indeed, studies that included large numbers of cirrhotic Systemic circulation
patients who underwent invasive hemodynamic monitor- Increased cardiac output
ing confirmed the presence of low systemic vascular resis- Hyperdynamic circulation
tance and reduced effective circulating blood volume in Decreased arterial blood pressure
cirrhotic patients with increased blood pooling in the Increased plasma and total blood volumes
splanchnic region.146,147 Reduced effective blood volume Reduced central blood volume
activates the RAAS, unloads the high-pressure barore- Vasoconstriction of the renal, femoral, and cerebral
ceptors in the carotid body and aortic arch with subse- vascular beds
quent activation of the SNS, and induces nonosmotic
release of vasopressin. These changes lead to intense
renal vasoconstriction and reduced GFR. Other vascular action of these mediators.151 Table 32-4 summarizes the
beds show similar changes, and studies have demon- changes in the splanchnic and systemic circulations
strated vasoconstriction in the cerebral, femoral, and occurring in HRS patients.
upper extremities circulations that correlated with
reduced renal blood flow in HRS patients.148-150 With Renal Prostaglandins
worsening of the liver disease and progression of cirrho-
sis, further splanchnic vasodilation occurs, creating a In the kidney, renal vasoconstriction is counterbalanced
vicious cycle that favors further activation of the RAAS, by increased intrarenal production of vasodilating prosta-
SNS, and vasopressin release, and subsequent intensifica- glandins. Indeed, patients with liver disease and ascites
tion of renal vasoconstriction.108 Indeed, HRS patients exhibit increased renal vasodilating prostaglandins pro-
exhibit higher levels of circulating renin, aldosterone, duction as evidenced by increased urinary excretion of
norepinephrine, and other neurohormonal mediators these substances compared to normal controls.152,153 In
compared to cirrhotic patients with normal kidney func- HRS both urinary prostaglandin excretion and renal
tion. Despite the presence of high circulating levels of medullary cyclooxygenase activity are reduced, a finding
vasoconstrictor substances, the abundance of vasodilators that is not present in patients with other causes of AKI,
in the splanchnic circulation precipitates a state of hypo- indicating a role of reduced renal prostaglandin produc-
responsiveness in this vascular bed to the vasoconstrictive tion in the development of HRS.154 Factors associated
426 PART IV Special Considerations in Patient Evaluation

with lower renal prostaglandin production in HRS are Other features associated with adrenal insufficiency were
unknown, but reduced renal blood flow from intense severe liver failure, arterial hypotension, vasopressor
renal vasoconstriction may be the cause.155 It is important dependency, and increased hospital mortality.164 The
to mention that the administration of cyclooxygenase second study showed that treatment with hydrocortisone
inhibitors to ascitic cirrhotic patients precipitates a syn- in cirrhotic patients with severe sepsis and adrenal insuf-
drome similar to HRS, and therefore NSAIDs should be ficiency is associated with a rapid improvement in sys-
strictly avoided in these patients.156 temic hemodynamics, a reduction of vasopressor
requirements, and lower hospital mortality.165 The
mechanisms of adrenal dysfunction in cirrhosis with
Role of Sympathetic Nervous System
severe sepsis have not been explored, but a reduction in
Both human and animal studies demonstrate increased adrenal blood flow secondary to regional vasoconstric-
renal SNS activity, which contributes to the renal vasocon- tion is a possible mechanism.
striction occurring in HRS. For example, Kostreva et al157
showed increased renal SNS activity following vena cava Abnormal Renal Autoregulation and
ligation in anesthetized dogs that ended only after severing Precipitating Factors
the hepatic nerves. In humans, transjugular intrahepatic
portosystemic shunt (TIPS) insertion was associated with Under normal conditions, effective renal autoregulation
improvement in renal blood flow and reduction of SNS maintains constant renal blood flow despite wide fluctua-
activity that subsequently reversed following TIPS occlu- tions in arterial blood pressure. In cirrhotic patients the
sion.158,159 Finally, lumbar sympathectomy increased GFR relationship between renal blood flow and perfusion
in five patients with HRS, suggesting that increased renal pressure is altered because of the activation of the SNS
sympathetic activity is implicated in HRS development.160 and other vasoconstrictor stimuli with rightward devia-
These studies suggest the presence of a hepatorenal reflex tion of the renal autoregulatory curve. Thus renal blood
that contributes to renal vasoconstriction in HRS. flow becomes increasingly dependent on the arterial
blood pressure with the progression of liver disease (Figs.
32-3 and 32-4).109 Therefore in patients with advanced
Myocardial Dysfunction
cirrhosis, events that lead to the slightest change in perfu-
Multiple lines of evidence, however, indicate that a rela- sion pressure will translate into major drops in renal
tive decline in CO develops before HRS diagnosis and blood flow that might precipitate intense renal vasocon-
contributes to renal hypoperfusion and renal vasocon- striction and HRS. Identifiable precipitating events
striction in HRS patients. For example, low baseline CO include intravascular volume depletion from aggressive
at the time of SBP diagnosis correlated with subsequent diuretic use or following large-volume paracentesis with-
development of HRS.161 After the resolution of infection, out albumin infusion, also known as postparacentesis syn-
CO further declined in those in the HRS group.161 Ruiz- drome. The incidence of postparacentesis syndrome is
del-Arbol et al162 studied the systemic and hepatic hemo- very low when the volume of ascites removed is less than
dynamics of 66 patients with cirrhosis and tense ascites 5 L, but it progressively increases up to 70% of cases
who had normal serum creatinine levels at baseline with when the amount of fluid removed is above this limit.166,167
repeat measurements in 27 patients who subsequently Probably the most important precipitating event is bacte-
developed HRS. At baseline, arterial blood pressure and rial infections, especially SBP. Twenty percent to 30% of
CO were significantly lower and RAAS and SNS activity patients with SBP develop HRS despite appropriate
were significantly higher in the group that later devel- treatment and resolution of infection.117,168 SBP patients
oped HRS, with further reduction in CO at the onset of with preexisting hyponatremia or elevated serum creati-
renal dysfunction.162 In another study that included 24 nine level or those with high plasma or ascitic fluid cyto-
patients with cirrhosis and ascites, cardiac index below kine levels at the time of SBP diagnosis are predisposed to
1.5 L/min/m2 was associated with lower GFR and HRS.155,168 The reason SBP is associated with a high risk
increased risk for subsequent type 1 HRS development for HRS is related to the role of the inflammatory
compared to those with higher cardiac indexes.163 response to SBP in HRS development.155,168 Another
Although these studies do not establish causality, they do possible explanation is the development of septic cardio-
suggest that low CO and HRS are interrelated. myopathy with secondary deterioration in renal func-
tion.162 Urinary tract infections can also precipitate HRS
in 15% of cases, but HRS is uncommon following other
Adrenal Insufficiency
infections such as cellulitis and pneumonia.169,170 Twenty-
Two studies examined the role of adrenal dysfunction in five percent of patients presenting with acute alcoholic
HRS, especially in the intensive care setting.164,165 In the hepatitis eventually develop HRS.129,171 Although AKI
first study, adrenal insufficiency was detected in 80% of following gastrointestinal hemorrhage occurs more fre-
patients with HRS, but only in 34% with a serum creati- quently in cirrhotic patients compared to those without
nine level below 1.5 mg/dL.164 Because normal adrenal liver disease (8% versus 1%, P <.05), AKI develops almost
function is essential for an adequate response of the arte- exclusively in patients with hypovolemic shock and
rial circulation to endogenous vasoconstrictors, adrenal responds to fluid resuscitation, making prerenal failure a
insufficiency could be an important contributory mecha- more plausible diagnosis.95 As previously mentioned,
nism of circulatory dysfunction associated with HRS, NSAIDs do precipitate HRS by blocking vasodilating
especially in patients with severe bacterial infections. prostaglandin synthesis in the kidneys.172
 32 Pretransplantation Evaluation: Renal 427

3
Normal

Renal blood flow (mL/min/g)

2

HRS Effect of renal sympathetic

stimulation on autoregulation

0
0 20 40 60 80 100 120
Renal perfusion pressure (mm Hg)
FIGURE 32-3 n Relationship between renal blood flow and renal perfusion pressure in normal condition (solid line) and in hepatorenal
syndrome (HRS) patients (dotted line). At any given renal perfusion pressure, renal blood flow is lower in HRS patients compared to
normal conditions. (Modified with permission from Stadlbauer V, Wright GA, Banaji M, et al. Relationship between activation of the sympa-
thetic nervous system and renal blood flow autoregulation in cirrhosis. Gastroenterology. 2008;134[1]:111-119.)

3
CLD no ascites
Renal blood flow (mL/min/g)

Normal subjects
2
CLD ascites
responding
to diuretics

HRS subjects

0
0 20 40 60 80 100 120
Renal perfusion pressure (mm Hg)
FIGURE 32-4 n Renal blood flow versus renal perfusion pressure for normal subjects, cirrhotic patients with no ascites, cirrhotic
patients with diuretic-responsive ascites, and patients with hepatorenal syndrome (HRS). There is progressive rightward shift in the
renal autoregulation curve to the right with worsening of liver disease. CLD, Chronic liver disease. (Modified with permission from
Davenport A. Management of acute kidney injury in liver disease. Contrib Nephrol. 2010;165:197-205.)

Diagnosis
following infectious complications, which are known to
There is no test or investigation that is specific for the precipitate HRS. Traditional markers to differentiate
diagnosis of HRS. Therefore the diagnosis is mainly ATN from HRS such as the presence of granular urinary
based on the exclusion of other causes of AKI, unrespon- casts, low fractional excretion of sodium, or elevated
siveness to volume expansion, and meeting the diagnostic BUN level are insensitive for differentiating between
criteria for HRS outlined earlier. As mentioned earlier, type 1 HRS and ATN.93,173 In one study that included 44
type 2 HRS can be confused with CKD; however, the cirrhotic patients with renal dysfunction who underwent
presence of diuretic-resistant ascites and the lack of other kidney biopsy as part of liver transplant evaluation, low
radiological and laboratory features of CKD (e.g., pro- fractional excretion of sodium (FeNa < 1) was present in
teinuria or renal cortical thinning) can differentiate 92% of cases despite biopsy evidence of ATN or glomer-
between the two conditions. The main differential diag- ulonephritis.174 Multiple urinary biomarkers, including
nosis of type 1 HRS is ATN because both conditions are interleukin-18, neutrophil gelatinase associated lipocalin,
characterized by an acute onset and rapid progressive and others, are currently under investigation to differen-
deterioration of kidney function. ATN may also develop tiate between type 1 HRS and ATN. Despite these
428 PART IV Special Considerations in Patient Evaluation

difficulties, pinpointing the cause of AKI in cirrhotic and fractional excretion of sodium in 19 HRS patients.184
patients is important for both prognostic and therapeutic In type 1 HRS patients, assessing the intravascular vol-
purposes (discussed later). ume status using central venous access or, preferably,
global end-diastolic volume index is essential to guiding
fluid resuscitation and albumin infusion.184 In accordance
Treatment
with the IAC criteria and because of its established ben-
Prevention. Because of its overall poor prognosis, HRS eficial effects in cirrhotic patients, albumin infusion
is better prevented than treated, and preventive measures should be aggressively used before labeling patients as
have been beneficial in specific situations. For example, having HRS.93,185,186 Synthetic plasma expanders are less
following large-volume paracentesis (≥5 L), albumin is effective than albumin and are not recommended.186 Pre-
superior to other plasma expanders in preventing post- cipitating or aggravating factors such as SBP or adrenal
paracentesis circulatory dysfunction and renal impair- insufficiency should be diagnosed and aggressively
ment.166,175 In a double-blind, controlled study treated. Many of these patients are bed-bound and decon-
pentoxifylline use for 28 days in patients with alcoholic dition rapidly; therefore management should include
hepatitis was associated with a lower risk for HRS devel- early and adequate planning for early ambulation, reha-
opment and lower mortality.171 The mechanism of the bilitation, and adequate nutrition.
protective effect of pentoxifylline is believed to be related Assessment for liver transplantation should start as
to its anti–tumor necrosis factor activity.171 Prophylactic soon as possible. In type 1 patients not candidates for
antibiotics prevent bacterial translocation and suppress liver transplantation, realistic expectations should be set
proinflammatory cytokine formation implicated in the and aggressive treatment modalities should be avoided.
pathogenesis of HRS.176,177 It is not therefore surprising Pharmacological treatment and other interventions can
that prophylactic antibiotic use in patients at risk for SBP be offered on a case-by-case basis to selected type 2 HRS
was effective in reducing both SBP and HRS risks. In one patients not suitable for liver transplantation. In many
study, daily norfloxacin was associated with lower 1-year cases, transplant candidacy is unclear. In these patients all
SBP probability (7% compared to 61%, P <.001) and therapeutic options should be attempted until suitability
lower 1-year HRS probability (28% compared to 41%, for liver transplantation becomes clearer. The ideal goals
P = .02).178 Once SBP has developed, treatment with of treatment for HRS are to prolong survival until a liver
intravenous albumin (1.5 g/kg of body weight at diagnosis transplant becomes available and to optimize conditions
followed by 1 g/kg 48 hours later) in addition to ceftriax- for successful liver transplantation.
one reduced the incidence of HRS to 10%, compared to
33% in those who received ceftriaxone alone (P = .002).117 Vasoconstrictor Therapy
Hospital mortality (10% versus 29%) and 3-month mor-
tality rates (22% versus 41%) were also lower in patients Intravenous terlipressin and albumin infusion are the treat-
receiving albumin and an antibiotic compared to those ment of choice for HRS patients in Europe, but terlipressin
who received an antibiotic alone.117 The mechanisms by has not yet been approved in the United States and Can-
which albumin prevents HRS are incompletely under- ada. Terlipressin is a long-acting synthetic vasopressin ana-
stood but may be related to albumin’s positive effect on logue composed of one molecule of lysine vasopressin and
circulatory function and its antioxidant properties.179-181 three glycine residues. It exerts its vasoconstrictive action
through binding to the vasopressin (V1) receptor, which is
preferentially expressed on the vascular smooth muscle
General Management
cells within the splanchnic circulation. It is metabolized
Type 1 HRS patients need to be managed in an intensive through exopeptidases to release small amounts of lysine
care unit because these patients have multiorgan failure vasopressin over a sustained period, allowing it to be
and they rapidly deteriorate. Type 2 HRS patients can be administered by bolus injection rather than by continuous
managed on an outpatient basis or in a non–intensive care infusion.187 However, continuous infusion of terlipressin is
setting. In either case, diuretic treatment should be associated with higher HRS reversal rate compared to
stopped and ascites should be managed with paracentesis. bolus injections.102 Multiple studies have demonstrated
Large-volume paracentesis (more than 5 L) should be improvement in clinical parameters (including arterial
followed by 8 g of albumin infusion for each liter of ascitic blood pressure, urine output, and hyponatremia) and ame-
fluid removed. There is enough evidence to recommend lioration in the neurohormonal abnormalities in 50% to
early paracentesis to exclude the adverse effects of 70% of HRS patients following terlipressin and albumin
increased intra-abdominal pressure on renal hemody- infusions.124,132,188-191 The median time to HRS reversal is
namics. For example, Cade et al182 reported a significant 7 days, with faster recovery in patients with lower serum
increase in urine flow rate and creatinine clearance fol- creatinine level at presentation. Other factors that predict
lowing reduction in intra-abdominal pressure from 22 to favorable response to terlipressin include lower serum bili-
10 mm Hg following paracentesis in patients with cirrho- rubin level (<171 μmol/L) and an increase of more than 5
sis and ascites. Umgelter et al183 studied 12 patients with mm Hg in mean arterial blood pressure following terlip-
established HRS and showed improvement in GFR and ressin initiation.192 Terlipressin has an acceptable side
urine output and Doppler ultrasound evidence of reduc- effects profile, with ischemic events occurring in 5% to
tion in renal resistive indexes following paracentesis. In 30% of cases, but most studies have excluded patients at
another study, paracentesis with albumin infusion but not high risk for ischemic events. Following completion of
albumin infusion alone improved creatinine clearance therapy, HRS recurred in up to 50% of cases.124,132,188-191
 32 Pretransplantation Evaluation: Renal 429

Factors associated with HRS recurrence are unknown, but and therapy was well tolerated.125 In the largest study to
renal function responds to the reintroduction of terlipres- date, which included 162 HRS patients, 75 patients received
sin.124 The benefits of terlipressin also seem to extend to octreotide, midodrine, and albumin, and their outcomes
type 2 HRS, with a slightly better response rate and longer were compared to a historical cohort of 87 patients who did
survival than in type 1.188,190,193 All studies used terlipressin not receive any therapy. Treatment with octreotide, mido-
until the serum creatinine level decreased to less than 1.5 drine, and albumin was associated with improvement in
mg/dL or for a maximum of 15 days; therefore it is unclear kidney function and survival and higher likelihood of liver
if longer duration of therapy will be of any benefit in transplantation compared to the no-treatment arm.203
increasing the HRS reversal rate. Although there are limited head-to head-studies com-
The beneficial effects of albumin infusion on HRS paring terlipressin to other vasoconstrictor agents, studies
reversal are well established.194,195 The results of two pro- so far have not demonstrated an advantage of any vasocon-
spective randomized studies that evaluated the effect of strictor agent over another on HRS reversal. One study
terlipressin and albumin infusions versus albumin alone in suggested that terlipressin-treated patients have a higher
type HRS patients confirmed higher rate of HRS reversal HRS recovery rate, longer survival, and greater likelihood
with terlipressin and albumin compared to albumin alone of receiving a liver transplant compared to those treated
in both type 1 and type 2 HRS.193,196 However, neither with an octreotide-midodrine combination, but this study
study confirmed a survival advantage of terlipressin use was nonrandomized and the results could have been
even in patients who responded to therapy with the excep- affected by selection bias.204 A meta-analysis has also con-
tion of improved 90-day (short-term) survival in the study firmed that terlipressin and norepinephrine were equiva-
by Sanyal and associates.196 A recent meta-analysis con- lent in terms of efficacy and side-effect profile in reversing
firmed that terlipressin and albumin infusions are associ- HRS.205 A recent meta-analysis has shown no difference
ated with improvement in short-term (90-day) survival.197 between various vasoconstrictors and patient survival.206
Midodrine and norepinephrine are two α1-adrenergic
receptor agonists that are readily available and have been Transjugular Intrahepatic Portosystemic
shown to be effective in the treatment of HRS. Continu- Shunt
ous norepinephrine infusion in association with albumin
and furosemide has been shown to be beneficial in revers- The effect of TIPS insertion on improving urinary
ing HRS.198 In a study that included 12 type 1 HRS sodium excretion and renal function in cirrhotic patients
patients, the norepinephrine dose was titrated to achieve with refractory ascites is well documented.158,207,208
an increase of 10 mm Hg in mean blood pressure or an Two studies have evaluated the effect of TIPS inser-
increase in urine output by more than 200 mL/4 hr. tion in patients with type 1 HRS and preserved liver func-
Norepi­nephrine was infused until either serum creatinine tion.209,210 Reversal of HRS occurred in almost 50% of
level decreased to less than 1.5 mg/dL or for a maximum cases within 3 months from TIPS insertion.209,210 These
of 15 days. The mean norepinephrine dose was 0.8 mg/hr clinical changes paralleled amelioration in renal hemody-
for a mean duration of 10 days. Ten of the 12 patients namics and reduction of the plasma levels of different
(83%) achieved HRS reversal; 2 of these had previously mediators of vasoconstriction. Patient’s survival ranged
failed terlipressin therapy. Ischemic events were observed from 10 to 570 days with 30 days’ survival achieved in five
in 2 patients (17%).198 Improvement in kidney function patients (71%).209 An important observation from these
was associated with improvement in patient survival, and two studies is the slow and delayed recovery of renal
4 of the responders did not require liver transplantation function following TIPS (within 2 to 4 weeks), unlike
6 to 18 months after recovery of renal function.198 vasoconstrictor therapy, in which responders have faster
Midodrine is a prodrug that is metabolized in the liver recovery of renal function (1 to 2 weeks). Hepatic enceph-
into an active metabolite, desglymidodrine, which is later alopathy was a common complication but was controlled
eliminated in the urine. The pharmacokinetics of mido- with medical therapy. Two pilot studies also assessed the
drine and desglymidodrine in HRS patients have not been effect of TIPS insertion on type 2 HRS reversal.210,211
studied. When given as monotherapy, oral midodrine Almost all patients had reversal of HRS, and 70% of the
slightly improved systemic hemodynamics but failed to patients were still alive 1 year following TIPS. The results
improve renal function in patients with HRS or with refrac- of these studies demonstrate that in selected groups of
tory ascites.199-201 When combined, however, with the glu- HRS patients, TIPS insertion might prolong survival
cagon inhibitor octreotide (glucagon mediates splanchnic long enough for patients either to receive a liver trans-
vasodilatation) and in combination with albumin infusion, plant or, if they are not candidates, to stay off dialysis. It
improvement in renal function, mean arterial pressure, and is noteworthy that a recent study has demonstrated that
plasma renin activity were observed. Unfortunately, there TIPS insertion improves post–liver transplant outcomes,
are no randomized trials that evaluate the effect of mido- probably through improving kidney function.212
drine and octreotide on HRS reversal, but two nonran-
domized studies that included 19 type 1 HRS patients Combination (Sequential) Therapy
demonstrated reversal of HRS in 70% to 100% of cases
treated with this protocol.125,202 Doses of midodrine and Vasoconstrictor therapy in conjunction with TIPS was
octreotide varied between these two studies, and in one evaluated in two studies.125,190 However, because of the
study the octreotide dose was titrated according to the cen- small number of cases and the limited applicability of
tral venous pressure measurement.202 In both studies no TIPS in patients with advanced cirrhosis, it is hard to use
significant treatment-related side effects were reported, this combination therapy on a large number of patients.
430 PART IV Special Considerations in Patient Evaluation

Table 32-5 summarizes the 30- and 90-day survival of neurohormonal levels normalize within 1 month from
untreated HRS patients and those who received therapy liver transplantation in the majority of patients.217 Renal
with different vasoconstrictor agents, TIPS, or a combi- artery resistive indexes, however, take up to 1 year to
nation of vasoconstrictor and TIPS. The important return back to their normal values.217,218 However, recov-
observations are (1) compared to no treatment, 30-day ery of renal function following liver transplantation is not
survival of HRS did improve with different treatment universal. For example, Marik et al219 studied renal func-
modalities and (2) 90-day survival of HRS remains dis- tion recovery following successful liver transplantation in
mal, irrespective of the treatment offered. Of note, the 28 HRS patients. Complete recovery of kidney function
90-day survival is overexaggerated in the combination occurred in only 58% of cases within 4 to 110 days from
therapy group as a result of the limited number of patients. orthotopic liver transplantation, whereas another 15%
partially recovered function.219 Importantly, kidney func-
tion never recovered in 25% of cases.219 In another study
Renal Replacement Therapy
30 of 32 (94%) HRS patients recovered kidney function
The indications for RRT initiation in HRS patients are no within a median of 24 days from liver transplantation.220
different than with other noncirrhotic patients with AKI Because of the limited number of studies addressing this
and include volume overload, intractable metabolic acido- question, reasons for lack of recovery of kidney function
sis, and hyperkalemia. In one study the most common rea- can be only speculated, but shorter HRS duration,
son for RRT initiation in HRS patients was volume younger recipients’ age, and immediate liver allograft
overload.130 However, given the dismal prognosis of HRS function as evidenced by lower posttransplantation day 7
patients, most nephrologists will offer RRT only to liver bilirubin level are factors that favor renal recovery.219
transplant candidates or those undergoing liver transplant One important predictor of post–liver transplantation
evaluation. The decision to initiate RRT in HRS patients dialysis requirement in HRS cases is prolonged RRT for
is further complicated by the presence of hepatic encepha- more than 8 weeks before liver transplantation.221 There-
lopathy, hypotension, and coagulopathy, which have been fore, although there is no survival advantage of liver-
associated with increased risks for hemorrhage and hypo- kidne­y transplantation compared to liver transplantation
tension, which directly contributed to mortality in some alone in patients with HRS, liver-kidney transplantation
cases.213,214 However, delaying RRT in HRS patients is is recommended in HRS patients who have been on RRT
associated with a mortality rate as high as 90%.215 Predic- for 8 weeks or more.221-223 It is important to mention that
tors of mortality following RRT initiation have been stud- unexpected post–liver transplant events such as primary
ied in 82 cirrhotic patients with AKI, 26 of them with allograft nonfunction, reoperation, infection, and hemor-
HRS. In general, patients with advanced liver disease as rhage are associated with increased risk for AKI in the
evidenced by the presence of hepatic encephalopathy, immediate post–liver transplantation period and can
malignancy, or thrombocytopenia had a 2.8- to 8.2-fold adversely affect HRS recovery.224
increased mortality rate.215 Therefore in HRS patients
waiting for a liver transplant, RRT is justifiable as a bridge
to transplantation but is associated with increased morbid-
Acute Kidney Injury: Parenchymal/Intrinsic
ity and mortality compared to patients with other forms of Parenchymal or intrinsic AKI usually results from injury
AKI. In HRS patients who are not candidates for liver resulting from ATN, acute interstitial nephritis (AIN),
transplantation, initiation of RRT is controversial.216 and glomerulonephritis and as a group is the second most
common cause of AKI (32%).99,101 ATN is caused by
ischemic or toxin injury to the kidney and accounts for
Liver and Liver-Kidney Transplantation
most AKI using the new or old definitions in some stud-
Liver transplantation is the ultimate treatment of HRS ies.100,132 Risk factors for this tubular damage are similar
patients. Renal sodium excretion, serum creatinine, and to those that produce prerenal/HRS disease.99,110,225

TABLE 32-5 T
 hirty-Day and 90-Day Survival Following Treatment of Hepatorenal Syndrome
by Treatment Modality
Number of Patients 30-Day Survival (%) 90-Day Survival (%) Author
No treatment 25 10 Gines et al129
Octreotide plus midodrine 5 80 33 Angeli et al202
NE 12 50 NA Duvoux et al198
Terlipressin 21 61 12 Ortega et al188
99 40 22 Moreau et al132
23 NA 27 Martin-Llahi et al193
TIPS 7 71 42 Guevara et al209*
14 81 64 Brensing et al210*
Vasoconstrictor plus TIPS 5 100 100 Wong et al125*

*Patients with advanced cirrhosis were not candidates for TIPS insertion.
NA, Not available; NE, norepinephrine; TIPS, transjugular intrahepatic portosystemic shunt.
 32 Pretransplantation Evaluation: Renal 431

Prakash et al100 attributed the cause of ATN to sepsis in 1.5 mg/dL, with duration of 3 months or more. Using
61%, hypovolemia in 36%, and nephrotoxic drugs in 2% these definitions, the incidence of CKD was as low as 1%
of patients. It is difficult to distinguish ATN from HRS. and as high as 30%.99,101,194 A new proposal for patients
By definition, neither responds to fluid challenge. ATN is with cirrhosis based on the definition used for the general
characterized by elevated urine sodium level (>20 to population classifies CKD as GFR less than 60 mL/min
40 mEq/L), fractional excretion of sodium greater than as determined by MDRD-6 estimation equation for a
1%, and isosthenuric urine (urine osmolality <350 period of 3 months or more. The MDRD-6 equation
mOsm/kg) often accompanied by muddy brown granular was chosen because it most closely approximates the
casts. Unfortunately, none of these are specific for ATN. iothalamate-determined GFR.84 This definition includes
Reports have described a low fractional excretion of those with HRS type 2. When this proposal was applied
sodium with an ATN injury because of severe salt reten- to a tertiary referral center population, the incidence of
tion of liver disease or transient renal vasoconstriction CKD was 15.6% (17.1% if AKI on CKD was included).100
that may be seen with nephrotoxins such as NSAIDs or The same culprits that commonly cause CKD in the
contrast that may produce ATN injury.‡ Amphotericin general population may produce CKD in c­ irrhosis, such
and aminoglycosides are antibiotics that may induce as diabetes or a past history of h ­ypertension-related
tubular injury and should be used cautiously in those with injury.233-235
advanced cirrhosis.228,229 Severe cholestasis, particular Glomerulonephritis presents as a primary (idiopathic)
associated with obstructive jaundice, may produce AKI process or may be disease related. A complete list of dis-
by way of vasoconstriction, decreased cardiac contractil- eases associated with the liver and kidney along with dis-
ity, the effect of endotoxin on the kidney, and direct ease-related forms of glomerulonephritis may be found in
tubular toxicity of bile acids.230 Proper diagnosis of ATN a review by Davis et al.233 The most common disease-
is important because outcomes in one study demonstrated associated forms of glomerulonephritis are summarized
a higher rate of posttransplant CKD than HRS (56% ver- in Table 32-6.
sus 16%).231 Another form of parenchymal AKI is AIN. Biopsy is usually reserved for diagnosis in patients with
In a study of hospitalized liver patients, Warner et al101 significant renal dysfunction or proteinuria. Histological
defined AIN as clinical exposure to a known nephrotoxin abnormalities are common in cirrhosis in spite of an
with documented AIN in the medical record or visualized absence of renal dysfunction or abnormal urinary sedi-
white blood cells, white blood cell casts, and eosinophils ment, and the causes are often multiple.236-238 Trawalé
in sterile urine. In this study 10% of the patients with et al235 described biopsy results for 18 patients with cir-
parenchymal AKI had AIN. Many medications have been rhosis and renal impairment (creatinine level >1.5 mg/dL)
implicated as causative factors, with antimicrobials, without significant hematuria or proteinuria. A wide vari-
NSAIDs, anticonvulsants, and diuretics being the pri- ety of diagnoses were found, and each patient had more
mary culprits.232 As an aside, histamine2 blockers and than one injury pattern, suggesting multiple causes of
proton pump inhibitors that are commonly used to treat renal injury.235 Please note that data describing the
gastrointestinal symptoms in cirrhosis have also been
linked to AIN.232 A history of nephrotoxin exposure
should be obtained in all cirrhotic patients with renal dys- TABLE 32-6 R
 enal Diseases Associated with
function. Glomerulonephritis is suggested by active uri- Cirrhosis
nary sediment with proteinuria, usually greater than 500
mg/day, and red blood cells/red blood cell casts. It more Liver Disease Renal Disease
commonly occurs in chronic forms than AKI and will be Hepatitis B Membranous nephropathy
covered in the section on CKD.100,132 Biopsy is a valuable Polyarteritis nodosa
tool in making a diagnosis of parenchymal disease, but IgA nephropathy
this benefit is tempered by the increased bleeding risk in Hepatitis C Membranoproliferative
cirrhosis. glomerulonephritis
Focal segmental glomerulosclerosis
Diabetic nephropathy
Acute Kidney Injury: Postrenal/Obstructive Fibrillary glomerulonephritis
Primary biliary Membranous nephropathy
The last category of AKI is postrenal or obstructive kid- cirrhosis Antiglomerular basement membrane
ney disease. This is an uncommon form of AKI in cirrho- disease
sis, accounting for less than 1% in one series.99,132 ANCA-associated disease
Interstitial nephritis
Diagnosis relies on imaging with ultrasonography or
α1-Antitrypsin IgA nephropathy
computerized tomography and if confirmed may benefit disease Membranoproliferative
from urology consultation. glomerulonephritis
Antiglomerular basement membrane
disease
Chronic Kidney Disease Sarcoidosis Interstitial nephritis
The role of CKD in cirrhosis is still being established. In Laënnec’s or IgA nephropathy
the past, CKD in cirrhosis has been defined in many cryptogenic Hepatic glomerulosclerosis
cirrhosis
ways, mostly by elevated creatinine level, usually above
Modified from references 230, 233, 270-273.
‡References 99, 110, 120, 226, 227. ANCA, Antineutrophil cytoplasmic antibody; Ig, immunoglobulin.
432 PART IV Special Considerations in Patient Evaluation

natural course of these kidney diseases in the setting of pressure and in those patients that are hemodynamically
cirrhosis and subsequent liver transplantation are lacking, unstable.248,251 One drawback of CRRT is the need for
making prediction imprecise.67,233 Biopsy and diagnosis continuous systemic anticoagulation, which might
may be valuable in predicting renal function after trans- increase the risk for bleeding; however, cirrhotic patients
plant, but more data are needed.174 Importantly, this are often coagulopathic, and anticoagulation may be
information may assist decision making regarding treat- safely avoided. The ultimate dialysis dose and timing for
ment while the patient is under evaluation. For example, RRT initiation have not been studied in cirrhotic patients
antiviral treatment of hepatitis C may improve glomeru- with HRS, but data can be inferred from other studies of
lar and cryoglobulin disease.239-243 In more severe dis- AKI in critically ill patients, which suggest that early
ease, particularly in the setting of vasculitis associated RRT initiation and maintenance of negative fluid balance
with cryoglobulin, aggressive therapy with plasmapher- improve patient survival.252,253 Two recent randomized
esis or immunosuppression should be considered.244,245 studies that included a large number of critically ill
There are no guidelines for the treatment of renal dis- patients with AKI that included a significant number of
ease in advanced liver failure. Difficult decisions using cirrhotic patients with AKI showed no clear benefit of a
aggressive treatment described in the earlier example, in higher dialysis dose on hospital mortality or the probabil-
addition to standard nephrological treatment such as ity of renal function recovery.254,255
dietary protein restriction, control of blood pressure, In summary, renal disease in cirrhosis is common.
and the use of angiotensin-converting enzyme inhibitors Ascertaining the degree of disease may help predict renal
or angiotensin receptor blockers requires highly indi- outcome after transplant and provides an opportunity to
vidualized therapy. This therapy should be designed treat/reverse the disease. The nature of the renal injury
using a team approach, including consultation with a predicts mortality. A large study of 562 consecutive hos-
nephrologist.67,233 pitalized patients with cirrhosis and renal disease classi-
fied 463 patients into four groups: (1) renal failure
associated with infection, (2) hypovolemia-related renal
Acute on Chronic Kidney Disease failure, (3) renal failure resulting from parenchymal disease,
Acute on CKD has been defined as an increase in serum and (4) hepatorenal syndrome. Three-month survival was
creatinine of more than 50% from baseline or a rise in 73% for group 3, 46% for group 2, 31% for group 1, and
creatinine level of 0.3 mg/dL or more in less than 48 hours only 15% for group 4 (P <.0005).136 Nadim et al231 iden-
in a patient with a baseline GFR of less than 60 mL/min tified patients with similar risk, injury, failure, loss, and
using the MDRD-6 equation for more than 3 months.84 end-stage renal disease (RIFLE) stage for AKI and looked
The frequency of this complication using this definition at outcomes after liver transplant in those with HRS ver-
has yet to be determined, but a prior published report sus ATN. The ATN group had higher mortality, less
applying a comparable definition suggests that the num- renal recovery by 90 days, lower estimated GFR, and
bers are small, with mortality similar to AKI alone.101 higher rates of CKD at 60 days than the HRS group.231
Accurate diagnosis of disease may assist decision making
Hepatorenal Disorders and Dialysis in patients under evaluation for liver transplant.
Support
As discussed in the HRS section, dialysis may provide EVALUATION
support for patients with advanced kidney injury of any
kind, yet deciding which patient with advanced/decom- Renal evaluation of liver transplant candidates requires
pensated cirrhosis should receive dialysis support is con- integrated work of the transplant team to best serve the
troversial.90,216 For AKI, Howard and Teitelbaum216 patient. Input from attending nephrologists, hepatolo-
recommend offering RRT to those being evaluated for gists, liver transplant surgeons, and transplant anesthe-
liver transplant, those with potentially reversible kidney tists is needed to determine not only the patient’s
or liver injury, and those in whom the HRS diagnosis is in candidacy for liver or liver-kidney transplantation but
doubt. For patients with cirrhosis and CKD the decision also the perioperative need for renal replacement therapy
to offer chronic RRT is challenging. Outcome data such (preoperative and intraoperative dialysis), or renal-spar-
as survival and quality of life are lacking in this group. For ing immunosuppression. Planning provides the best
those being evaluated for transplant, dialysis is indicated, opportunity for kidney success. Table 32-7 summarizes
but for nontransplant patients, decisions must be made the renal evaluation in patients with advanced liver
on an individual basis.216 Criteria for initiating dialysis disease.223,256
that are specific for those with cirrhosis and advanced The history should include queries concerning dia-
renal disease are not available.90,216 The criteria used for betic or hypertensive history, exposure to contrast, need
uncomplicated AKI have been suggested but present for paracentesis, complications of bacterial peritonitis
challenges in identifying true uremic symptoms from and gastrointestinal hemorrhage, and use of diuretics,
complications of cirrhosis.216 Continuous renal replace- lactulose, NSAIDs, and nephrotoxic antibiotics. On
ment therapy (CRRT) is better tolerated than intermit- physical examination, careful assessment of volume is
tent, but there is no clear advantage of CRRT over necessary with attention to blood pressure, weight, urine
hemodialysis in HRS patients.246-250 CRRT may offer an volume, skin turgor, mucous membranes, lung fields,
advantage over intermittent dialysis in patients with ful- heart sounds, and the presence of edema or ascites. Labo-
minant hepatic failure complicated by increased cranial ratory tests should include measurement of electrolyte,
 32 Pretransplantation Evaluation: Renal 433

cirrhosis.256,257 Biopsy would have a more prominent role

TABLE 32-7 R
 enal Evaluation in Liver
in evaluating patients if not for the increased bleeding
Transplant Candidates
risk in cirrhosis. The coagulopathic state of the patient,
Electrolytes exemplified by thrombocytopenia and abnormal pro-
Blood glucose (hemoglobin A1c) thrombin time, creates increased bleeding risk, particu-
Blood urea nitrogen larly for percutaneous biopsy.174 Additional data in this
Creatinine (MDRD-6 to be used to estimate GFR) series of patients indicate that undergoing kidney biopsy
Arterial blood gas, if necessary only when the international normalized ratio (INR) is
Urinalysis corrected to less than 1.5 reduces serious bleeding (more
Urinary spot sodium, protein, and creatinine than 2 units of blood transfusion or radiological interven-
24-hour urine for creatinine clearance and protein tion to stop bleeding) to 8%.174 A transjugular approach
GFR measured by radiotracer, isotope, or contrast studies appears to decrease bleeding risk, but prior experience
Sonogram of kidneys suggests that the adequacy of the biopsy is less than that
Kidney biopsy, if necessary with percutaneous technique.235,256,258,259 Nonetheless,
transjugular biopsy appears to be safer given current data.
GFR, Glomerular filtration rate; MDRD, Modification of Diet in Given the frequency of histological abnormalities in cir-
Renal Disease. rhosis, the opportunity to treat potentially reversible dis-
eases, and the purported role of chronic histological
blood glucose, BUN, and creatinine levels and, in the set- changes in the progression of renal disease, biopsy will
ting of suspected acid-base disturbances, an arterial blood likely have a strong role in evaluation guidelines in the
gas determination. Querying records to determine past future.
creatinine values will help establish baseline kidney func- The selection of patients for liver transplant alone ver-
tion. Urine should be inspected for protein, cells of sus simultaneous liver-kidney transplant using the workup
inflammation, and casts. Spot urine tests for sodium and described has been debated among several groups. Guide-
creatinine provide information for the calculation of frac- lines have been published with consensus opinion, includ-
tional excretion of sodium, which may prove helpful in ing an OPTN proposal, but standard criteria are still
determining effective arterial blood volume, particularly lacking.90,223,256,260 Two studies report outcomes of native
in a setting of low urine output. Determining true GFR renal function (using nuclear medicine renal scanning) in
in patients with cirrhosis is difficult. Recommendations liver-kidney recipients selected by individual center crite-
from reviews and consensus conferences are mixed, with ria and retrospectively evaluated using the OPTN crite-
recommendations varying from the use of creatinine ria.15,261 Francis and associates261 found that only 8 of the
value to estimation equations to some measurement of 13 patients studied met OPTN criteria for liver-kidney
GFR. GFR should be measured. A 24-hour urine for pro- transplant and 4 of these had significant native renal func-
tein excretion should be collected with the creatinine tion after transplant. Only 1 of the 5 patients not meeting
clearance. Isotope and nonradioactive clearance studies OPTN criteria recovered native renal function. Levitsky-
have not been validated in advanced liver failure but may and colleagues15 evaluated 78 liver-kidney recipients, of
prove helpful in evaluating GFR. Ultrasonography of the whom 31 met OPTN criteria. Using the criteria of native
kidney screens for structural abnormalities, and, if abnor- kidney GFR of 20 mL/min or less, 21 of the OPTN cri-
malities are found, additional tests, including computed teria candidates did not recover significant native renal
tomography, magnetic resonance imaging, cystoscopy function. Only 17 of the 47 liver-kidney recipients not
with retrograde studies, and urology consultation, should meeting OPTN criteria for liver-kidney transplant recov-
be considered. ered native kidney function to GFR above 20 mL/min.
A renal biopsy may add value in characterizing kidney Using that GFR criteria for native renal recovery, the
disease. Francoz et al67 propose considering kidney positive predictive value of the OPTN criteria was 67.7%
biopsy in the following patients: (1) those with AKI who with negative predictive value of 63.8%. Conclusions of
have abnormal duration of injury or lack of recovery, sus- these papers were that the OPTN criteria were not accu-
picion for CKD, or potential curative kidney injury (such rate and current selection criteria needed modification
as drug-induced interstitial nephritis or forms of micro- with possible use of other predictors.
angiopathy), and (2) those with CKD with GFR of 15 to A national survey of transplant centers to determine
30 mL/min/1.73 m2, CKD with GFR of 30 to 60 mL/ practice patterns revealed wide disparity of selection cri-
min/1.73 m2 and proteinuria of more than 500 mg/day or teria for simultaneous liver-kidney transplant.17 The
more than 50 red blood cells per high-power field or his- authors attribute this in part to inconsistency in centers
tory of diabetes, hypertension, or hepatitis B or C. They following their own criteria, center policies differing
do not recommend kidney biopsy for GFR of less than 15 from the OPTN guidelines, and gaps in knowledge and
or more than 60 mL/min/1.73 m2. Other consensus guidelines to discriminate those who would benefit from
guidelines use kidney biopsy results to select candidates, kidney transplant from those that would not. The various
although the Organ Procurement and Transplantation guidelines present a commitment to place a kidney in
Network (OPTN) proposal did not.17,223,256 The use of only those patients requiring one. Broader use of pro-
arterial hyalinosis, glomerulosclerosis, and in particular posed definitions for AKI, CKD, and acute on CKD in
interstitial fibrosis as a surrogate of renal progression that future research will allow more accurate comparison of
has been established for kidney disease in the general data to draw stronger conclusions. Additional work is
population has not been evaluated formally in those with needed in defining what degree of posttransplant native
434 PART IV Special Considerations in Patient Evaluation

patients with significant renal dysfunction should be dis-

TABLE 32-8 C
 riteria for Simultaneous
cussed preoperatively to reduce potential renal toxicity
Liver-Kidney Transplant
after surgery.
Patients with AKI for ≧4 weeks and one of the following:
Stage 3 AKI as defined by modified RIFLE (threefold
increase in Cr from baseline, Cr ≧ 4.0 mg/dL with acute SUMMARY
rise ≧0.5 mg/dL or renal replacement therapy
eGFR ≦ 35 mL/min (MDRD-6) or GFR ≦ 25 mL/min Preoperative evaluation of renal function is a team effort.
(iothalamate clearance) A thorough workup may identify those who may best
Patients with CKD (GFR < 60 mL/min for 3 or more mo) and benefit from liver versus simultaneous liver-kidney trans-
one of the following:
plant. Proposals defining AKI and CKD in liver disease
eGFR ≦ 40 mL/min (MDRD-6) or GFR ≦ 30 mL/min
(iothalamate clearance) should be adopted and with research, modified as needed.
Proteinuria ≧2 g/day These definitions are a first step in moving the transplant
Kidney biopsy with >30% global glomerulosclerosis or community toward improved characterization of renal
>30% interstitial fibrosis disease in cirrhosis, which may improve outcomes for our
Metabolic disease patients through earlier treatment of disease. Studies are
needed to test these definitions as well as the proposed
Modified from Nadim MK, Sung RS, Davis CL, et al. Simultaneous criteria to select liver-kidney candidates to champion
liver-kidney transplantation summit: current state and future
directions. Am J Transplant. 2012;12(11):2901-2908.
progress in managing renal disease in cirrhosis.
AKI, Acute kidney injury; CKD, chronic kidney disease; eGFR,
estimated glomerular filtration rate; GFR, glomerular filtration
rate; MDRD, Modification of Diet in Renal Disease; RIFLE, risk, Pearls and Pitfalls
injury, failure, loss, and end-stage renal disease.
• In assessing renal function, use the Modification of
Diet in Renal Disease (MDRD)-6 as the estimation
equation, or measure glomerular filtration rate with
renal dysfunction would benefit from simultaneous kid- iothalamate or other isotope markers.
ney transplantation. Meanwhile a group of experts in the •  Use the definitions of acute kidney injury (AKI),
field representing the OPTN and participants from prior chronic kidney disease (CKD), and AKI on CKD
consensus groups met in Los Angeles in 2011, reviewed established by the Working Group proposal.
prior guidelines and new research, and published recom- •  Consider using one of the consensus guidelines in
mended criteria for selecting simultaneous liver-kidney choosing candidates for simultaneous liver-kidney
transplant patients, which are presented in Table 32-8. It transplantation.
will be important for the transplant community to adopt • Avoid using creatinine value alone as a marker of renal
function.
one of these set of guidelines for general use to allow • Avoid offering simultaneous liver-kidney transplant
comparison of results between trials, study of new predic- to those with AKI likely to have reversible renal
tors, and future refinement of criteria.    ­dysfunction.

Operative Planning
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stability during continuous modes of renal replacement therapy in 271. di Belgiojoso GB, Ferrario F, Landriani N. Virus-related glomer-
critically ill patients with acute hepatic and renal failure. Crit Care ular diseases: histological and clinical aspects. J Nephrol. 2002
Med. 1993 Mar;21(3):328-338. Sep-Oct;15(5):469-479 [Review].
249. Detry O, Arkadopoulos N, Ting P, et al. Intracranial pressure during 272. Komatsu T, Utsunomiya K, Oyaizu T. Goodpasture’s syndrome
liver transplantation for fulminant hepatic failure. Transplantation. associated with primary biliary cirrhosis. Intern Med. 1998
1999 Mar 15;67(5):767-770. Jul;37(7):611-613 [Case Reports].
250. Gonwa TA, Mai ML, Melton LB, et al. Renal replacement ther- 273. Os I, Skjorten F, Svalander C, et al. Alpha-1-antitrypsin deficiency
apy and orthotopic liver transplantation: the role of continuous associated with hepatic cirrhosis and IgA nephritis. Nephron.
veno-venous hemodialysis. Transplantation. 2001 May 27;71(10): 1997;77(2):235-237 [Case Reports].
1424-1428.
 CHAPTER 33

Pretransplantation Evaluation:
Infectious Disease
Marian G. Michaels • Michael D. Green

CHAPTER OUTLINE

PRETRANSPLANT SCREENING OF THE DONOR Bacteria

PRETRANSPLANT EVALUATION OF THE Parasites and Fungi
CANDIDATE Candidate Immunizations
Prior Infections Evaluating Fever at Time of Transplant
Viruses CONCLUSION

Despite great progress in liver transplantation, infec- Studies from the 1980s clearly established the donor as
tions remain a major cause of morbidity and mortality. the source of CMV and EBV after transplantation, par-
Although not every infection can be anticipated, many ticularly to naive recipients, and have been the basis for
types can be predicted, and some can even be pre- informing a variety of preventive strategies that are dis-
vented. The sources of pathogenic organisms can be cussed in the chapter on posttransplantation infections
from the recipient’s endogenous flora, the environ- (see Chapter 78). Although infection with these particu-
ment, or the donor. Accordingly, infectious disease lar agents is anticipated, a much larger repertoire of
evaluation and screening of both the candidate and the donor-derived pathogens has been identified. Examples
donor are important to identify potential pathogens include acute bacterial infection; viruses such as HIV,
and risk factors for infection as well as to devise pre- hepatitis B virus (HBV), hepatitis C virus (HCV), West
ventive strategies. The decision to screen a candidate Nile virus, and rabies; chronic fungi (e.g., coccidiomyco-
or donor for specific pathogens should take into sis, histoplasmosis); and parasites (e.g., Toxoplasma gondii,
account the impact of potential disease, the availability Strongyloides).1 Accordingly, the goal of the infectious dis-
of reliable testing methods, the cost of testing, the ease evaluation of the donor is to accurately assess the
amount of specimen required, and governmental presence of and risk for transmission of such pathogens.
requirements. In general the infectious disease evalua- Although historical or laboratory screening is not practi-
tion includes obtaining a history of prior infections, cal or even available for all potential pathogens, a careful
physical examination, serological screening for past donor history and laboratory evaluation can help to rec-
immunity or ongoing infection, and testing for specific ognize the presence of risk factors or laboratory markers
pathogens along with counseling of the candidate and that can identify a donor as being more likely to transmit
his or her family. This chapter discusses the infectious a pathogen. Accomplishing this allows the transplant
disease approach to the pretransplantation evaluation team to minimize the risk for unintended transmission
of both candidates and donors. and, where appropriate, to initiate prophylactic strategies
against relevant donor-derived pathogens. In addition, it
provides more accurate data when the team reviews the
PRETRANSPLANT SCREENING OF risks for associated infections for a specific donor with a
THE DONOR candidate and his or her family as part of the informed
consent process.
Transmission of infections such as human immunodefi- Inherent limitations exist with screening deceased
ciency virus (HIV) or rabies from a donor organ to a donors for potential pathogens, including the inability
recipient is rare but highlights the risk inherent with any to directly ask about exposures, the confounding pres-
procedure involving placement of biological material ence of passive antibody within the donor secondary to
from one person into another. Although many organisms receipt of blood products, and the limited time available
are associated with only rare transmission events, others, to complete the evaluation before transplantation. The
such as cytomegalovirus (CMV) or Epstein-Barr virus ability of families to provide accurate information is
(EBV), are recognized as being unavoidable and are fac- limited by the fact that they are being asked about
tored into the risk-benefit analysis of accepting an organ. potential risks for exposure in the donor during a period

441
442 PART IV Special Considerations in Patient Evaluation

TABLE 33-1 P
 retransplant Infectious Disease TABLE 33-2 P
 retransplant Infectious Disease
Evaluation of Liver Transplant Evaluation of Candidates for Liver
Organ Donor Transplantation
Serological or NAT Assays History
HIV 1 and 2 (EIA or NAT) Special Emphasis
Hepatitis B: sAg, cAb Immunization history
Hepatitis C (EIA, ± RIBA or NAT) Previous episodes of spontaneous bacterial peritonitis
Hepatitis D Previous episodes of bacterial cholangitis
CMV: IgG, IgM Travel history
EBV: VCA IgG Residence in areas endemic for specific organisms
RPR or other syphilis screening assay Physical Examination
cAb, Core antigen; CMV, cytomegalovirus; EBV, Epstein-Barr virus; Screening Studies
EIA, enzyme immunoassay; HIV, human immunodeficiency virus; Tuberculin skin test or IGRA
Ig, immunoglobulin; NAT, nucleic acid test; RIBA, recombinant Serological Studies
immunoblot assay; RPR, rapid plasma reagin; sAg, surface HIV 1 and 2
antigen; VCA, viral capsid antigen.
Hepatitis A Ig G/IgM
Hepatitis B: sAg, sAb, cAb, eAg
Hepatitis C
of time that is likely to be accompanied by intense emo-
Hepatitis D
tion. As important or more so, they may not know all
CMV: IgG, IgM
potential exposures and risk behaviors relevant to the
EBV: VCA IgG, VCA IgM, EBNA
donor.
VZV: IgG
In the United States, federal regulation mandates spe-
Measles IgG*
cific types of testing that are performed for deceased
RPR or other syphilis screening assay
donation. These policies are set by the Organ Procure-
ment and Transplantation Network (OPTN). Current *Some centers perform testing for antibody against rubella and
OPTN policy dictates screening for HIV, HBV, HCV, mumps as well.
syphilis, EBV, and CMV along with bacterial culture of cAb, Core antigen; CMV, cytomegalovirus; eAg, e antigen; EBNA,
the blood and urine for donors who have been hospital- Epstein-Barr nuclear antigen; EBV, Epstein-Barr virus; HIV,
human immunodeficiency virus; Ig, immunoglobulin; IGRA,
ized at least 72 hours. Additional specific tests may be interferon-γ release assay; RPR, rapid plasma reagin; sAb,
requested based on case-by-case criteria. surface antibody; sAg, surface antigen; VCA, viral capsid antigen;
Transplantation of a segment of liver from a living VZV, varicella-zoster virus.
donor has also occurred in the more recent era of
transplantation. Since 2000, approximately 200 to 500
such procedures have been performed annually, par- for the candidate and family to be educated about
ticularly for children or small adults. Because these infections associated with transplantation. Patients can
donors are available for physical examination and to be made aware of the implications of immunosuppres-
provide their own history, infectious disease assess- sion, including its impact not only on infectious agents
ment can be performed in a fashion more akin to that contracted following the transplant procedure but also
of candidates. Potential living donors can also be edu- on the potential for reactivation of latent microbes
cated about ways to avoid infection, minimizing the already present in the patient’s body or that come from
risk to their potential recipients, before organ dona- the donor. It is particularly important to inform candi-
tion. Federal regulations defining testing for living dates that no screening process is infallible and that an
donors are currently being developed but have not inherent risk exists for infections being present in the
been finalized yet. Recommended screening for donors donor organ that could complicate the patient’s out-
is noted in Table 33-1. come despite the current screening tests used. Patients
can be further educated about the availability of pre-
ventive strategies and treatment regimens for a num-
PRETRANSPLANT EVALUATION OF ber of potential infectious complications associated
THE CANDIDATE with liver transplantation, as well as strategies for safe
living to minimize acquisition of infections from their
The infectious disease evaluation of the liver trans- environment. Finally, the infectious disease evaluation
plant candidate should help physicians (1) recognize provides the opportunity to document the patient’s
potential pathogens with which the patient has previ- immunization history and to develop a plan for the
ously been infected or colonized, (2) review antimicro- delivery of appropriate vaccines before the institution
bial sensitivities of potential bacterial pathogens to of immune suppression (Table 33-2).
help guide prophylactic and treatment strategies, and
(3) document the candidate’s immunological experi-
ence that influences the risk for developing infection
Prior Infections
following transplantation. Perhaps as important, the After transplantation, microbiological species that are
pretransplantation evaluation provides an opportunity harbored innocently in the candidate may reactivate
 33 Pretransplantation Evaluation: Infectious Disease 443

under immunosuppression. Typically these are organisms

TABLE 33-3 Prophylactic Management
that exist in a latent state and can include viruses, bacteria,
Strategy for Preexisting Infections
fungi, and parasites. Likewise, the donor organ can har-
in Liver Transplant Candidates
bor transmissible agents within either hepatocytes or
Early After Transplantation
“passenger leukocytes” that can be passed to the trans-
plant recipient. Many of these organisms are the same Organism Management Strategy
latent pathogens that can cause potential problems if
Cytomegalovirus Ganciclovir or valganciclovir alone or
reactivation occurs in the recipient. in combination with CMV hyperim-
mune globulin or preemptive
monitoring or combination of
Viruses prophylaxis and monitoring
Herpesviruses. Members of the herpesvirus family, Epstein-Barr virus No prophylaxis currently proven to
including CMV, EBV, herpes simplex virus (HSV), and be effective; viral load monitoring
advocated for at-risk patients
varicella-zoster virus (VZV) are particularly important
Herpes simplex Short-term oral acyclovir or valacyclo-
viral pathogens affecting recipients of liver transplanta- virus vir in individuals not receiving CMV
tion. However, other herpesviruses, such as human her- prophylaxis with individualized
pesvirus 6 (HHV6), 7 (HHV7), and 8 (HHV8), are also treatment thereafter
increasingly recognized after transplantation. A healthy Varicella-zoster Can consider short-term oral
person usually acquires these viruses during childhood or virus acyclovir or valacyclovir in
individuals not receiving CMV
young adulthood. These DNA viruses remain latent in prophylaxis
target cells for the life of the host, long after symptoms of Human immunode- If HIV is controlled, consider
the primary infection have abated. Reactivation can occur ficiency virus transplantation at centers with HIV
at any time, with immunosuppression being recognized experience
as a potent stimulator. Both the donor organ and the Hepatitis B virus Antivirals along with HBIg and serial
recipient can harbor viruses that can reactivate after monitoring of viral load
transplantation. Obtaining pretransplant serological Hepatitis C virus Serial monitoring for reactivation,
studies for the major herpesviruses is important for pre- consideration of interferon and
antivirals
dicting risk for developing, as well as preventing, disease
Previous peritonitis Obtain antibiotic susceptibilities of
caused by these pathogens (Table 33-3). or cholangitis microorganisms recovered from
CMV is one of the most common causes of infection last episode of cholangitis
after liver transplantation.2,3 Reactivation of CMV has infection; devise perioperative
been noted to cause symptomatic disease in 8% to 40% of antibiotic prophylaxis accordingly
previously immune liver transplant recipients.4-6 Because Mycobacterium Isoniazid with close follow-up of liver
tuberculosis enzyme levels; vitamin B6
prior seropositivity is common, especially in adult popula- (latent)
tions (approximately 40% to 70%), reactivation disease Histoplasmosis Long-term maintenance with azole
constitutes a significant component of clinical infection.7,8 therapy with or without induction
However, the major risk factor for severe CMV disease is with amphotericin B products
primary infection, typically attributable to transplantation Coccidioidomycosis Long-term maintenance with azole
of a seronegative recipient with an organ from a seroposi- therapy with or without induction
tive donor.5 The source of CMV has been documented as with amphotericin B products
donor derived both epidemiologically5 and by restriction CMV, Cytomegalovirus; HBIg, hepatitis B immune globulin; HIV,
enzyme digests of donor and recipient CMV isolates.9 human immunodeficiency virus.
Serological screening for CMV should be performed
in all candidates and donors. Various prophylactic strate-
gies for CMV disease using antiviral agents, such as gan- EBV, another cause of disease after transplantation,
ciclovir or valganciclovir, as well as CMV hyperimmune often produces asymptomatic infection in young children
globulin, have been studied in solid organ transplantation. or a self-limited mononucleosis syndrome in adolescents
Additional preventive strategies that monitor patients for and adults. After initial infection the virus is maintained in
the presence of specific risk factors for CMV disease (e.g., a latent state within B lymphocytes. Asymptomatic pha-
treatment of rejection) or the presence of subclinical ryngeal shedding of replicative virus periodically occurs in
infection (as demonstrated by quantitative CMV DNA or up to 23% of normal individuals.11 In immunosuppressed
pp65 antigenemia monitoring) as an indicator for initia- populations, such as those with acquired immunodefi-
tion of preemptive antiviral therapy have been adopted by ciency syndrome (AIDS) or those that have undergone
some centers, whereas a combination of prophylaxis and organ transplantation, viral shedding may occur in 65% to
monitoring has been proposed by other groups.10 In gen- 94% of seropositive patients.11,12 More worrisome is the
eral, decisions regarding which approach to use, as well as ability of EBV to cause B-cell proliferation or lymphoma
the duration of prophylaxis, are frequently tied to the in the context of impaired T-cell function. The highest
combined results of serological screening obtained from risk for EBV-driven posttransplantation lymphoprolifera-
the donor and recipient. Detailed descriptions of these tive disorders (PTLDs) is primary infection of the recipi-
preventive strategies, as well as treatment algorithms for ent after transplantation.13-15 However, PTLD does occur
those patients who develop disease following liver trans- in up to 2% of previously immune orthotopic liver trans-
plantation, are discussed in more detail in Chapter 78. plantation recipients. Most transplant centers perform
444 PART IV Special Considerations in Patient Evaluation

EBV serological tests on candidates. Data suggest that following transplantation and is particularly germane to
EBV-mismatched patients (EBV seropositive donor/sero- pediatric patients and young adults. Furthermore, iden-
negative recipient) are at the highest risk for developing tification of transplant candidates as being susceptible to
EBV-associated disease, though EBV-seronegative recip- varicella provides the opportunity to immunize them
ients of organs from seronegative donors are also at with the varicella vaccine before transplantation.
increased risk compared to seropositive recipients. Although the efficacy of this vaccine has not been estab-
Accordingly, screening donors for evidence of EBV to lished in patients with end-stage liver disease, provision
identify mismatched donor-recipient pairs is recom- of the vaccine at this time would seem preferable to
mended. As is the case with CMV, the availability of this allowing such patients to be exposed to wild-type vari-
information may guide the implementation of evolving cella virus while they are immunosuppressed following
strategies aimed at the prevention of EBV disease. These the transplant procedure. Because VZV remains latent in
are discussed in greater detail in Chapter 78. ganglionic nerve endings, it could be transmitted only by
Reactivation of viral infection can also occur with a donor who was actively undergoing primary viremia.
HSV after transplantation. In one large series highlight- Only a single case of donor-associated transmission of
ing the potential of HSV disease after immunosuppres- VZV has been reported. Accordingly, donor screening is
sion, 75% of adult liver transplantation recipients were not recommended for VZV.
noted to be seropositive for HSV.2 Most often HSV Infection with HHV6 and HHV7 universally occurs
causes persistent, localized lesions within the first month during the early years of life, and neither donors nor
after transplantation or after treatment of rejection epi- recipients have been routinely screened for these diseases
sodes. Disseminated HSV disease is rare but can occur. before liver transplantation. Increasing data suggest that
HSV hepatitis occurred in 8 of 1664 patients (0.5%) who coincidental reactivation of one or both of these viruses
underwent liver transplantation in the 1980s at the with CMV can amplify the severity of disease typically
University of Pittsburgh.16 Seven of eight instances of seen with CMV alone.18 In addition, case reports suggest
HSV hepatitis were believed to be caused by reactivation that HHV6 in the absence of other pathogens can cause a
of disease rather than primary acquisition. Prophylactic febrile illness with or without a rash. Donor transmission
strategies using oral acyclovir or related compounds of HHV6 was also found to cause febrile illnesses in
(e.g., valacyclovir, famciclovir) for patients found to have young infants receiving living related liver transplants
serological evidence of HSV before transplantation can from their mothers. In all but one case the illness attrib-
safely decrease the incidence of reactivation. Likewise uted to HHV6 was self-limited.19 At this time routine
ganciclovir used for CMV prevention has activity against screening for HHV6 and HHV7 is not recommended.
HSV and VZV. Although possible, donor-associated The most recently recognized human herpesvirus,
transmission of HSV is rare because this virus does not HHV8, is a gamma herpesvirus that is endemic in Africa
establish latent infection in the liver. Donor screening is and has relatively high rates of prevalence in Mediterra-
therefore not routinely recommended for HSV. nean countries. The virus has been associated with
Varicella can cause disease both from primary infec- development of Kaposi’s sarcoma. Currently donor
­
tion and from reactivation after transplantation. In one transmission and reactivation disease have been postu-
study of 121 adult liver transplant recipients, VZV devel- lated to lead to disease for individuals (or their donors)
oped in 8 patients 19 to 575 days after transplantation.2 who are from geographical areas with high prevalence
One of these patients died of disseminated zoster despite rates of HHV8. Limitations in serological testing are a
acyclovir treatment. Patients without preexisting immu- current problem for screening. Although it is reasonable
nity are at risk for severe disease after transplantation if to consider screening for recipients and donors that
they are exposed to chickenpox. Although most adults come from moderately to highly endemic areas, routine
currently have previous immunity based on wild-type screening of transplant candidates and donors from
disease, this is anticipated to change and immunity will North America, Asia, and much of Europe, where rates
be dependent on vaccination. Young pediatric transplant of the virus are quite small, cannot be endorsed at this
recipients are often still susceptible to VZV. In one time.20
study, 51 of 90 children undergoing liver transplantation
were susceptible to chickenpox.17 Twenty-five of the Hepatitis Viruses. Hepatitis B is a pathogen that causes
susceptible children were exposed to varicella and serious disease after transplantation. Screening of the
received varicella-zoster immune globulin (VZIG). candidate for hepatitis B should include the full panel of
Seven of these children and seven others who did not hepatitis B serological studies (see Table 33-2). Trans-
receive VZIG developed chickenpox. Two of the 14 plant candidates who have not had previous hepatitis B
children died; both received acyclovir late in the course infection and are seronegative for hepatitis B surface anti-
of their infection. VZIG is no longer available, but a body should receive the hepatitis B vaccination series
similar Canadian product, VariZIG, can be used as a before transplantation. This vaccination will also protect
postexposure prophylactic strategy, with administration against infection with hepatitis D virus. Transplantation
within 72 hours of varicella exposure. Alternatively, acy- of patients found to have chronic hepatitis B infection has
clovir prophylaxis for 7 days begun on day 7 after expo- been associated with an increase in morbidity compared
sure may decrease the incidence or severity of disease. with those without evidence of hepatitis B infection. Risk
Knowledge of the potential recipient’s serological status factors were identified to include high viral load and HBV
against VZV is necessary to determine who should e antigen seropositivity. Relapses of HBV that occurred
receive postexposure prophylaxis after such an exposure after transplantation had more rapid progression of
 33 Pretransplantation Evaluation: Infectious Disease 445

disease than in the nonimmunosuppressed host. Further- The potential for donor transmission of HCV is well
more, subsequent retransplantations resulted in increas- established. In general, patients who are known to be
ingly rapid hepatic deterioration.21 The use of prophylactic HCV positive are not considered to be acceptable
strategies using hepatitis B immune globulin (HBIg) and donors for liver transplantation with the exception of
interferon-α improved but did not prevent a high relapse the use of a hepatic allograft from a donor who is HCV
rate in patients transplanted for chronic hepatitis B.21 positive for a recipient who is also known to have HCV.
However, starting in the mid 1990s the landscape for Although reinfection can occur, data from numerous
transplant candidates with HBV changed with the avail- studies suggest that the use of such organs is safe in the
ability of effective antiviral therapy. Lamivudine was used HCV-positive recipient.26 It is worth noting that the
initially but more recently has been replaced by entecavir potential use of an HCV-positive donor should be con-
and tenofovir (because of lamivudine resistance) along sidered only with the informed consent of the recipient
with HBIg administration at least early after transplanta- or his or her family.
tion. Treatment affects both the incidence and the rate of Hepatitis A virus (HAV) can cause more severe liver
relapsed disease.22-25 The availability of preventive and disease in a patient whose liver function is already com-
treatment strategies has led to the acceptance of hepatitis promised.21 In addition, a highly effective vaccine against
B–positive patients as appropriate recipients of liver HAV is available. For these reasons, candidates for liver
transplantation. transplantation should be tested for previous immunity to
In general, potential donors found to be positive for hepatitis A. Those lacking antibody should be vaccinated.
active hepatitis B infection should be disqualified except Routine testing and preventive strategies are not available
in unusual circumstances. Organs from donors with for hepatitis E and G at this time.
antibody against hepatitis B surface antigen and negative
for anti-hepatitis B core antigen are immune on the basis Retroviruses. HIV is a potential pathogen in transplant
of previous vaccination and are safe to use for transplan- candidates and donors that may not be clinically appar-
tation. Individuals with both antibody against hepatitis B ent.31,34-36 Since 1985, candidate screening for HIV
surface and core antigens had prior infection but are infection has been part of the routine pretransplantation
considered to be immune and low risk candidates for evaluation at most institutions. Retrospective reviews
non hepatic transplantation. However, these individuals from the era before the availability of current combina-
can still maintain HBVDNA in the liver and thus their tion active antiretroviral therapy (ART) found that indi-
use as liver donors is associated with some risk for trans- viduals infected with HIV who received transplants had
mission of HBV.26 This is particularly true for donors high morbidity and mortality compared to those with-
with the presence of anti-hepatitis B core immunoglob- out HIV.34,36 In the current era of ART, individuals
ulin (Ig)M antibody. Donors who are anti–hepatitis B with end-stage liver disease have been shown to benefit
core antigen positive but surface antigen and surface from liver transplantation despite infection with
antibody negative are considered to be in the window HIV.37,38 Review of the United Network for Organ
phase. There is an increased risk for transmitting HBV Sharing (UNOS) database since the time of ART noted
to recipients of their livers.27 Accordingly, avoidance of reasonable survival rates of liver transplant recipients
donors has been recommended by some; however, in with HIV without concurrent infections; those coin-
recent years a number of centers have been able to suc- fected with HCV had poorer graft survival than liver
cessfully use these livers as a result of an aggressive pro- transplant recipients with HCV but without concurrent
phylaxis strategy.28,29 HIV.39 Close monitoring is critical and should be done
End-stage liver disease caused by HCV is a major indi- at centers familiar with transplantation in individuals
cation for liver transplantation. Although the presence of with HIV.
HCV infection in the candidate before transplantation is On rare occasions HIV may be transmitted to a trans-
associated with a nearly 100% reinfection rate of the plant recipient via the organ or blood transfusions.
allograft, and despite the fact that 50% to 80% of these Simonds et al35 at the Centers for Disease Control and
patients will develop hepatitis of the allograft, the patient Prevention reported the transmission of HIV from a sin-
and graft survival of these recipients is not adversely gle donor to all four recipients of solid organ grafts and
affected for the first 5 to 10 years.21,30,31 Although the three of four recipients of bone grafts. The donor was
impact of reinfection with HCV appears to be limited for seronegative during screening, indicating a very early
most patients, data suggest a risk for development of stage of infection when HIV antibody was not yet detect-
rapid progression to fibrosing cholestatic hepatitis in a able, highlighting limitations of screening methods that
subset of patients who have very high viral loads, need for rely on antibody tests. Recently a similar transmission40
early aggressive rejection treatments, receipt of organs occurred with the donor having concurrent infection
from older donors, and concurrent infections with HIV with HIV and HCV that were missed with currently used
or CMV.30,32,33 Research regarding treatment to reduce serological assays. Molecular assays are more sensitive
the viral load before transplantation and increasing infor- but are not always available in a timely fashion and are
mation on specific genetics of HCV should assist with costly. Likewise, screening all donors by nucleic acid test-
screening procedures to allow more selective timing of ing may lead to loss of organs because of false-positive
transplantation in some patients. In the meantime the results in a low-risk population.41 Some have advocated
overall reasonable survival rates for 5 and 10 years allow the use of fourth-generation serological assays, but these
centers to perform liver transplantation for individuals are not currently approved for donor screening in the
with cirrhosis resulting from HCV. United States. Screening by risk factors and using
446 PART IV Special Considerations in Patient Evaluation

molecular assays when doubt is present have assisted in Bacterial cholangitis is another infection observed in
decreasing the inadvertent use of HIV-infected donors. the candidate awaiting liver transplantation. This is par-
Newer recommendations on risk assessment and donor ticularly common in children who have undergone a
screening are in preparation by the Public Health Kasai procedure for biliary atresia.46 Similarly, episodes
Service. of bacterial cholangitis are noted among adult transplant
candidates with underlying liver diseases such as scleros-
Other Viruses. A number of additional viruses can ing cholangitis or secondary biliary cirrhosis. To date
theoretically be transmitted if a donor is undergoing there is no documentation of an increase in postoperative
acute viremia at the time of harvest, but the ability to morbidity or mortality in patients with a pretransplant
screen for them is limited. However, it is conceivable history of bacterial cholangitis. However, knowledge of
that in the future nucleic acid–based assays may be the bacterial species causing infections before transplan-
designed for such a purpose. For this reason the process tation and their antimicrobial susceptibility might guide
of screening must remain flexible and responsive to perioperative prophylaxis and subsequent empirical ther-
emerging pathogens. This is noted by the transmission apy. This is increasingly important in the current era of
of West Nile virus to all four recipients of a single organ frequent multidrug-resistant bacteria. Accordingly,
donor followed by several subsequent case reports of knowledge of the candidate’s experience with bacterial
donor transmission.40,42 Although testing all donors for infections and exposures to antibiotics will help inform
West Nile virus is not necessary, it does make sense to decisions after transplantation if empirical treatment is
avoid or to test potential donors that have had an unex- warranted.
plained encephalitis process during months when mos- Tuberculosis (TB) is a particular concern in immuno-
quitoes are prevalent. suppressed hosts. This is especially true with the ongoing
concerns for increased prevalence of multidrug-resistant
TB. Little published information is available describing
Bacteria
the incidence and outcome of TB in liver transplant
Patients awaiting liver transplantation may experience recipients.47,48 All candidates should be queried about
one or more episodes of spontaneous bacterial peritonitis past exposures to TB and have a tuberculin skin test or
(SBP). The major risk factor for developing SBP is the blood interferon-γ release assay (IGRA) looking for spe-
presence of ascites. A careful history of previous episodes cific immunological activity against Mycobacterium tuber-
of SBP should be obtained. The clinician must anticipate culosis.49 Because of the high risk for TB reactivation after
the possible development of this complication in trans- transplantation, induration greater than 5 mm at 48 to
plant candidates, because SBP results in substantial mor- 72 hours should be interpreted as a positive skin test
bidity and mortality.43 Infection is typically signaled by result. Patients known to have positive tuberculin skin
the presence of fever, abdominal pain, and hypoactive or test results or who come from an endemic area are at
absent bowel sounds. Bacteremia may be present in up to increased risk for symptomatic reactivation of TB after
50% of episodes. Diagnosis is confirmed by paracentesis transplantation.47,48 Other risk factors for reactivation of
(see Table 33-3). latent TB after transplantation include severe hepatic
Developing an episode of SBP before transplantation failure at the time of transplant, aggressive antirejection
carries prognostic implications for patients after trans- therapy, and/or concurrent HIV infection.47,48 Review of
plantation. In one series SBP was identified in 25 of 277 the larger experience of TB in other transplant recipients
adult liver transplant candidates who subsequently offers additional insight.50-52 TB after renal transplanta-
received a liver transplant.43 A significant increase in the tion has been reported as occurring as much as 15 times
rate of postoperative complications (both technical and more commonly than the rate seen in the general popula-
infectious) was noted in these patients compared with the tion53 and is also more likely in patients coming from
252 patients who did not experience an episode of SBP. areas endemic for TB. Concern exists with prophylaxis
The mortality rate in the SBP group was 76%, compared because of hepatic toxicity from isoniazid, especially in
with 8% in the non-SBP group. Of interest, 5 of 14 patients older than 35 years. Although it has generally
patients experiencing postoperative peritonitis were been found to be safe after renal transplantation, extrapo-
infected with the same bacterial species identified during lation from the kidney transplant population is limited by
their pretransplant episode of SBP. However, a second differences in immunosuppressive regimens and the
series identified a rate of posttransplant sepsis in only underlying health of liver transplant candidates. Despite
8.8% of liver transplant recipients with a history of SBP, the lack of studies specifically in liver transplant recipi-
compared with a 10% rate in controls. The authors of ents, many experts opt to initiate isoniazid prophylaxis
this second study concluded that the history of SBP did with close monitoring of liver enzyme levels to assess for
not lead to an increased rate of posttransplant sepsis if the hepatotoxicity. Vitamin B6 prophylaxis should also be
patient had received 4 days or more of appropriate treat- used to prevent neurotoxicity.
ment before undergoing transplantation.44 A more recent Living related donors should be screened by history
review in adult liver transplant recipients found an overall for infection or exposure to TB, as well as by tuberculin
rate of 5% having had SBP before transplantation. skin testing or IGRA. Donor transmission did occur
Although they did not find a difference in long-term sur- when a mother with an unrecognized TB infection
vival in those who did or did not have preceding SBP, donated a lobe of her liver to her child. The recipient
those with SBP were more likely to require surgery within developed a hepatic abscess from M. tuberculosis, and the
the first year after transplant and to die from sepsis.45 mother concomitantly was diagnosed with pulmonary
 33 Pretransplantation Evaluation: Infectious Disease 447

TB.43 Donation from someone with a positive history for from whom the risk for transmission is considerably
TB or positive skin test results should not be considered higher. However, on rare occasions, donor transmission
without documentation of adequate anti-TB treatment. of T. gondii has occurred in noncardiac transplant recipi-
Time constraints do not permit skin testing of deceased ents, leading some experts to recommend screening for all
donors nor have IGRA tests been validated for this use, organ donors.58 Trimethoprim-sulfamethoxazole, used at
but information regarding a history of active TB and most centers as prophylaxis against Pneumocystis jiroveci,
treatment should be elicited. In addition, the chest radio- also has activity against toxoplasmosis and can protect
graphs of potential donors should be reviewed for find- against reactivation of donor-transmitted disease.
ings that suggest TB infection. Antifungal prophylaxis should be considered in candi-
Transmission of bacterial pathogens from the donor to dates with a positive history of prior fungal infection with
the recipient has long been a concern after transplanta- pathogens known to recur after resolution of the primary
tion. Cultures of blood, urine, and peritoneal fluid or per- infection. Experience with coccidioidomycosis in trans-
fusate are routinely obtained at most institutions. Two plant recipients suggests that antifungal therapy, such as
large studies retrospectively evaluated the finding of bac- an azole agent, should be given in transplant recipients
teremia in donors of solid organs, including livers.54 with this history to prevent reactivation.59 Similarly,
Despite finding bacteremia in approximately 5% of donors reactivation of histoplasmosis after organ transplantation
in both series, no transmission was documented in the can occur; therefore prophylaxis with an azole agent
recipients. However, recipients in all cases were receiving should also be given indefinitely. Donor transmission of
antibiotic coverage, and caretakers were informed of the histoplasmosis has also been documented in a recipient of
bacteremia so that appropriate changes in antibiotic regi- a kidney transplant whose donor was from an endemic
mens to cover these pathogens could be made. These area.50 Blastomycosis has been noted on rare occasion
studies suggest that prophylactic antibiotics can allow the after transplantation. Amphotericin B or a liposomal for-
successful use of organs even from bacteremic donors. mulation is the most reliable therapy in the immunocom-
Blood cultures from the donor at the time of harvest are promised host, although azoles (itraconazole, fluconazole,
recommended. Another study evaluating the use of organs and voriconazole) that have good in vitro activity against
from donors with bacterial meningitis (Escherichia coli, Blastomyces dermatitidis may be effective.60 Aspergillus col-
Streptococcus pneumoniae, and Neisseria meningitidis) also onization present before transplantation can lead to sub-
found an absence of adverse events in recipients; donors stantial morbidity and mortality after the transplant.
had been treated before organ harvest, and recipients Accordingly, individuals known to have active disease
received 5 to 10 days of antibiotic treatment.55 with Aspergillus should receive aggressive therapy aimed
Serological assays are typically obtained on both at eradication. Colonization with Candida species can
donors and candidates for syphilis screening. In the past, occasionally be found before liver transplantation, par-
a confirmed positive test result for syphilis was consid- ticularly in patients who have been on broad-spectrum
ered a contraindication to use of the organ. However, antibiotic treatment. If yeast is found, low-dose ampho-
successful transplantation has been carried out by giving tericin, azoles, or echinocandins should be used to treat
penicillin to the deceased donor before harvest and by disease or eradicate colonization. Because of the risk for
then treating the recipients.56 hepatotoxicity with azoles in patients awaiting liver trans-
plantation, many prefer the use of echinocandins or low-
dose amphotericin or liposomal formulations over
Parasites and Fungi
fluconazole. Screening for past fungal disease for liver
Parasitic or fungal pathogens harbored with few or no transplantation recipients has not been routine, but it
symptoms in the normal host can cause disease (both pri- should be considered in patients from endemic areas or
mary and reactivation) after transplantation. Examples of those who have high-risk factors.
these infections include toxoplasmosis, cryptococcosis,
coccidioidomycosis, and histoplasmosis. More exotic dis-
eases (e.g., malaria, Chagas’ disease, strongyloidiasis)
Candidate Immunizations
have been reported after organ transplantation in patients It is critical to document the immunization history of the
(or donors) from countries with endemic disease.57 transplant candidate. This is too often overlooked, par-
Because patients often travel to transplant centers distant ticularly in adult patient populations. The Advisory
from their homes, it is imperative that transplant physi- Committee on Immunization Practices routinely updates
cians be aware of the local environmental risks for each recommended vaccinations for children, adolescents, and
patient and donor (see Table 33-3). adults in the United States (http://www.cdc.gov/vaccines/
Screening of candidates should include a careful his- acip/). Attempts to update the candidate’s immunization
tory of prior illness with fungal or parasitic infections. status should be made before transplantation, when vac-
Stool should be screened for ova and parasites in patients cination is more likely to be effective. In particular, atten-
coming from areas where parasitic diseases are frequently tion should be paid to ensuring protection against HAV
encountered. Routine serological screening for Toxo- and HBV. Likewise, evidence of protection against mea-
plasma gondii is not universally recommended for those sles, mumps, rubella, and varicella should be documented
undergoing liver transplantation but is advocated by because these require live virus vaccines that are contra-
some. Likewise, liver donors are not routinely screened, indicated after transplantation. Finally, attention should
because T. gondii does not have a propensity to remain be given to more recent vaccine recommendations for
latent in this organ; this contrasts with cardiac donors, adolescents and young adults to protect against human
448 PART IV Special Considerations in Patient Evaluation

papillomavirus, meningococcus, and pertussis. Seasonal Pearls and Pitfalls

influenza vaccination is recommended for all candidates
over 6 months of age, household contacts, and health care Pretransplant screening should do the following:
workers. Once the patient is listed for transplant, live • Identify potential pathogens present in:
virus vaccinations such as those against varicella, measles, • Candidate
mumps, and rubella (MMR) are controversial because the • Donor
time until an organ becomes available is difficult to pre- • Allow team to devise appropriate prophylaxis strategies
dict. If patients do not have protective antibody and more Screening assays can have false-negative results for the
than 1 month is anticipated between the time of evalua- following reasons:
• Recent infection
tion and transplantation, administration of these vaccines • New infection in candidate since time of initial evaluation
is recommended. Patients expected to undergo transplan- • Level below the limit of detection
tation within several weeks of the evaluation in general To decrease false-negative results, at the time of transplanta-
should not receive live virus vaccines. However, many tion repeat serological tests that previously had negative results.
centers, including the Children’s Hospital of Pittsburgh, Screening assays can have false-positive results because
opt to still give varicella vaccine because acyclovir or gan- of the following:
ciclovir can be administered to prevent disease if an organ • Passive antibody from blood products
becomes available within the following 4 weeks. • Maternal antibody in children younger than 12 to
18 months
   • Cross-reacting assay

Evaluating Fever at Time of Transplant

Fevers in candidates may represent acute episodes of infec-
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Evaluation of a fever without a known focus should laxis of cytomegalovirus disease after primary CMV exposure in
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length polymorphism analysis of IR2, IR3, and IR4. J Virol. 1991;
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Careful screening of the candidate and donor will help and DNA hybridization studies in posttransplantation lymphoma
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15. Paya CV, Fung JJ, Nalesnik MA, et al. Epstein-Barr virus-induced 39. Mindikoglu AL, Regev A, Magder LS. Impact of human immuno-
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17. McGregor RS, Zitelli BJ, Urbach AH, Malatack JJ, Gartner JC, Jr. (NAT) of organ donors: is the ‘best’ test the right test? A consensus
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2002;8(8):651-658. 43. Ukah FO, Merhav H, Kramer D, et al. Early outcome of liver
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2003;7(1):1-3. nitis before liver transplantation does not affect patient survival.
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1996;61(9):1358-1364. tion after liver transplantation: a report of three cases and review of
23. Daude M, Rostaing L, Saune K, et al. Tenofovir therapy in hepatitis the literature. in Clin Transplant. 1992:55-61.
B virus-positive solid-organ transplant recipients. Transplantation. 48. Higgins R, Kusne S, Reyes J, et al. Mycobacterium tuberculosis
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24. Karlas T, Hartmann J, Weimann A, et al. Prevention of lamivu- tion. Clin Transplant. 1992;6:81-90.
dine-resistant hepatitis B recurrence after liver transplantation with 49. Theodoropoulos N, Lanternier F, Rassiwala J, et al. Use of the
entecavir plus tenofovir combination therapy and perioperative QuantiFERON-TB Gold interferon-gamma release assay for
hepatitis B immunoglobulin only. Transpl Infect Dis. 13(3):299-302. screening transplant candidates: a single-center retrospective study.
25. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. Transpl Infect Dis. 14(1):1-8.
2009;50(3):661-662. 50. Munoz P, Rodriguez C, Bouza E. Mycobacterium tuberculosis
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27. Wachs ME, Amend WJ, Ascher NL, et al. The risk of transmission 51. Subramanian A, Dorman S. Mycobacterium tuberculosis in solid
of hepatitis B from HBsAg(-), HBcAb(+), HBIgM(-) organ donors. organ transplant recipients. Am J Transplant. 2009;9(Suppl
Transplantation. 1995;59(2):230-234. 4):S57-S62.
28. Dodson SF, Bonham CA, Geller DA, et al. Prevention of de novo 52. Torre-Cisneros J, Doblas A, Aguado JM, et al. Tuberculosis after
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32. Charlton M, Ruppert K, Belle SH, et al. Long-term results and 56. Ko WJ, Chu SH, Lee YH, et al. Successful prevention of syphilis
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2004;10(9):1120-1130. 57. Cantarovich F, Vazquez M, Garcia WD, et al. Special infections in
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 CHAPTER 34

Role of the Clinical Nurse

Coordinator
Kathy Manley

CHAPTER OUTLINE

GOAL OF THE CLINICAL TRANSPLANT TRANSPLANT SELECTION COMMITTEE:

COORDINATOR DETERMINING THE BEST TREATMENT PLAN
THE REFERRAL PROCESS THE LIVER TRANSPLANT WAITING LIST
EVALUATION OF PATIENTS WITH END-STAGE TRANSPLANTATION
LIVER DISEASE
CONCLUSION
Outpatient Transplant Evaluation
Inpatient Transplant Evaluation

Less than 25 years ago, a major nursing medical-surgical families. To assist with this process the transplant coordi-
textbook stated: “The successful transplantation of organs nator must be the primary contact for patients and their
and tissues as a means of preserving life, correcting defor- caregivers. As the primary contact, the CNC actively par-
mities, and repairing organic damage has been an age old ticipates in all levels of the patient’s care, communicates
dream of physicians. In recent years, as a result of scien- openly with the patient and other members of the health
tific advances in both surgery and physiology, that dream care team regarding patient care issues, takes the oppor-
seems to be coming true.”1 The “dream” of successful tunity to continually monitor the patient and assesses any
transplantation and the possibilities that exist in assisting educational needs, and finally, advocates for the patient
these critically ill patients to regain their quality of life because a patient with end-stage liver disease can often
have had a direct and immense impact on the field of experience significant deterioration before transplanta-
nursing. tion becomes an option.
This impact is especially true for the registered nurses
who work specifically in the role of clinical nurse coordi-
nator (CNC), also known as transplant coordinator. The THE REFERRAL PROCESS
following text examines the role of these clinical experts,
specifically, pretransplant liver coordinators, who under Referral for liver transplantation can come from a variety
the direction of a hepatologist facilitate the care of of different sources, including but not limited to a primary
patients with end-stage liver disease. care physician, a hepatologist or gastroenterologist, an
oncologist, and possibly an insurance case manager. No
matter the source of the referral, it is essential that the
GOAL OF THE CLINICAL TRANSPLANT CNC obtain accurate and current medical information
COORDINATOR from the referral source so that decisions on the patient’s
care can be made in a timely fashion. This information
The goal of the CNC is to successfully guide patients may be gathered verbally and also through obtaining cur-
with end stage liver disease through a maze of processes rent medical records. As with many other areas of nursing,
that may ultimately lead to liver transplantation. This with experience a CNC will find that one question leads
maze includes the referral process, transplant evaluation, to the next and to the next, thus giving the pretransplant
determination of transplant candidacy in a multidisci- team a good picture of the patient before arrival at the
plinary committee, financial clearance for transplanta- transplant center. A complete review of a patient’s medical
tion, placement on a transplant waiting list, and follow-up information by the CNC ensures the appropriateness of
needed to remain on the list. Not only are several steps the referral for liver transplant evaluation and efficient
involved, but multiple health care professionals are also coordination of care.
involved at each step. Navigating the steps in this process One consideration is the medical condition of the
can be an overwhelming task to patients and their patient at the time of referral. If the patient is presented as

450
 34 Role of the Clinical Nurse Coordinator 451

a critically ill patient, the urgency of the referral must be period of 4 or 5 days the information needed to deter-
communicated immediately so that physician-to-physician mine a patient’s candidacy for liver transplantation can be
communication can take place. Such communication may obtained through testing and consultation. At the same
prompt urgent financial clearance for transplant evaluation, time the educational process intensifies with the patient
followed by a hospital-to-hospital transfer in which a medical and the designated support team. To obtain success in
evaluation can be completed in a matter of just a few hours. both, it is essential that the evaluation be well organized
Patients may also be referred for a transplant evaluation and patient friendly. Because each patient may learn dif-
very early in the patient’s disease process. A patient in ferently, it may be necessary to present the same informa-
whom liver disease has been diagnosed but who has nor- tion in several different formats. Obviously the stress of
mal laboratory values and scans without evidence of malig- chronic liver disease, as well as issues with encephalopa-
nancy may be too early for transplant listing but will need thy, can make patients with end-stage liver disease chal-
close follow-up to monitor the disease process. Review of lenging to educate.
the medical information at the time of referral may lead to During the outpatient evaluation the first person
a hepatology consultation and an opportunity for the that the patient should have direct contact with is a
patient to be closely monitored by a liver specialist with- CNC, who can handle any immediate issues. The Sim-
out having to undergo a complete transplant evaluation. mons Transplant Institute at Baylor University Medical
This is of great benefit to the patient, who may possibly Center meets with prospective candidates at a liver
have an opportunity to be treated with other medical ther- evaluation orientation each Monday morning. This
apies and thus be “in the system” in case transplantation is group orientation provides a general overview of the
needed in the future. This practice is also of great benefit transplant program and the many steps involved in the
to the payer, because unnecessary or too early evaluation evaluation and briefly touches on the regulatory stan-
for transplantation is a costly practice. dards set by the United Network for Organ Sharing
Once the medical information has been obtained, the (UNOS), specifically regarding the Model for End-
CNC then works closely with the team of financial Stage Liver Disease (MELD) scoring system,2 accep-
experts to obtain clearance to begin the transplant evalu- tance as a candidate, placement on the list, and the
ation process. At the same time the CNC begins to build transplant surgery.
the relationship with the patient and family by laying the Immediately after this group meeting, each patient
groundwork for open communication. This is easily meets with a specific CNC, who again will discuss and
accomplished by an introductory phone call or corre- reinforce information regarding the transplant process
spondence to let the patient know that a referral has but more specifically the evaluation schedule that has
been received. Other topics discussed with the patient in been established for that particular patient.
these early conversations or correspondence include During this initial time with the patient the CNC also
specific information regarding the medical center, avail- reviews highlights of the patient’s medical history to
able housing, transportation, and any information that is make sure that the medical information obtained from
helpful during the evaluation, such as the availability of the referring physician is complete. After this review the
radiology films or biopsy slides for review. Once the patient is also provided the Patient Manual for Liver
medical information has been fully reviewed and the Transplantation. Originally published in 1988, this publi-
payer has given financial clearance, the transplant evalu- cation is now undergoing its seventh edition update to
ation can begin. reflect the most recent changes in liver transplantation.
Written specifically with the pretransplant liver patient in
mind, this text discusses all aspects of transplantation
EVALUATION OF PATIENTS WITH from transplant evaluation to the long-term follow-up
END-STAGE LIVER DISEASE needed after transplantation.
Whether through group presentations, written litera-
Transplant protocols, including a pretransplant evalua- ture, or one-on-one meetings, each transplant patient
tion order set, should be developed and approved by both and family will need reinforcement of the information
the hepatology staff and the transplant surgery staff. At and how it applies to their situation personally. As the
the time of transplantation, both the medical and surgical transplant evaluation week continues, the CNC has regu-
physician teams must be satisfied with the information larly scheduled meetings with the patient to answer any
that is known about the patient. This starts with the questions that may have come up during the week or to
information obtained during the transplant evaluation. A notify the patient that additional tests or consultations
standard pretransplant evaluation order set should be have been added to the schedule based on the recommen-
used. This order set should not be inclusive but should dation of a consulting physician. This time is used to
allow for additional testing and consultations to be reinforce the patient’s basic knowledge of transplanta-
ordered as deemed necessary by the physician team; how- tion, and often by the midpoint of the evaluation, the
ever, these guidelines should be followed by the CNC for patient and family are ready to begin taking in additional
all patients being evaluated for liver transplantation. information regarding the transplant experience. Accord-
ingly, additional group meetings are scheduled to con-
tinue the educational process and discuss topics such as
Outpatient Transplant Evaluation what to expect at the time of liver transplantation and
For the majority of patients, the transplant evaluation can afterward, living donor liver donation, and transplant
be completed efficiently in an outpatient setting. In a finances.
452 PART IV Special Considerations in Patient Evaluation

Inpatient Transplant Evaluation team brings together the expertise of many to make life-
changing decisions one patient at a time. The structure of
Although the majority of liver transplant evaluations can the transplant selection committee should truly follow the
be completed on an outpatient basis, the CNC must meaning of many disciplines. Members on this committee
always be prepared for patients who may present at the may include physicians from the following disciplines:
transplant facility at any time and need an inpatient trans- hepatology, gastroenterology, transplant surgery, general
plant evaluation. Such patients include those with chronic surgery, internal medicine, oncology, and psychiatry.
liver failure in a period of decompensation and patients in Others included are psychologists, social workers, trans-
acute fulminant liver failure. plant dietitians, and members from the pretransplant and
The CNC must work closely with the admitting physi- posttransplant CNC staff. A quorum of members must be
cian, physician consultants, and the nursing staff to ensure present to begin the patient presentation process. This
that all of the evaluation testing and consultations are quorum includes the presenting hepatologist, as well as
completed and communicated in a timely manner. Using one other hepatologist, a transplant surgeon, and a social
standardized order sets located on the nursing units is key worker. It is also essential that this committee have close
to initiating the evaluation at the time of admission with- ties with the hospital ethics committee to ensure that any
out delay. Staff in the intensive care units and medicine patient situation presenting an ethical dilemma can have
floor units must be knowledgeable about pretransplant immediate response and resolution.
protocols, including the evaluation process. Because of patient confidentiality issues, few visitors
If a patient with chronic liver failure has stabilized and are allowed to attend the transplant committee meeting—
is ready for discharge from the hospital before completion and then only at the discretion of the chairperson. Patients
of the evaluation, the patient will need to complete the and their family members are not allowed to attend the
evaluation on an outpatient basis. Careful review and plan- weekly transplant conference.
ning by the CNC can help alleviate duplications in testing The CNC who has assisted the patient through the
once the patient converts to an outpatient evaluation. evaluation process summarizes all essential information
Patients who arrive at the facility in acute liver failure obtained during the evaluation into a condensed written
may not have the luxury of an extended transplant evalua- format that is used by the treating hepatologist when pre-
tion. Under the guidance of the transplant hepatologist, senting the patient’s case to the transplant committee.
the CNC must work diligently to make sure that informa- Essential information includes the hepatologist’s history
tion deemed necessary for urgent listing is gathered and and physical examination, as well as all consultations,
reviewed within a period of a few hours. Once the patient radiological examinations, and laboratory values.
is placed on the transplant list, the pretransplant CNC The patient’s treating hepatologist presents the medical
must also continue to gather the evaluation information information to the transplant selection committee. Other
and communicate it to the entire transplant team as the team members who saw the patient in evaluation will also
patient waits for the lifesaving organ. This information is share their findings. Each consulting physician or member
often critical for the hepatologist because the cause of the of the transplant team who has had an opportunity to
acute liver failure is being investigated and needed therapy assess the patient discusses the pros and cons of liver trans-
is being determined while the wait for transplantation con- plantation for this particular patient. At the end of each
tinues. This information is also critical to the transplant patient discussion, the group will come to a consensus
surgeon because organ offers are beginning to be received regarding the appropriateness of liver transplantation.
from the local organ procurement organization and post- This decision is recorded and becomes a part of the official
transplant immunosuppression is being considered. meeting minutes of the transplant selection committee.
The educational needs of the patient and family must During the transplant selection committee meeting, the
be individualized as determined during the inpatient trans- CNC works diligently to ensure that the members follow
plant evaluation. For the majority of inpatient evaluations all regulatory guidelines, that clinical information is pro-
the CNC will have ample opportunity to meet with the vided as needed to the decision-making team, and that notes
patient and family to begin the educational process during are made to update any new data brought forward. New
the hospital admission. Patients who are critically ill may information may be hospitalizations that have occurred
not have the capacity to participate in the pretransplant since the patient has returned home, medication changes,
education. In such cases it is essential that the CNC work or additional diagnoses that the transplant team needs to be
directly with the patient’s family or designated support aware of for pretransplant and posttransplant care.
team to provide education and emotional support. After the transplant selection committee meeting, the
CNC contacts the patient and referring physician to
notify them of the decision regarding candidacy for liver
TRANSPLANT SELECTION COMMITTEE: transplantation. In certain instances the hepatologist will
discuss this recommendation with the patient and desig-
DETERMINING THE BEST TREATMENT nated support team, and in all cases the hepatologist is
PLAN available for questions or concerns regarding the com-
mittee decision.
The goal of the transplant selection committee is to rec- The transplant committee recommendation typically
ommend the best medical therapy that is available for the falls into one of three separate categories:
patient and more specifically to determine whether that 1. Accepted as a transplant candidate—this candidate
therapy is liver transplantation. This multidisciplinary meets the national standards set by UNOS, as well
 34 Role of the Clinical Nurse Coordinator 453

as the inclusion criteria that have been established placed on the liver transplant list according to all UNOS
for the individual transplant program. The transplant requirements. Depending on the amount of time that it
evaluation is completed, and the candidate will pro- has taken to obtain financial clearance, the CNC may
ceed to the next step. need to contact the patient to obtain updated laboratory
2. Denied as a transplant candidate—this candidate work to satisfy the requirements of the MELD system. It
has been found to not be a candidate for liver trans- is also the responsibility of the CNC to ensure that two
plantation. The patient does not meet the national separate ABO blood types have been obtained, as required
standards set by UNOS or may have a contraindica- by UNOS.4 It is essential to have a system of checks and
tion that has been established by the individual balances to make sure that all patients are listed correctly
transplant program. An example is a patient who and in a timely fashion. The listing process may include a
has a comorbidity such as heart disease or a patient listing form to ensure that all necessary information is
who does not meet the individual transplant pro- available for placement on the waiting list. Using two
gram’s sobriety guidelines. Another example would CNCs in the listing process is a system of checks and bal-
be a patient who has a single tumor that is larger ances to ensure that the transplant team is in agreement
than hepatocellular carcinoma criteria established with transplant selection committee decisions, final test-
by UNOS (single tumor larger than 5 cm in total ing results, and financial clearance, and that any regula-
diameter)3 or criteria established by Region 4 tory requirements for placement on the waiting list are
Regional Review Board guidelines (single tumor met.
larger than 6 cm in total diameter). Once listed, the patient is notified by the CNC by
3. Deferred—this candidate is still being considered phone and by mail regarding placement on the trans-
for liver transplantation, but further testing is plant waiting list. The CNC provides education
required based on the results of the evaluation and regarding the patient’s MELD score, and when future
the recommendations of the transplant commit- MELD laboratory tests will be needed. The phone call
tee. The patient will be brought back to the trans- notifying the patient of listing is another critical oppor-
plant committee with further information at a tunity to educate the patient. A common question by
later date. all patients at the time of placement is, “Where am I on
Regardless of the decision made in the transplant the list?” Since its inception in 2002 the MELD system
selection committee, it is the role of the CNC to help the has made it more difficult to predict the average amount
patient understand the recommendation and future plan of time that each patient will be on the waiting list
of care. The CNC will need to assess the learning needs because it can change randomly. Obviously, higher
of the patient and support team and will continue to be MELD scores would mean shorter waiting list times,
the primary contact for questions or concerns regarding but for patients with an average or below-average
the decision. MELD score, the wait can be long. At this time the
For patients who have been accepted as a candidate to CNC has the opportunity to educate the patient and
be placed on the liver transplant waiting list, the CNC the care team about the need for continuous monitor-
requests that the transplant financial experts obtain ing of the listed patient, including immediate reporting
clearance from the payer so that placement on the wait- of laboratory values that may have been obtained
ing list can proceed. The CNC assists with this process from a physician outside the transplant center, all
by providing the financial team medical records from the ­hospitalizations, and any changes in the medical condi-
transplant evaluation and a letter of medical necessity, tion of the patient. This communication can ensure
which states the justification for liver transplantation. that as a patient’s medical condition changes, the status
Obtaining financial clearance for transplantation occurs on the transplant list reflects this change in medical
through working with the payer case manager or directly condition.
with the medical director. Payers may have questions A protocol established by the hepatology and surgical
regarding the transplant center’s protocol, testing transplant team must be in place to monitor patients
results, or as with some payers, the addition of some tests while on the waiting list. Laboratory values must be
or consultations based on their own established guide- obtained at frequencies established by UNOS based on
lines. Examples of payer-required testing might include MELD score. The CNC must also ensure that the patient
dental clearance or additional laboratory tests not completes the required testing that is needed while on the
required in the transplant center’s own protocol. Once waiting list according to the transplant center’s individual
again the CNC is the primary contact for the insurance protocol. Monitoring may include laboratory and radio-
representative regarding clinical needs and works closely logical tests to monitor for the occurrence of hepatocel-
with the case manager to ensure that all questions are lular carcinoma. Additional testing can include monitoring
satisfactorily answered to facilitate placement on the viral serological screening, cardiac function, renal func-
waiting list. tion, and psychosocial factors. The transplant center’s
individual protocols give guidance to the CNC regarding
monitoring patients on the waiting list to ensure that the
THE LIVER TRANSPLANT WAITING LIST patient continues to be a good candidate for transplanta-
tion. This also ensures that the transplant team has the
Once financial clearance has been obtained, it is the most current information available at the time of
responsibility of the CNC to make sure that the patient is transplantation.
454 PART IV Special Considerations in Patient Evaluation

TRANSPLANTATION Pearls and Pitfalls

At the time of transplantation the pretransplant CNC is • Always listen carefully to your patients and their
notified of the imminent surgery. Such notification gives caregivers—by listening and educating, the clinical
the CNC an opportunity to discuss any known medical nurse coordinator (CNC) can prevent problems in
changes that would have to be communicated to the crisis management.
transplant surgeon to assist in successful transplantation. • Standardized protocols are an essential component of
Follow-up with the patient and family by the pretrans- quality patient-centered and cost-effective pretrans-
plant CNC before surgery or immediately afterward can plant care.
• CNCs are the regulatory experts—know the national
assist the patient in the transition from the phase of guidelines, as well as your own center’s protocols.
chronic illness and waiting for a transplant to the phase of • Always have complete medical and financial clearance
learning how to take care of himself or herself after having before placing the patient on the transplant waiting list.
a liver transplant. • Have all critical medical information readily available
when the patient’s case is being presented to the liver
transplant committee and at the time of transplantation.
CONCLUSION • Always remember that liver transplantation is a life-
changing experience and that we all do not handle
Liver transplantation has brought a whole new dynamic stress in the same way. Be a patient advocate.
to the field of nursing by creating the role of the CNC.    • Find and use your resources—this is a team effort.
Knowledge and proficiency in the care of patients with
end-stage liver disease, the ability to successfully coor- REFERENCES
dinate care among a multidisciplinary transplant team, 1. Luckmann J, Sorensen KC. Medical-surgical nursing: a psycho-
and expertise in the field of liver transplantation and physiologic approach. Philadelphia: WB Saunders; 1980, p 167.
UNOS regulations are essential requirements of the 2. Organ Distribution: Allocation of Livers 10 August 2012. p 1-8. 26
pretransplant CNC. As patients are discharged from June 2012. http://optn.transplant.hrsa.gov/policiesAndBylaws/polic
the hospital and eventually back to local medical care, ies.asp.
3. Organ Distribution: Allocation of Livers 10 August 2012. p 14. 26
the CNC knows that each step in the pretransplant pro- June 2012. http://optn.transplant.hrsa.gov/policiesAndBylaws/polici
cess was instrumental in successful transplantation and es.asp.
ultimately the patient’s return to life before liver 4. Organ Distribution: Definitions 10 August 2012. P 1. 26 June 2012.
disease. http://optn.transplant.hrsa.gov/policiesAndBylaws/policies.asp.
 CHAPTER 35

Radiological Evaluation
in Transplantation
Antoinette S. Gomes

CHAPTER OUTLINE

PRETRANSPLANTATION EVALUATION Inferior Vena Cava and Hepatic Vein

Computed Tomographic Imaging Complications
Magnetic Resonance Imaging EVALUATION OF THE BILIARY SYSTEM
Magnetic Resonance Imaging Technique Biliary Tract Complications
POSTTRANSPLANTATION EVALUATION Evaluation and Management of Bile Leaks
Ultrasonography Radiographic Diagnosis and Management of
Biliary Obstruction
EVALUATION OF VASCULAR COMPLICATIONS
AFTER TRANSPLANTATION SUMMARY
Hepatic Artery Complications
Portal Vein Complications

Diagnostic and interventional radiological procedures IVC, which is necessary for liver transplantation to be
have an important role in liver transplantation. They are performed. The extrahepatic portal vein may be absent in
used before operation in the selection and presurgical patients with biliary atresia, and the IVC may be absent in
management of candidates and posttransplantation in the polysplenia syndrome. If the portal vessels are clearly
follow-up, diagnosis, and treatment of complications. identified, ultrasonography alone is sufficient.5,6 How-
ever, nonvisualization or equivocal visualization of the
portal vein owing to thrombosis of the portal vein with
PRETRANSPLANTATION EVALUATION cavernous transformation and large collateral vessels
requires arteriography or magnetic resonance angiography
Radiological evaluation of the liver transplant patient is (MRA) for accurate assessment.
usually performed on an outpatient basis. The goal is to
determine abnormalities that preclude transplantation
along with abnormalities that will affect the operative
Computed Tomographic Imaging
procedure. Real-time ultrasonography is used routinely A computed tomographic (CT) scan of the chest, abdomen,
to evaluate the liver, the biliary system, and the portal and pelvis is indicated for all patients being evaluated for
system. Ultrasonography has been found to have a sensi- liver transplantation because of a hepatic tumor. The size,
tivity rate of 80% to 100% in detecting bile duct obstruc- number, and location of intrahepatic masses can be seen on
tion.1-4 It is also used to evaluate hepatic echo texture. a CT scan. In addition, a CT scan provides information
Focal or diffuse heterogeneity may be seen in cases of regarding splenomegaly, varices, ascites, vascular anomalies,
fatty infiltration, cirrhosis, or tumor. In addition, ultraso- and morphological pancreatic anomalies. It also allows
nography is used to exclude occult hepatic carcinoma and evaluation of the entire abdomen for primary tumors,
to detect adenopathy in the porta hepatis, ascites, or vas- metastases, and abscesses. The preoperative CT scans
cular invasion by tumor. Doppler ultrasonography is used provide information regarding liver size and shape from
to assess the portal vasculature. The patency and size of which liver volume can be calculated, facilitating the
the extrahepatic portal vein must be ascertained and the selection of a donor liver of appropriate size.
patency of the inferior vena cava (IVC) determined, CT scans are used initially to determine whether a
because narrowing or occlusion of either of these vessels patient with a hepatic tumor is a candidate for partial
alters surgical technique. The hepatic artery and hepatic hepatic resection or requires transplantation.
veins are also evaluated. Patients with thrombosis of the Most cases of liver cancer occur in the presence of end-
hepatic veins in the Budd-Chiari syndrome may have stage cirrhosis, which distorts the hepatic parenchyma
thrombosis of the IVC and patency of the suprahepatic and may produce focal abnormalities and nodules.7

455
456 PART IV Special Considerations in Patient Evaluation

The differentiation of focal liver lesions such as hepa- triple-pass CT scan during early arterial, late arterial, and
tocellular carcinoma (HCC) on CT is based on the portal venous phases. Studies show that a significant
attenuation differences in density between normal liver number of additional HCC lesions can be found during
and the lesion. HCCs receive most of their blood supply the arterial phase compared with the portal or delayed
from the hepatic artery, whereas normal liver parenchyma phases.8
is supplied mainly through the portal vein. On CT, Currently the recommended CT protocol is a triple-
lesions with arterial-dominant vascularity show brisk phase CT with an arterial phase, a portal phase, and an
enhancement during the arterial phase (20 to 40 seconds equilibrium phase (10 to 15 minutes) following injection,
after contrast injection) and are better detected in the when most HCC becomes hypovascular relative to the
background of normal liver parenchyma, which remains liver parenchyma. Generally HCCs show brisk hyper-
relatively hypovascular during this phase. During the enhancement during the arterial phase and rapidly
portal phase (60 to 90 seconds after the actual injection), become isoattenuating or hypoattenuating during the
the liver still receives opacified blood from the arterial portal phase. In a small number of cases, however, HCC
system and also receives four times more blood from the lesions may be hypoenhancing and nearly isodense in the
portal system. During this phase, hypervascular lesions arterial phase and persist as hypoattenuating lesions
such as HCC can be isodense relative to normal liver during the portal phase.
because both enhance similarly. In patients with hepatic cirrhosis an enhancement
With older nonhelical CT units, contrast images were pattern consisting of hyperattenuation in the arterial
acquired during the portal dominant phase. In this phase, phase and hypoisodensity in the portal phase is virtually
hypovascular lesions are well seen, but hypervascular diagnostic of HCC (Fig. 35-1).9
lesions were usually missed because they can be isodense Other features characteristic for HCC are the pres-
relative to the liver parenchyma. The development of ence of a prominent fibrous capsule on contrast-enhanced
faster helical scanners permitted biphasic imaging, with images, focal macroscopic adipose tissue within the
completion of the liver examination, during the arterial- tumor, and coexistence of a liver mass and portal vein
dominant and portal-dominant phases of contrast thrombosis.10 Although the majority of nodules in the
enhancement. Multirow helical scanners now allow a setting of chronic liver disease are HCC, other lesions

A B

C D
FIGURE 35-1 n Triple-phase computed tomography of patient with hepatocellular carcinoma (HCC) and cirrhosis. Typically HCCs show
brisk enhancement in the arterial phase and become isoattenuating or hypoattenuating in the portal and equilibrium phase. A, Early
in the injection the left lobe HCC (arrow) is nearly isointense with the remaining liver. A few small abnormal arterial branches are
seen. B, Slightly later in the injection a capsule is seen outlining the tumor. C, In the late arterial–early venous phase there is enhance-
ment of the tumor, which is now seen as a bright lesion (arrow). D, In the late venous phase (equilibrium) there is evidence of washout
of contrast from the tumor, and the tumor is hypointense.
 35 Radiological Evaluation in Transplantation 457

may be detected in cirrhotic patients undergoing screen- Following these criteria, the reported actuarial survival
ing with helical CT.11 Hyperenhancing lesions in the rate is 75% at 4 or 5 years.15,16
arterial phase include small hemangiomas, transient
hepatic attenuation differences, atypical dysplastic nod-
ules, focal nodular hyperplasia, liver cell adenoma, and
Magnetic Resonance Imaging
hypervascular metastases. In chronic liver disease the Magnetic resonance imaging (MRI) is now frequently
differential diagnosis of HCC consists largely of heman- used in transplant imaging. It is used as an alternative in
gioma, transient hepatic attenuation differences, and the patients who are allergic to iodinated contrast media. It
rare hypervascular dysplastic nodule. In patients with can provide information on focal liver lesions and can
chronic liver disease the differential diagnosis of clarify CT findings in cases of focal fatty change. It can
hypodense lesions in the portal or equilibrium phase is provide information regarding the biliary tree, and three-
hypovascular HCC, peripheral cholangiocarcinoma, dimensional time-of-flight gadolinium-enhanced MRA
dysplastic nodules, and regenerative nodules. Other techniques permit visualization of the arterial and portal
lesions, such as liver metastases from other primary venous system. MRI is used to help distinguish dysplastic
tumors, are rare.12 nodules from HCC. Dysplastic nodules are typically
Multiple benign masses occurring in the cirrhotic liver hyperintense on nonenhanced T1-weighted images and
can mimic a malignant tumor. By definition, regenerative of low signal intensity on T2-weighted images. They are
nodules are present in all cirrhotic livers.10 Regenerative almost never hyperintense on T2-weighted images.17
nodules are formed by regenerative hepatocytes sur- Regenerative nodules typically are isointense on
rounded by fibrotic septa. They can vary from 1 to 3 mm T1-weighted images and low signal intensity nodules on
in micronodular cirrhosis to 3 to 15 mm in macronodular T2-weighted and gradient-recalled images. HCCs are
cirrhosis. Histologically they are composed of normal isointense or hyperintense on nonenhanced T1-weighted
hepatocytes, and their blood supply is predominantly images and hyperintense, isointense, or hypointense on
portal. Because the blood supply and architecture of T2-weighted images (Fig. 35-2). Hyperintensity on
regenerative nodules are similar to adjacent normal liver T2-weighted images is characteristic of HCC and is
parenchyma, visualization of regenerative nodules is related to a lower degree of histological differentiation. On
difficult. On unenhanced scans they blend in with other contrast-enhanced images, most HCCs exhibit diffuse
regenerative nodules and fibrosis, and those seen are enhancement during the arterial phase, with rapid washout
typically revealed as low-attenuation nodules because during the portal (venous) phase.18
they contain iron or glycogen or are surrounded by low- Other typical findings of HCC on MRI include a visible
attenuation fibrous tissue. Occasionally they appear as tumor capsule, a mosaic pattern, intratumoral fat deposi-
slightly hyperdense lesions on noncontrast studies. More tion, portal or hepatic vein invasion, and arterioportal
often they appear in the equilibrium phase as tiny venous shunting.19,20 These major findings may be absent
hypodense lesions. Although infrequent, large regenerative in very small tumors, with only the hypervascularity
nodules may present as low-density lesions in the arterial, detected.
portal, and equilibrium phases, mimicking hypovascular The HCC capsule, a major morphological finding in
HCCs.12 HCC, is a fibrous area surrounding the tumor formed by
Dysplastic nodules are regenerative nodules containing condensation and collagenation of reticulum fibers after
cellular atypia without frank malignant characteristics the disappearance of hepatocytes from compression of the
and are seen in 15% to 25% of cirrhotic livers.13 They are tumor. It usually is hypointense on unenhanced T1- and
supplied primarily by the portal vein, although high-grade T2-weighted spin-echo images, hypointense on unen-
dysplastic nodules may develop arterial hypervascularity. hanced gradient echo images, and hyperintense on delayed
In a series of patients undergoing hepatic transplantation, postgadolinium images. The presence of fatty change
the sensitivity of helical CT was 39% (9 of 23) with all of within the tumor is another primary and characteristic
the lesions being hypoattenuating.14 finding in HCC.
Large studies are needed to determine the exact sen- Fibrous septa and a mosaic pattern are characteristic of
sitivity and specificity of helical CT in the detection of HCC21 and are well seen, especially after contrast
HCC. Lim et al14 reported a sensitivity of 71% (15 of 21) injection.
for helical CT in the detection of HCC. The detection
rate for lesions less than 2 cm was 60%, and the detec- Magnetic Resonance Imaging Technique
tion rate for lesions larger than 2 cm was 82%. In the
series of Valls et al12 helical CT had a sensitivity of Currently breath-hold T1- and T2-weighted images of
79.6% (39 of 49) and a positive predictive value of 86.6% the liver are recommended because they avoid the motion
in the detection of HCC. There were six false-positive artifact commonly seen with conventional longer spin-
results, largely related to macronodular regenerative echo MRI sequences. For T2-weighted images, breath-
nodules and hyperplastic dysplastic nodules. hold turbo spin echo (TSE) with long echo train or
The detection and staging of HCC is essential in the half-Fourier acquisition single-shot turbo spin-echo
pretransplant evaluation. Studies support liver trans- (HASTE) sequences are recommended. For T1-weighted
plantation in patients with a solitary HCC that is less images, breath-hold gradient-echo sequences permit
than 5 cm or with no more than three tumor nodules scanning of the entire liver in a single breath-hold and
(each 3 cm or less in diameter) as long as there is no allow dynamic contrast–enhanced images, which allow
evidence of vascular invasion and extrahepatic spread. the entire liver to be imaged in the arterial phase.
458 PART IV Special Considerations in Patient Evaluation

A B

C D

E
FIGURE 35-2 n Magnetic resonance imaging of same patient as in Figure 35-1 with hepatocellular carcinoma (HCC) and cirrhosis per-
formed a few weeks later using the extracellular-hepatobiliary agent gadoxetic acid. A, Precontrast T1-weighted in-phase images
show the left lobe lesion to be hypointense relative to the rest of the liver (arrow). B, Precontrast T-2 half-Fourier acquisition single-
shot turbo spin-echo (HASTE) image shows the left lobe lesion to be hypointense similar to the rest of the liver. C, In the early arterial
phase of the contrast injection the left lobe lesion is seen to be hyperintense. D, Three minutes following injection the HCC is showing
patchy washout with decreased signal. In the dynamic phases (arterial, portovenous, and equilibrium phases) the extracellular-
hepatobiliary agents behave similarly to conventional extracellular gadolinium-containing contrast agents with rapid arterial enhance-
ment followed by washout. E, Twenty minutes following gadoxetic acid injection the HCC is seen to be hypointense relative to the
rest of the liver because of its inability to take up the gadoxetic acid. The rest of the liver is bright because the hepatocytes have taken
up the gadoxetic acid.

Breath-hold chemical shift (in phase and opposed Imaging in the portal venous phase (60 seconds after
phase) can show fatty infiltration of the liver as well as fat injection) and the equilibrium phase (90 seconds to 5
within hepatic nodules.22 Chemical-shift MRI tech- minutes after injection) after contrast is important for
niques, which are based on the difference in resonance showing washout of HCC and delayed enhancement of
frequency of water and fat protons, is the most reliable the capsule.
MRI technique in detecting intratumoral fat.23,24 Lesions Although MRI has helped solve diagnostic questions
containing a mixture of fat and water protons exhibit low in cirrhotic patients, because the development of HCC
signal intensity on opposed-phase images because the sig- in chronic liver disease is a progressive process ranging
nal from water cancels the signal from fat. High signal from regenerative nodules to low- or high-grade dys-
intensity is seen on in-phase images because the signals plastic nodules and HCC, the detection and character-
are summed. ization of nodular lesions in cirrhotic livers remains a
After the T1 and T2 unenhanced MRI study, extracel- challenge. With MRI, regenerative nodules may be
lular-type gadolinium chelate contrast agent is injected, hypointense on all pulse sequences if they contain iron
and contrast-enhanced images are obtained in the arterial, and may be hyperintense on T1-weighted images. They
portal, and equilibrium phases. Images in the arterial phase do not enhance on the arterial phase postgadolinium
(15 to 20 seconds after injection) are needed in cirrhotic and do not show a capsule in delayed-phase images.22
livers to show hypervascular lesions or small HCCs. Iron-containing siderotic regenerative nodules are well
 35 Radiological Evaluation in Transplantation 459

shown as low-signal-intensity nodules on MRI and are (see Fig. 35-2). Regenerative nodules typically show
seen much better than with CT. Gd-EOB-DTPA uptake and excretion because of pre-
Although there is considerable overlap in signal inten- served hepatic function and intact ion transporters and
sity on unenhanced T1- and T2-weighted images between have signal similar to that of background liver. In the
dysplastic nodules and HCC, it has been reported that hepatocyte phase, dysplastic nodules that have retained
low-grade dysplastic nodules have a tendency to show the ability to take up the agent but not to excrete it
hypointensity on T2-weighted images and hyperintensity appear hyperintense because of intracellular cholestasis,
on T1-weighted images. HCC has an isointense or hyper- whereas nodules that have lost the ability to take up the
intense pattern on T1-weighted images and is isointense agent are hypointense.32
with partial hyperintensity on T2-weighted images.22 Although some benign hyperenhancing nodules such as
Because of their predominantly portal supply, low-grade small hemangiomas and focal nodular hyperplasia rarely
dysplastic nodules do not typically capture extracellular are encountered in cirrhotic patients, the diagnosis of HCC
contrast in arterial-phase images. Even though it has been is highly likely when a hypervascular nodule is identified in
shown that 96% of dysplastic nodules have a portal blood a cirrhotic liver.34 In the absence of other major character-
supply and 94% of HCCs have an arterial blood supply,25 istic findings of HCC, the hypervascularity of the nodule in
the blood supply of dysplastic nodules is controversial and the arterial phase may be the only feature that helps to
variable. diagnose small HCC. These small HCCs should be dif-
Currently, although some imaging features on MRI ferentiated from the hyperattenuating transitory parenchy-
are reported to be characteristic for dysplastic nodules, it mal areas detected on the arterial phase of dynamic CT or
remains difficult to diagnose them definitively by any MRI,35,36 which are attributed to nonspecific arterioportal
imaging technique. shunts caused by cirrhotic changes or produced by iatro-
Difficulties with lesion characterization have been genic vascular injury. A rounded nodular shape and delayed
affected by the development of newer gadolinium-based washout favor the diagnosis of HCC. Geographical mor-
contrast agents. The detection and characterization of phological characteristics and isointensity on delayed
liver lesions using gadolinium-based contrast agents is venous-phase images favor the diagnosis of vascular nontu-
based mainly on the assessment of vascularity and per- moral change. With Gd-EOB-DTPA, areas of transient
fusion. However, because cirrhosis is characterized by arterial enhancement are usually isointense to parenchyma
variable disturbances in hepatic blood flow because of because they contain functional hepatocytes.32
disruption of normal anatomy, assessment of blood flow Portal or hepatic venous invasion is characteristic of
to hepatocellular nodules may be difficult with conven- HCC. On MRI, portal vein tumor thrombus shows as an
tional extracellular gadolinium-containing agents. intravascular mass of intermediate signal on T1-weighted
Well-differentiated HCC may have portal supply and images. Similar to liver tumor, the intravascular mass
show hypoenhancement, which may evade detection enhances in the arterial phase after contrast injection.
and be confused with benign nodules. With cirrhosis Gadolinium-enhanced MRA techniques are particularly
the presence or absence of contrast may be difficult to useful in visualization of the hepatic artery and the portal
assess in small (<2-cm lesions). The newer combined venous system.37
extracellular-hepatobiliary agents have imaging proper- With triphasic contrast-enhanced helical CT or
ties of conventional extracellular agents but also possess dynamic gadolinium-enhanced MRI, small, 2-cm, hyper-
hepatocellular function. In contrast to extracellular vascular HCCs may be detected in the arterial phase.22
agents these agents are actively taken up by hepatocytes Although ultrasound, CT, and MR imaging are all
and subsequently secreted into the biliary system. Two useful in the diagnosis of HCC in cirrhotic patients, a
agents currently approved by the Food and Drug recent study has shown that significantly higher diag-
Administration are gadolinium-ethoxybenzyl-diethyl- nostic accuracy, sensitivity, and negative predictive
enetriamine pentaacetic acid (gadoxetate disodium value is achieved with dynamic plus hepatobiliary phase
[Gd-EOB-DTPA], gadoxetic acid [Eovist or Primovist]) MRI compared with ultrasonography, multidetector
and gadobenate dimeglumine (MultiHance).26–29 In cir- computed tomography, and dynamic phase MRI alone.
rhotic livers the peak parenchymal enhancement may The specificity and positive predictive value of ultraso-
be delayed and may not be achieved for 40 minutes or nography was significantly lower than that of multide-
more because of impaired transport mechanisms.30–32 tector computed tomography, dynamic phase MRI, and
There may also be delayed biliary excretion with dynamic plus hepatobiliary phase MRI.38 The MRI
delayed and reduced enhancement of the bile ducts. imaging was performed using the extracellular gadolinium-
Blood pool enhancements may be prolonged, but peak containing contrast agent (MultiHance).
enhancements of hepatic and portal veins is of shorter Several organizations have convened study groups to
duration and lower intensity. On Gd-EOB-DTPA develop a comprehensive reporting and data system for
administration the contrast behavior of HCCs in the CT and MRI of the liver in patients with cirrhosis and
dynamic phases (arterial, portovenous, and equilibrium other risk factors for HCC. These include the American
phases) is comparable to that with extracellular fluid Association for the Study of Liver Diseases, the United
Gd-based contrast agents with rapid arterial enhancement Network for Organ Sharing (UNOS), and the American
followed by rapid washout.32,33 In the hepatocyte phase, College of Radiology. In 2011 UNOS released its Organ
however, typical HCCs are seen as areas of low inten- Procurement and Transplantation Network (OPTN)
sity relative to surrounding liver parenchyma because transplant imaging criteria policy for liver transplant can-
they do not have the ability to take up Gd-EOB-DTPA didates with HCC.39 The criteria were designed to
460 PART IV Special Considerations in Patient Evaluation

improve specificity of the diagnosis of HCC in imaging A bone scan is indicated for patients being evaluated
and determining eligibility for HCC exception points. for liver transplantation because of a hepatic tumor.
Under the criteria, lesions must be classified according to Mammography is performed in women who are 45
the OPTN classification. OPTN class 5 lesions corre- years of age or older and have a family history of breast
spond to an imaging diagnosis of HCC. The imaging cancer.
diagnosis is based on lesion hyperenhancement on late
hepatic arterial images and depending upon lesion size,
other features, including washout on venous/delayed POSTTRANSPLANTATION EVALUATION
phase images, late capsule or pseudocapsule enhance-
ment, and lesion growth. The imaging criteria currently Multiple imaging modalities are available for evaluation
do not take into account hepatobiliary contrast agents or of the liver transplant patient. In the immediate postop-
imaging-based criteria for the diagnosis of vascular erative period, chest radiographs are obtained daily to
invasion.40 evaluate for atelectasis, pneumonia, diaphragmatic paralysis,
Cholangiography, although not a routine part of the and pleural effusions. Doppler ultrasonography is the
pretransplant evaluation, may be performed in cases of preliminary imaging modality for gross evaluation of the
sclerosing cholangitis, which is the third most common liver parenchyma, biliary tree, and vasculature. When
indication for liver transplantation. Magnetic resonance ultrasound findings are indeterminate or do not correlate
cholangiography is useful.41 The technique is noninva- with clinical findings, CT is usually performed. The major
sive and can provide useful images of the biliary tree. The indications for CT are detection of bile leak, hemorrhage,
technique does require patient cooperation. Limitations or abscess. CT and MRI are useful for assessment of
include image degradation by motion artifact and diffi- vasculature. For suspected biliary strictures, T-tube chol-
culty detecting and assessing severity of strictures. Its angiography and MR cholangiopancreatography are
sensitivity and specificity are yet to be determined. used.52 Conventional arteriography or cholangiography
Because occult cholangiocarcinoma is found in 10% is indicated for confirmation of noninvasive imaging
of the resected liver specimens of patients with primary findings or at time of treatment.
sclerosing cholangitis,42 biopsy of suspicious narrowed
areas should be considered before transplantation. Arte-
riography is performed when suspected vascular prob-
Ultrasonography
lems are detected on ultrasound studies or in difficult Ultrasonography has an important role in the postopera-
cases. In many cases MRA techniques can obviate the tive monitoring of the liver transplantation patient. It is
need for arteriography and venography, because the IVC routinely used to assess the status of the vascular anasto-
and hepatic veins are well seen with MRA. The portal moses. At most institutions Doppler ultrasonography is
vein is also well seen (see Fig. 35-2). Another angio- performed at the bedside in the intensive care unit within
graphic procedure useful in the management of patients the first 24 hours after transplantation to assess vascular
awaiting liver transplantation is the transjugular intrahe- anastomoses; it is repeated as clinically indicated. The
patic portosystemic shunt (TIPS) procedure, which ultrasound examination should include gray-scale ultra-
involves the creation of a tract between a hepatic vein sonography of liver homogeneity, bile duct caliber, and
and the portal vein with placement of a stent in the the presence of perihepatic and intra-abdominal fluid
tract.43–45 The procedure is performed with jugular vein collections. Perihepatic and intra-abdominal fluid is com-
access for catheterization of a hepatic vein. With fluoro- mon in the first postoperative days and gradually disap-
scopic guidance, a specially designed needle-catheter pears. Focal low-attenuation regions of liver parenchyma
system is used to create a channel from the hepatic vein may represent infarction and prompt more careful assess-
through the hepatic parenchyma to the portal vein. ment of the hepatic artery branches. The ultrasonography
When the tract has been created, it is dilated with a bal- study should include a pulsed and color Doppler evaluation
loon angioplasty catheter, and a metallic stent is placed of the hepatic artery as well as the portal vein and IVC.
in the tract to maintain patency. Various stents are used, Normal Doppler ultrasonography study results may indi-
including bare metal and polytetrafluoroethylene-cov- cate a nonvascular cause of graft dysfunction.
ered stents, which have been shown to have higher Each vessel has a characteristic Doppler signal that
patency rates.46–48 The procedure permits effective non- enables its identification.53 In adults the normal hepatic
operative decompression of the portal system. The TIPS artery is readily recognized on Doppler ultrasonography.
procedure has been used successfully to stabilize patients A complete examination should include demonstration of
during the period before transplantation.49 Liver trans- flow within the hepatic artery proximal and distal to the
plantation was not impeded in any of these cases. When anastomosis and in both the right and left hepatic arteries.
the stents are properly placed well within the liver, with The normal hepatic artery has a low-impedance wave-
minimal extension into the portal vein or IVC, liver form pattern with flow demonstrated through diastole
transplantation can be performed in the standard man- (Fig. 35-3). In some cases a high-impedance pattern with
ner. Experience indicates that TIPS is also useful for the low or absent flow or diastole has been noted early in the
treatment of intractable ascites.50 postoperative period, with later return to a more normal
Radionuclide imaging studies are rarely performed on appearance. This finding is not an indicator of prognosis,
donors. Occasionally, single-photon emission CT liver- nor does it correlate with allograft rejection.54–56 Abnormal
spleen scans using technetium Tc 99m sulfur colloid are Doppler flow patterns are seen with significant stenoses
performed to determine the volume of the native liver.51 (Figs. 35-4 and 35-5). The normal hepatic vein waveform
 35 Radiological Evaluation in Transplantation 461

pattern shows cyclical variations in flow velocity with res-

piration and reversal of flow with right-sided heart con-
traction (Fig. 35-6). Complications involving hepatic
veins are rare following transplantation.56 Although a
preliminary report suggested that abrupt loss of pulsatil-
ity in the hepatic veins may be an early indicator of graft
rejection, subsequent studies have not found the hepatic
vein waveforms to be useful in the diagnosis of rejection.56
Nonphasic hepatic vein waveforms can also be observed
in normal grafts and in cases of vena cava stenosis.
The IVC is seen best in a parasagittal plane, and find-
ings vary depending on the liver transplant operative
technique. In patients with the cava interposition anasto-
mosis, the infrahepatic portion is usually readily identifi-
able, but the suprahepatic anastomosis may be more
difficult to see. Close to the heart, a waveform pattern
similar to that of the hepatic veins is seen. With increas-
ing distance from the heart, a dampening of the flow pat-
tern occurs and a continuous wave pattern is seen (Fig.
35-7). A triphasic waveform can be seen in the piggyback
FIGURE 35-3 n Doppler ultrasonography study shows a normal
anastomosis, reflecting the transmission of pressure
hepatic artery, with its characteristic low-impedance waveform changes from the right heart.
pattern with flow demonstrated throughout diastole. On an ultrasonography study, the portal vein reveals
almost continuous flow, with variation secondary to ven-
tilatory motion (Fig. 35-8).
Radionuclide studies are performed in liver transplant
recipients, primarily in the posttransplant period. The

A-1 B-1

A-2 B-2
FIGURE 35-4 n Abnormal hepatic flow pattern in a patient with hepatic artery stenosis. A, Doppler ultrasonography velocity profile at
the site of the stenosis shows a high-velocity jet with spectral broadening, indicating turbulence. Aliasing is present, suggesting that the
velocities are higher than recorded. B, Doppler ultrasonography study of a vessel distal to the stenosis shows a dampened abnormal
waveform with a high diastolic flow.
462 PART IV Special Considerations in Patient Evaluation

A B

A-1
FIGURE 35-5 n Doppler ultrasonography study performed following balloon angioplasty of the stenotic hepatic artery. A, The hepatic
artery Doppler pattern in the proximal hepatic artery is normal. B, At the site of prior stenosis the flow pattern has a more normal
appearance. The loss in diastolic flow may be secondary to a high wall filter.

FIGURE 35-6 n Doppler ultrasonography study of a normal FIGURE 35-7 n Normal Doppler ultrasonography study of the
hepatic vein shows flow reversal, reflecting the change in pres- inferior vena cava shows a cyclical variation of the Doppler
sure in the right side of the heart during contraction. waveform pattern.
 35 Radiological Evaluation in Transplantation 463

radionuclides most frequently used are the technetium

Tc 99m iminodiacetic acid (IDA) compounds (hepa-
EVALUATION OF VASCULAR
toiminodiacetic acid [HIDA] and the derivative diiso- COMPLICATIONS AFTER
propyl iminodiacetic acid). These compounds are TRANSPLANTATION
transported from plasma to the hepatocyte by the same
transport mechanism as that for bilirubin.57 High levels Vascular complications after liver transplantation are not
of bilirubin can competitively inhibit technetium Tc 99m uncommon. They present a major threat to allograft and
IDA transport and decrease IDA uptake disproportion- patient survival. Vascular compromise may occur in the
ately to the loss of hepatocyte function. Radionuclide immediate transplant period at the hepatic artery, portal
evaluation is used to assess the functional status of the vein, or hepatic vein anastomoses.
graft and to identify structural complications such as
infarcts, abscesses, and bile leaks. In addition to serial
radionuclide images, time-activity curves are generated
Hepatic Artery Complications
for regions of interest such as over the graft and in the left Complications occurring at the site of arterial revascular-
ventricular blood pool. Measurements of the clearance of ization include stenosis, thrombosis, pseudoaneurysm,
IDA compounds from the blood pool graft and their and hepatic artery rupture. Hepatic artery thrombosis
excretion on the gastrointestinal tract permit qualitative can occur in the early or late posttransplant period. Ste-
and semiquantitative assessment of graft function. nosis of the hepatic artery most commonly occurs at the
anastomosis of the donor and recipient arteries (Fig.
35-9). It may also occur adjacent to the anastomosis from
a vascular clamp injury. The frequency of hepatic artery
stenosis is 11% to 13%.58–60 Stenosis of the hepatic artery
can cause graft ischemia, with resultant deterioration of
function and formation of biliary strictures. Progression
to thrombosis may result in liver infarction, abscess, or
biloma formation. The early clinical signs of vascular
occlusion are often nonspecific, and differentiation from
other causes of graft dysfunction, such as acute rejection,
infection, and prolonged cold or warm preservation isch-
emic injury, may be difficult.
On HIDA or hepatobiliary HIDA radionuclide studies,
regions of hepatic infarction are seen as photopenic areas
in the graft (Fig. 35-10). In the absence of a hepatic
infarction or total absence of graft perfusion, however,
these imaging studies may show only nonspecific findings
that appear as a decline in functional capacity of the liver
with decreased hepatocyte extraction of HIDA and pro-
longed retention of the agent in the blood pool.61 The
scintigraphic appearances of rejection and infections in
FIGURE 35-8 n Normal portal vein Doppler ultrasonography the graft (bacterial, viral, or fungal) are essentially identical,
study shows continuous hepatopetal flow. showing high retention of the HIDA compound in the

A B
FIGURE 35-9 n Hepatic artery stenosis. A, Selective celiac artery injection shows an apparent mild stenosis at the anastomosis of the
donor and recipient hepatic arteries (arrow). B, A digital subtraction arteriogram with oblique angulation of the image intensifier
shows the stenosis to be severe (arrow).
464 PART IV Special Considerations in Patient Evaluation

A B
FIGURE 35-10 n Hepatic infarction. A, Hepatoiminodiacetic acid (HIDA) scan shows a large photopenic region in the right lobe of the
liver that is consistent with a hepatic infarction (I) in this patient with severe hepatic artery stenosis. A smaller photopenic region is
identified in the left lobe of the liver (short arrow). This area could represent another area of infarction, an abscess, or a cyst. The
presence of a biliary drainage catheter is visible (long arrow). B, Computed tomographic scan of the same patient shows multiple
low-density lesions in the right lobe of the liver that are consistent with infarcts and correspond to the area of infarction seen on the
HIDA study. A small collection of gas is visible in the right lobe of the liver. It may represent air in a necrotic region or an abscess. In
the left lobe a documented hepatic abscess containing gas is identified. (A, Courtesy C. Loh, MD; B, Courtesy B. Kadell, MD, UCLA Medical
Center, Los Angeles.)

blood pool and poor graft uptake. Photopenic regions on and graft placement may also be used in treating hepatic
the HIDA studies may also be seen with abscesses.62 artery stenosis.67
Indium In 111 white blood cell and gallium citrate Ga 67 Hepatic artery thrombosis is a serious complication
studies are also useful screening procedures for identify- following liver transplantation. The incidence ranges
ing inflammatory processes in the graft. from 3% to 10% in adults and 8% to 19% in children.68,69
Hepatic artery obstruction is often detected on high- In living donor liver transplantation the incidence ranges
resolution CT scans or CT angiograms, and on MR from 0 to 10%.70 Early thrombosis of the hepatic artery
angiography. In suspected hepatic artery obstruction, following liver transplantation is more common in pedi-
arteriography should be performed to confirm the ultra- atric patients because of technical difficulties in the
sonographic or cross-sectional imaging findings. Arteri- reconstruction and maintenance of flow through the
ography should also be used when the clinical findings do small-caliber anastomoses.71
not correlate with the noninvasive imaging findings. In The ultrasonographic diagnosis of hepatic artery
pediatric patients it is particularly important to know the thrombosis is made when no arterial Doppler signal is
type of anastomosis that was performed to avoid unneces- obtained at the hilum and in the right and left intrahepatic
sary injections of contrast material and to reduce study branches. Thrombosis usually occurs at the anastomosis.
time. Once a stenosis is detected angiographically, the Because a variety of hepatic arterial anastomoses can be
treatment indicated depends on the clinical symptoms performed, knowledge of the type of anastomosis is impor-
and liver function. Stenoses occurring in the immediate tant for accurate interpretation of the studies (Fig. 35-12).
postoperative period are usually caused by technical Flint et al72 reported the correct diagnosis of hepatic artery
problems and generally require operative revision. Steno- thrombosis with Doppler ultrasonography in 34 of 37 cases
ses that occur after the anastomosis has healed may be (92%); the diagnoses were confirmed by angiography or
treated by percutaneous transluminal angioplasty (PTA). surgery. In three instances the results were false-positive,
A small-caliber, low-profile balloon is passed to the site of and hepatic arteries that appeared patent with Doppler
the stenosis. Several case reports63,64 describe successful ultrasonography proved on angiography to be occluded.
hepatic artery PTA with improvement in liver function Hall et al73 observed false-negative Doppler ultrasonogra-
following the procedure. At UCLA the experience is phy studies in 4 of 13 cases (31%). These occurred because
similar. The stenosis recurrence rate is low. Recurrent of mistaken identification of an arterial periportal collateral
stenosis was reported by Raby et al65 in hepatic artery as the hepatic artery (Fig. 35-13). False-positive results,
anastomoses at 4 and 6 months in two of three patients; although uncommon, have also been reported. They may
both stenoses responded to another balloon dilation. be a result of slow flow within a small but patent vessel,
This technique is a useful method of treating hepatic high-grade stenosis, or technical failure.74
artery stenosis (Fig. 35-11). There is limited experience Once hepatic artery thrombosis occurs, hepatic infarc-
with endovascular hepatic artery stent placement, but in tion and biliary ischemia are likely sequelae. It is not
selected cases they can be placed.66 Operative revision uncommon for the thrombosis to remain undetected by
 35 Radiological Evaluation in Transplantation 465

A B
FIGURE 35-11 n Percutaneous transluminal angioplasty of a stenotic hepatic artery. A, Arteriogram shows high-grade stenosis at the
hepatic artery anastomosis (arrow). B, Following balloon angioplasty, residual narrowing persists, but there is a marked improve-
ment in blood flow through the anastomosis.

A B
FIGURE 35-12 n Hepatic artery thrombosis. A, Flow was not identified in the hepatic artery on Doppler ultrasonography. Real-time
ultrasonographic assessment of the liver reveals a heterogenous appearance in the liver parenchyma with multiple discrete areas of
low echogenicity, findings consistent with hepatic ischemia or infarction (+). B, Celiac axis arteriogram demonstrates occlusion of the
hepatic artery proximally (arrow).

ultrasonography. Intrahepatic flow may be detectable diagnosis may allow emergency surgical thrombectomy
from the arterial collaterals in the porta hepatis. It is or hepatic artery reconstruction, or both, which might
important to avoid this diagnostic error because delay in prevent or postpone the need for retransplantation, or
diagnosis may result in loss of the allograft. The symp- serve as a bridge until a donor becomes available.75–77 For
toms of hepatic artery thrombosis are highly variable. acute thrombosis, transcatheter hepatic artery thrombol-
When detected early by postoperative ultrasonography, ysis has been employed. Recanalization has been accom-
symptoms may be minimal. When detected late, symp- plished with tissue plasminogen activator in several cases
toms usually relate to ischemic biliary injury and manifest (Fig. 35-14). Because thrombolysis with tissue plasmino-
as recurrent cholangitis, intrahepatic infarction and gen activator can entail a risk for bleeding, we recommend
abscess, bile duct stenosis, or bile leak. Presentation as that the patient remain in the angiography suite while the
fulminant hepatic necrosis is uncommon when ultraso- infusion is taking place so that extravasation can be
nography is used for postoperative monitoring. CT detected. Tissue plasminogen activator exerts its throm-
angiography (CTA) is often employed in suspected cases bolytic effect in 3 to 6 hours. The viability of the liver
of hepatic artery thrombosis because it allows rapid, following thrombolysis is dependent on many factors,
accurate determination of hepatic artery occlusion and and the reestablishment of blood flow does not guarantee
demonstration of areas of hepatic infarction. Early graft survival.
466 PART IV Special Considerations in Patient Evaluation

False aneurysms of the hepatic artery are uncommon, Intrahepatic aneurysms may be treated with transcath-
occurring in less than 2% of patients.60,76,78-80 Because eter embolization. If a catheter cannot be passed to the
they may rupture and produce fatal hemorrhage, early aneurysm because of allograft tortuosity, direct transhe-
diagnosis is necessary. False aneurysms usually occur at patic embolization can be performed. Extrahepatic aneu-
the extrahepatic arterial anastomosis. Intrahepatic false rysms may be treated with stent placement or surgical
aneurysms may occur following a percutaneous liver resection.
biopsy or transhepatic biliary drainage. Some false
aneurysms are asymptomatic and detectable only on
imaging; others may manifest as gastrointestinal bleed-
Portal Vein Complications
ing, hemobilia, or hemoperitoneum. On Doppler ultra- Extrahepatic portal vein complications are uncommon.
sonography they appear as spherical fluid collections Portal vein stenosis is rare, and portal vein thrombosis
showing internal flow.81 occurs in only 1% to 2.2% of liver transplant recipi-
ents.60,76,78,82 Portal vein stenosis usually occurs in the
porta hepatis at the anastomosis of the donor and recipi-
ent vessels (Fig. 35-15, A). The clinical manifestations of
portal vein thrombosis are variable and include graft
failure, ascites, varices, and gastrointestinal bleeding. Sig-
nificant stenosis can usually be detected by duplex and
color Doppler ultrasonography.83,84 In portal vein throm-
bosis, a real-time echo may demonstrate echogenic
thrombus, with Doppler ultrasonography confirming
either the absence or the presence of blood flow around a
nonoccluding thrombus. Portal vein stenosis is identified
on Doppler ultrasonography by the presence of normal
proximal flow, a high-velocity jet at the anastomosis, and
distal turbulence.
Air in the portal vein has occasionally been detected
FIGURE 35-13 n Severe hepatic artery stenosis. Celiac angiogram on Doppler ultrasonography as highly echogenic, non-
shows a severe stenosis of the hepatic artery with numerous shadowing particles moving within the portal vein.
collaterals in the porta hepatis. The left hepatic artery is large.
Confusion of these collaterals with the main hepatic artery may Although air was reported in one case in association
lead to erroneous interpretation of the ultrasound study and with a gangrenous colon,85 it may be a transient finding
result in the false-positive interpretation that the hepatic artery without other serious complication in the first 2 weeks
is patent. after transplantation.86

A B
FIGURE 35-14 n Hepatic artery thrombolysis. A, Flush aortogram shows the stump of an occluded donor iliac artery graft from the
infrarenal aorta to the liver transplant (arrow). B, Following 4.5 hours of thrombolytic infusion with recombinant tissue plasminogen
activator, blood flow in the hepatic artery is restored. A mild irregularity consistent with residual thrombus is seen in the hepatic artery.
The patient could not be treated with heparin because of heparin allergy; reocclusion occurred, necessitating retransplantation.
 35 Radiological Evaluation in Transplantation 467

Both CTA and three-dimensional time-of-flight gado- sedation in the pediatric patient. Both CTA and MRA
linium-enhanced MRA provide excellent depiction of allow three-dimensional reconstructions of the images,
filling defects and focal stenosis of the portal vein. Because but imaging of venous structures is often better achieved
MRA does not involve the use of ionizing radiation, it is with MRA. Contrast-enhanced MRA provides high-
frequently used when evaluating children. However, quality images of the hepatic artery, hepatic veins, portal
because it is a longer examination than CTA, it requires venous system, and varices37,87 (Fig. 35-15, B and C).

B C
FIGURE 35-15 n A, Venous phase of superior mesenteric artery arteriogram shows a normal portal vein anastomosis with mild defor-
mity at the anastomotic site (arrow). B, Arterial phase of three-dimensional time-of-flight gadolinium-enhanced magnetic resonance
angiography (MRA) in a patient after liver transplantation. The celiac axis is seen and the hepatic artery anastomosis (arrow) is patent.
C, Portal phase of three-dimensional time-of-flight gadolinium-enhanced MRA shows a patent portal vein anastomosis (arrow). The
hepatic veins are well seen and the inferior vena cava is patent.
468 PART IV Special Considerations in Patient Evaluation

In symptomatic patients, balloon angioplasty is the 10 cases of stenosis and two cases of thrombosis. The
treatment of choice for portal vein stenosis. The portal most common site of IVC stenosis of the donor and
vein is entered via a transhepatic puncture; after entry to recipient is at the suprahepatic or infrahepatic anastomo-
the portal system is achieved, pressures are measured sis of the donor and recipient. The “piggyback anastomo-
across the stenosis and balloon angioplasty is performed. sis” (with preservation of the recipient vena cava and
A stent may also be placed if angioplasty is insufficient. cavocaval anastomosis) may result in venous obstruction.
Raby et al65 treated three patients with portal hyperten- Technical factors such as size discrepancy between donor
sion and variceal hemorrhage caused by anastomotic and recipient vessels or suprahepatic caval kinking from
stenosis of the portal vein with PTA. Success was obtained rotation may cause acute IVC stenosis. Delayed caval ste-
in two patients, both of whom were asymptomatic at 1 nosis may be due to fibrosis, a chronic thrombus, or neo-
year follow-up. We routinely perform portal vein angio- intimal hyperplasia. Chronic caval stenoses are more
plasty in patients, usually children who develop portal common after retransplantation and in children.87 Rarely,
vein stenosis after transplant. Complete portal vein stenoses may occur secondary to extrinsic compression by
thrombosis has generally required retransplantation if a hematoma. Infrahepatic IVC stenoses typically produce
associated hepatic failure develops (Fig. 35-16). Olcott lower extremity edema, and suprahepatic caval stenoses
et al88 described their experience with balloon angio- generally produce obstruction of the hepatic veins, with
plasty in four patients with portal vein occlusion. Three symptoms similar to those of the Budd-Chiari syndrome.
of the four treated patients died of multiple problems Although most significant caval stenoses can be detected
unrelated to the angioplasty. The researchers also on duplex ultrasonography, and MRA may be helpful,
described the placement of a metal stent in a patient contrast venacavography is the most reliable technique
with portal vein occlusion. This patient died of a brain for diagnosis (Fig. 35-17). Pressure measurements should
abscess 1 month later, and the stent was patent at autopsy. be obtained in the inferior vena cava and across the
Zajko et al59 reported the placement of a Palmaz stent hepatic veins. PTA of suprahepatic and infrahepatic IVC
following unsuccessful PTA. However, thrombus devel- stenosis and of hepatic vein stenosis is now routinely
oped above the stent and failed to lyse with thrombolytic performed.65,89,90 Recurrence of stenosis has been
therapy. Portal vein thrombosis developed, necessitating reported; however, as with venous stenoses in other parts
retransplantation. of the body, another dilation can result in long-term
patency.65 Metallic stents can be placed if repeat PTA
Inferior Vena Cava and Hepatic Vein fails to produce durable results.
Complications
IVC complications are rare. Raby et al,65 in a series of
more than 600 liver transplantations, found only four
cases of IVC anastomotic stenosis. In a large series of
more than 2200 transplantations, Zajko et al59 observed

FIGURE 35-16 n Portal vein occlusion as seen on a digital sub-

traction superior mesenteric angiogram in a liver transplant
recipient. The portal vein is occluded, and there is filling of a
dilated coronary vein and varices (short arrow). Cavernous FIGURE 35-17 n Inferior venacavogram in a liver transplant recipi-
transformation of the portal vein is present, and there is faint ent with right pleural effusion. The infrahepatic portion of the
filling of abnormal intrahepatic portal branches (long arrow). inferior vena cava is attenuated; however, contrast material
A, Superior mesenteric artery incompletely subtracted; V, superior drained freely into the right atrium, no gradient was detected,
mesenteric vein. and the ultrasonography study was normal.
 35 Radiological Evaluation in Transplantation 469

EVALUATION OF THE BILIARY SYSTEM guidewire, and a temporary drain is placed in the tract to
avoid leakage of bile into the peritoneum. Because liver
Ultrasonography and T-tube cholangiography are the transplant patients are given immunosuppressive therapy,
imaging techniques used most frequently to evaluate the there is poor granulation of the T-tube tract. Simple
biliary system in the first few months following trans- removal of the T tube using standard techniques can
plantation. After removal of the T tube the methods result in bile leakage. At our institution, patients devel-
used include MR cholangiopancreatography, endo- oped bilomas and serious bile peritonitis following simple
scopic retrograde pancreatography, and percutaneous removal of the T tube. Therefore a small-caliber, multiple-
cholangiography.87 sidehole, straight catheter is positioned in the T-tube
The appearance of the common duct is variable after a tract. This straight catheter is withdrawn progressively
liver transplant choledochocholedochostomy. Size dis- over the course of 24 to 48 hours. Because the T tubes are
crepancies between the donor and recipient ducts may be anchored when placed initially, there are instances in
seen (Fig. 35-18). In uncomplicated cases the size of the which the tube cannot be removed percutaneously. In
ducts tends to remain stable over time; however, a mild these cases the T tube is removed endoscopically and a
increase in the size of the ducts may occur without clinical plastic endoscopic stent placed. If the T-tube fractures as
evidence of obstruction. Diffuse biliary tree changes are it is removed and a portion is retained subcutaneously,
often seen in the absence of obstruction or leakage. Atten- operation may be required for removal of the T-tube
uation, narrowing, and separation of the intrahepatic fragment.
ducts may be seen. These are nonspecific findings that are
seen with rejection, hepatitis, preservation injury, and Biliary Tract Complications
infarction.91
Although evaluation of the biliary tract is not done Biliary tract complications occur in 10% to 13% of liver
routinely in the liver transplant patient unless a problem transplant recipients.92–94 The biliary complications that
is suspected, the performance of T-tube cholangiography can occur include stricture formation, bile leakage with
at some time before the removal of the T tube is standard or without biloma formation, intraductal stone or debris
care. formation, diffuse biliary dilatation, and dysfunction of
T tubes placed in the recipient bile duct at the time of the sphincter of Oddi. After rejection, biliary complica-
liver transplantation are removed 2 to 4 months after sur- tions are the most common cause of hepatic dysfunction.
gery. Antibiotics are administered before the cholangiog- In many instances the clinical symptoms associated with
raphy is performed. If the cholangiographic findings biliary complications may be indistinguishable from those
reveal no abnormality, the T tube is removed over a associated with a variety of problems, such as rejection,
hepatic artery occlusion, primary graft dysfunction, and
viral infection. Biliary complications may be the result of
primary biliary tract problems or a variety of other post-
transplant problems that affect the integrity and function
of the biliary tree. The biliary system of the liver trans-
plant is susceptible to ischemic injury. The main source
of the blood supply to the normal human common bile
duct is from branches of the gastroduodenal artery or a
retroportal artery. These branches are divided in the
transplant procedure. Because the main source of the
blood supply is from below, the donor bile duct is more
susceptible to ischemic injury than is the recipient duct.
Bile duct ischemia can result in nonanastomotic bile
leaks, intrahepatic strictures, and bilomas. Biliary compli-
cations usually occur within the first 3 months after
transplantation, but they can also occur later. Most bile
leaks occur within the first month, and most stenoses
develop later.56
Biliary complications in the liver allograft manifest
primarily as biliary obstruction and bile leakage. Reduced
bile output from the T tube or a significant change in bile
color may indicate mechanical obstruction of the duct,
dislodgment of the T tube, or liver dysfunction. Obstruc-
tion of the T tube often resolves with simple flushing.

Evaluation and Management of Bile Leaks

Most bile leaks occur in the early postoperative period,
FIGURE 35-18 n Normal T-tube cholangiogram in a liver trans-
with the most frequent site of leaking being the T-tube
plant recipient. Note the size discrepancy between the donor choledochotomy. Leaks may also occur at the site of the
and recipient ducts. biliary anastomosis and at nonanastomotic sites. Small
470 PART IV Special Considerations in Patient Evaluation

A B
FIGURE 35-19 n Anteroposterior (A) and right anterior oblique
(B) views of a delayed (24 hours) hepatoiminodiacetic acid
(HIDA) scan show a subdiaphragmatic collection of radioiso-
tope projected over the dome of the liver, representing a bile
leak. (Courtesy C. Loh, MD, UCLA Medical Center, Los Angeles.)

leaks detected on a T-tube cholangiogram usually resolve

spontaneously and can be managed conservatively by
leaving the T tube in place for a longer period. Large
leaks may appear as leakage from the surgical drain or
wound or may cause abdominal pain, distention, fever,
and sepsis. Large leaks require reoperation.
Suspected bile leakage can be confirmed with an IDA
scan. The demonstration of radiolabeled material95 out-
side the bile ducts or in the gastrointestinal system on
FIGURE 35-20 n Biloma. Endoscopic retrograde cholangiopancre-
early or delayed scans is pathognomonic for bile leakage atography shows filling of the common bile duct (C) and right
(Fig. 35-19). Bile leaks and collections can also be diag- biliary ducts. The left biliary ducts are obscured by communica-
nosed with ultrasonography and CT scans, on which tion with and opacification of a large biloma. Two drainage cath-
they appear as hypoechoic or low-attenuation areas. eters are in place, and contrast material is seen draining into the
However, with CT and ultrasonography studies, bile superiorly positioned catheter.
collections cannot always be distinguished from other
types of collections, such as blood, ascites, pus, or
lymph. Fine-needle aspiration biopsy enables determi- intrahepatic ducts is seen with delayed or absent transit to
nation of fluid composition. Cholangiography is the the gastrointestinal tract. Ultrasonography1,91 and CT
most frequently used method of diagnosis and provides may be helpful for diagnosis (Figs. 35-22 to 35-24). Ultra-
specific information (Fig. 35-20). Although small anas- sonography, however, is less reliable, particularly in the
tomotic leaks can be managed conservatively, large leaks detection of mild obstruction.97 The presence of appar-
at the anastomosis are associated with high morbidity ently normal ducts on ultrasonography studies does not
and mortality and require immediate operation. Leaks exclude the possibility of significant biliary obstruction.
resulting from dislodgment of the T tube require imme- There is a variable relationship between biliary obstruc-
diate exploration (Fig. 35-21) or endoscopic retrograde tion and dilatation. Biliary distention after obstruction
cholangiopancreatography with nasobiliary stent place- does not occur simultaneously throughout all branches of
ment. Leakage of contrast material from the donor bili- the biliary system. The degree of dilatation depends not
ary tree at nonanastomotic sites is a serious event, only on the degree and duration of the obstruction but
possibly indicative of bile duct necrosis secondary to also on the pliability of both the extrahepatic bile ducts
hepatic artery occlusion. Such leaks usually occur in the and the parenchymal supporting skeleton of the intrahe-
hilar and parahilar areas; intrahepatic or extrahepatic patic ducts. Because prolonged biliary obstruction leads
locations are less common. Bilomas occurring with to inflammatory changes and fibrosis of the biliary tract,
hepatic artery occlusion are often associated with a poor even long-term obstruction may occur without significant
outcome and require retransplantation.96 proximal dilatation. Patients with cirrhosis, for example,
may have high-grade obstruction with little or no intrahe-
Radiographic Diagnosis and Management patic dilatation.98,99 As in other patients, liver enzyme
of Biliary Obstruction level elevation, particularly alkaline phosphatase level
elevation, is a more sensitive indicator of biliary obstruc-
The symptoms of biliary obstruction may initially be tion. Magnetic resonance cholangiography is also useful
indistinguishable from a variety of other problems, to assess biliary duct obstruction100 but tends to overesti-
including rejection, hepatic artery occlusion, primary mate stricture severity.101 Cholangiography, either via the
graft dysfunction, and viral infections. Biliary obstruction T tube or a percutaneous transhepatic approach, is often
may be detected on IDA radionuclide studies if liver func- necessary for accurate assessment. On T-tube cholangio-
tion is maintained and uptake of the agent in the grams, areas of mild narrowing at the anastomosis site are
 35 Radiological Evaluation in Transplantation 471

A B
FIGURE 35-21 n Dislodged T tube. A, T-tube cholangiogram shows filling of the common bile duct (C) and free leakage of contrast
material from the T tube into the peritoneal space (arrows). B, Passage of a guidewire into the T tube shows that the wire passes freely
into the peritoneum, confirming dislodgment of the T tube.

FIGURE 35-22 n Biliary dilatation. Ultrasonography study shows

dilated bile ducts.
FIGURE 35-23 n Computed tomographic scan shows dilated bile
ducts in a child with hepatic artery stenosis. This is the same
a frequent occurrence, and removal of the T tube does patient as shown in Figures 35-13 and 35-28.
not usually result in symptoms of obstruction.
Biliary obstruction in the transplant patient can be
caused by problems such as stricture, biliary sludge,102 multiple and involve the confluence of the right and left
stones, a retained stent, T-tube dysfunction, and, rarely, ducts, the common duct, and the intrahepatic ducts
an allograft cystic duct remnant mucocele and common (Fig. 35-26). They are usually the result of ischemic duct
duct redundancy. injury from hepatic artery obstruction, and the status of
Posttransplant biliary strictures are the most common the hepatic artery should be assessed in these patients.
cause of biliary obstruction and can be classified as anas- In some instances, the indwelling straight stents used in
tomotic and nonanastomotic. Those strictures occurring patients undergoing a Roux-en-Y choledochojejunostomy
at the biliary anastomosis are attributed to scar formation may cause obstruction. These stents usually pass out of
with retraction and narrowing (Fig. 35-25). Untreated, the anastomosis several weeks after transplantation, but
these may lead to ascending cholangitis with intrahepatic in some instances they become encrusted and cause
multifocal stricture formation.41 obstruction. Biliary obstruction also occurs as a result of
Nonanastomotic strictures almost always occur in the the presence of masses of inspissated bile or “biliary
donor biliary tree. They may be single but are usually sludge.” This sludge can be seen radiographically on
472 PART IV Special Considerations in Patient Evaluation

T-tube or transhepatic cholangiograms as amorphous such as that caused by cyclosporine-induced crystal

collections of radiopaque material in both the intrahepatic deposition.41
and extrahepatic portions of the donor ducts (Fig. Rarely, recurrent strictures may occur in patients
35-27). Histological examination of the material with cholangiocarcinoma. Dilatation of the donor duct
reveals a composition of sheets of necrotic collagen
impregnated with bile pigments.102 The high necrotic
content of the biliary sludge suggests that the primary
mechanism, at least in some patients, may be necrosis
of the donor bile duct wall and mucosa. This necrosis
may be the result of ischemic damage during preserva-
tion of the donor liver, ischemia from hepatic artery
obstruction following transplantation, superimposed
infection, rejection, or a combination of factors. It has
also been attributed to alterations in bile composition

FIGURE 35-26 n Nonanastomotic biliary stricture. Typically, non-

anastomotic biliary strictures involve both the right and left
hepatic ducts and a Roux-en-Y choledochojejunostomy. A tran-
shepatic biliary drainage catheter was placed. This patient had
severe hepatic artery stenosis.

FIGURE 35-24 n Computed tomographic scan with good contrast

enhancement shows portal vein filled with contrast material
(arrow). Immediately adjacent is a low-signal area representing
dilated bile ducts.

FIGURE 35-27 n Biliary sludge. Cholangiogram performed after

placement of a transhepatic drainage catheter shows multiple
FIGURE 35-25 n T-tube cholangiogram shows an anastomotic filling defects (arrows) in the common bile duct and outlining of
stricture in the common bile duct. The stricture was treated the left hepatic duct, which are consistent with the presence of
successfully with balloon angioplasty. biliary sludge. A mild stricture is seen in a right biliary duct.
 35 Radiological Evaluation in Transplantation 473

may occur. Progressive dilatation of both the donor When transhepatic cholangiography is used to decom-
and recipient common ducts has been observed in press the obstructed biliary system, it is important to be
patients who have undergone choledochocholedochos- aware that in cases of complete obstruction it may not be
tomy biliary reconstruction.103 The cause is uncertain, possible to cross the obstruction initially. Standard treat-
but stenosis and dysfunction of the sphincter of Oddi as ment is initial decompression and placement of a tempo-
a result of common bile duct neural denervation have rary drainage catheter. After 48 to 72 hours, when the
been suggested as causative. By surgically changing the edema has subsided, it is usually possible to traverse the
choledochocholedochostomy to a choledochojejunos- stricture.
tomy, and thereby bypassing the sphincter of Oddi, Biliary strictures are best treated with balloon dilation
clinical and laboratory improvement usually can be of the stricture (Fig. 35-28). Stricture dilation is accom-
achieved. plished through transhepatic percutaneous puncture. The

A B

C
FIGURE 35-28 n Biliary stricture dilatation. A, Transhepatic cholangiogram in a 6-year-old liver transplant recipient shows biliary
dilatation, with biliary strictures in the right and left biliary ducts and at the choledochojejunostomy. B, An inflated balloon
angioplasty catheter is seen in the right ducts. C, Cholangiogram after angioplasty shows residual stricture in the left duct,
improved caliber in the right ducts, and relief of the stricture at the choledochojejunostomy. A transhepatic biliary drainage
catheter is in place.
474 PART IV Special Considerations in Patient Evaluation

balloon catheter is passed over a guidewire to the area of ischemic bile duct injury when hepatic artery occlusion
obstruction, and dilation is performed. Following dila- occurs. Pediatric complications are managed with the
tion, an external biliary drainage catheter is left in place interventional techniques used in adults. The proce-
for approximately 2 weeks, and then cholangiography is dures are usually performed under general anesthesia.
performed again. If the appearance is satisfactory, the These interventional techniques play a major role in the
tube is removed. If not, additional dilation is performed. maintenance of the allograft and avoidance of additional
Most patients require one to three dilations. It is the prac- surgery.
tice at our institution not to leave these tubes in place for Although the interventional biliary procedures are
long-term stenting because of the risk for infection. important aids to the maintenance of the allograft, com-
In a recent series of 48 patients Giampalma et al104 plications may occur as a result of the intervention. Biliary
reported overall 1- and 3-year primary patency rates of interventions should be performed under broad-spectrum
94% and 45% for nonischemic versus ischemic stric- antibiotic coverage.
tures, (P = .032). The overall secondary patency rates A serious complication in these immunosuppressed
were 94% and 83% at 1 and 3 years with no significant patients is the development of a biliary vascular commu-
difference between the ischemic and nonischemic or nication secondary to placement of a transhepatic biliary
between the anastomotic versus and nonanastomotic drainage catheter. The hemobilia associated with tube
strictures. Balloon dilation (bilioplasty) is an effective placement is poorly tolerated by these patients, so persis-
method of management for these strictures.94 Both tent hemobilia through the drainage tube requires
intrahepatic and extrahepatic strictures can be dilated; prompt correction. Cholangiography should be per-
however, the results with multiple strictures may be less formed to determine the site of vascular communication,
satisfactory, especially if the stricture has occurred as a which may be venous or arterial. If a communication
result of ischemia caused by hepatic artery occlusion.105 with the vascular system is identified by cholangiogra-
Balloon dilation through the T-tube tract is not rec- phy, a new transhepatic puncture should be performed at
ommended because of the potential for bile leakage a different entry site, and drainage should be established.
through the T-tube insertion site. At the same sitting, the offending tube should be
Patients with obstruction caused by the presence of exchanged for a straight catheter. Embolization should
biliary sludge can be managed in several ways. In patients be performed on both sides of the bleeding vessel to iso-
with an indwelling T tube, a guidewire may be passed late the biliary system and the vessel. Absorbable gelatin
through the T tube and the tip passed up into the biliary sponge (Gelfoam) or metallic coils may be used. Emboli-
tree, where it can be rotated in the occluded ducts to zation of the parenchymal tract should be performed
disrupt the material. This method, coupled with gentle with absorbable gelatin sponge while the straight cathe-
irrigation, is effective in producing passage of the mate- ter is withdrawn. If the bleeding site is not identified on
rial down into the distal duct from which it is cleared. In cholangiography, hepatic arteriography should be per-
some instances, however, it is necessary to use a percuta- formed. Hemobilia arising from false aneurysms of the
neous transhepatic approach to relieve the obstruction. A hepatic artery and occurring after transhepatic tube
balloon occlusion catheter may then be used to clear the placement has been treated with removal of the tube fol-
occluded ducts gently. Short-term internal-external biliary lowed by arteriography and transcatheter embolization.
catheter stenting is then performed. When the bleeding site cannot be identified on arteriog-
To date there are only a few reports of the use of raphy, some physicians recommend that the offending
indwelling metallic stents in the management of biliary tube be removed and another arteriogram be performed
strictures in liver transplant recipients. In a recent series, when and if bleeding recurs and the site of arterial injury
because of problems with stricture recurrence in 14% to is determined.108 The author and colleagues have found
25% of patients and stent migration observed in 33% to that embolization of the bleeding site via the tube tract at
45%, metallic stent placement is not recommended as the the time of removal of the tube avoids the risk for
primary treatment modality of biliary strictures in liver rebleeding and is an effective method in the treatment of
transplant patients. In patients who fail to respond to bil- most biliary vascular communications.
ioplasty, temporary metallic stents may be placed, but The transjugular approach is used when liver biopsy
recurrence and stent migration are a problem.106 Current is needed in transplant patients who are poor candidates
evidence also does not demonstrate a clear advantage of for percutaneous biopsy because of diffuse liver disease,
covered self-expandable metallic stents over stents placed ascites, or coagulopathy. This technique, performed via
by endoscopic retrograde cholangiopancreatography, jugular vein access, minimizes the risk for bleeding.109
and covered self-expandable metallic stents have a signifi-
cant migration rate.107 It is important to note that the
bare metal stents may become incorporated in the wall of SUMMARY
the duct, rendering later surgical removal difficult.
Biliary complications occur in both pediatric and Diagnostic and interventional radiological techniques
adult liver transplant recipients. Although children, in play an important role in the management of biliary
contradistinction to adults, manifest early collateral complications in the liver transplant recipient. These
arterial growth into the allograft liver, which may main- techniques are often important in the maintenance and
tain viability of the liver, they remain susceptible to survival of the allograft.
 35 Radiological Evaluation in Transplantation 475

14. Lim JH, Kim CK, Lee WJ, et al. Detection of hepatocellular
Pearls and Pitfalls carcinomas and dysplastic nodules in cirrhotic livers: accuracy of
helical CT in transplant patients. AJR Am J Roentgenol.
• Both triple-phase computed tomography and mag- 2000;175:693-698.
netic resonance imaging (MRI) are used to diagnose 15. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for
hepatocellular carcinoma (HCC). Careful selection of the treatment of small hepatocellular carcinomas in patients with
MRI pulse sequences and contrast agent can provide cirrhosis. N Engl J Med. 1996;334:693-699.
important information regarding the presence of other 16. Llovet JM, Bruix J, Fuster J, et al. Liver transplantation for small
liver pathological conditions such as regenerative and hepatocellular carcinoma: the tumor-node-metastasis classification
does not have prognostic power. Hepatology. 1998;27:1572-1577.
dysplastic nodules.
17. Choi BI, Han JK, Kim TK, et al. Dysplastic nodules of the liver:
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the post–liver transplant patient to assess the status of 18. Krinsky GA, Lee VS. MR imaging of cirrhotic nodules. Abdom
the vascular anastomoses. Imaging. 2000;25:471-482.
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variable, and false-negative results can be obtained on hepatocellular carcinoma: evaluation of CT and MR appearance
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ing in liver transplantation: what radiologists should know. Radio- 1484-1486.
graphics. 2010;30:339-351. doi:10.1148/rg.302095124 PubMed 77. Klintmalm GB, Olson LM, Nery JR, et al. Treatment of hepatic
PMID: 20228321. artery thrombosis after liver transplantation with immediate vas-
53. Taylor KJW, Burns PN, Woodcock JP, Wells PNT. Blood flow cular reconstruction: a report of three cases. Transplant Proc.
in deep abdominal and pelvic vessels: ultrasonic pulsed Doppler 1988;20(suppl 1):610-612.
analysis. Radiology. 1985;154:487-493. 78. Lerut JP, Gordon RD, Iwatsuld S, Starzl TE. Human orthotopic
54. Longley DG, Skolnick ML, Sheahan DG. Acute allograft rejec- liver transplantation: surgical aspects in 393 consecutive grafts.
tion in liver transplant recipients: lack of correlation with loss of Transplant Proc. 1988;20:603-606.
hepatic artery diastolic flow. Radiology. 1988;169:417-420. 79. Hesselink EJ, Slooff MJH, Schurr KH, et al. Consequences of
55. Marder DM, DeMarino GB, Sumkin JH, Sheahan DG. Liver hepatic artery pathology after orthotopic liver transplantation.
transplant rejection: value of the resistive index in Doppler US of Transplant Proc. 1987;19:2476-2477.
hepatic arteries. Radiology. 1989;173:127-129. 80. Merion RM, Burtch GD, Ham JM, et al. The hepatic artery in
56. Garcia-Criado A, Gilabert R, Bargallo X, Bru C. Radiology in liver transplantation. Transplantation. 1989;48:438-443.
liver transplantation. Semin Ultrasound CT MR. 2002;23:114-129. 81. Tobben PJ, Zajko AB, Sumkin JH, et al. Pseudoaneurysms com-
57. Chervu LR, Nunn AD, Loberg MD. Radiopharmaceuticals for plicating organ transplantation: roles of CT, duplex sonography,
hepatobiliary imaging. Semin Nucl Med. 1982;12:5-17. and angiography. Radiology. 1988;169:65-70.
58. Wozney P, Zajko AB, Bron KM, et al. Vascular complications 82. Lerut J, Tzakis AG, Bron K, et al. Complications of venous
after liver transplantation: a 5-year experience. AJR Am J Roentgenol. reconstruction in human orthotopic liver transplantation. Ann
1986;147:657-663. Surg. 1987;205:404-414.
 35 Radiological Evaluation in Transplantation 477

83. Dalen K, Day DL, Ascher NL, et al. Imaging of vascular compli- 97. Zemel G, Zajko AB, Skolnick ML, et al. The role of sonography and
cations after hepatic transplantation. AJR Am J Roentgenol. transhepatic cholangiography in the diagnosis of biliary complica-
1988;150:1285-1290. tions after liver transplantation. AJR Am J Roentgenol. 1988;151:
84. Longley DG, Skolnick ML, Zajko AB, Bron KM. Duplex Dop- 943-946. doi:10.2214/ajr.151.5.943 PubMed PMID: 3051961.
pler sonography in the evaluation of adult patients before and 98. Zeman RK, Taylor KJ, Rosenfield AT, et al. Acute experimental
after liver transplantation. AJR Am J Roentgenol. 1988;151: biliary obstruction in the dog: sonographic findings and clinical
687-696. implications. AJR Am J Roentgenol. 1981;136:965-967.
85. Taylor KJ, Morse SS, Weltin GG, et al. Liver transplant recipi- 99. Shawker TH, Jones BL, Girton ME. Distal common bile duct
ents: portable duplex US with correlative angiography. Radiology. obstruction: an experimental study in monkeys. J Clin Ultrasound.
1986;159:357-363. 1981;9:77-82.
86. Chezmar JL, Nelson RC, Bernardino ME. Portal venous gas 100. Fulcher AS, Turner MA. Orthotopic liver transplantation: evalu-
after hepatic transplantation: sonographic detection and clinical ation with MR cholangiography. Radiology. 1999;211:715-722
significance. AJR Am J Roentgenol. 1989;153:1203-1205. PubMed PMID: 10352596.
87. Caiado AH, Blasbalg R, Marcelino AS, et al. Complications of 101. Ward J, Sheridan MB, Guthrie JA, et al. Bile duct strictures after
liver transplantation: multimodality imaging approach. Radio- hepatobiliary surgery: assessment with MR cholangiography.
graphics. 2007;27:1401-1417. doi:10.1148/rg.275065129 PubMed Radiology. 2004;231:101-108. doi:10.1148/radiol.2311030017
PMID: 17848699. PubMed PMID: 14990819.
88. Olcott EW, Ring EJ, Roberts JP, et al. Percutaneous transhepatic 102. McMaster P, Herbertson B, Cusick C, et al. Biliary sludging fol-
portal vein angioplasty and stent placement after liver transplan- lowing liver transplantation in man. Transplantation. 1978;25:
tation: early experience. J Vasc Interv Radiol. 1990;1:17-22. 56-62.
89. Zajko AB, Claus D, Clapuyt P, et al. Obstruction to hepatic 103. Miller WJ, Campbell WL, Zajko AB, et al. Obstructive dilatation
venous drainage after liver transplantation: treatment with bal- of extrahepatic recipient and donor bile ducts complicating ortho-
loon angioplasty. Radiology. 1989;170:763-765. topic liver transplantation: imaging and laboratory findings. AJR
90. Rose BS, Van Aman ME, Simon DC, et al. Transluminal balloon Am J Roentgenol. 1991;157:29-32.
angioplasty of infrahepatic caval anastomotic stenosis following 104. Giampalma E, Renzulli M, Mosconi C, et al. Outcome of post–
liver transplantation: case report. Cardiovasc Intervent Radiol. liver transplant ischemic and nonischemic biliary stenoses treated
1988;11:79-81. with percutaneous interventions: the bologna experience. Liver
91. Letourneau JG, Hunter DW, Payne WD, Day DL. Imaging of an Transplantation. 2012;18:177-187. doi:10.1002/lt.22450.
intervention for biliary complications after hepatic transplanta- 105. Ward EM, Kiely MJ, Maus TP, et al. Hilar biliary strictures after
tion. AJR Am J Roentgenol. 1990;154:729-733. liver transplantation: cholangiography and percutaneous treat-
92. Zajko AB, Campbell WL, Bron KM, et al. Diagnostic and inter- ment. Radiology. 1990;177:259-263.
ventional radiology in liver transplantation. Gastroenterol Clin 106. Tarantino I, Traina M, Mocciaro F, et al. Fully covered metallic
North Am. 1988;17:105-143. stents in biliary stenosis after orthotopic liver transplantation.
93. Gomes AS. Diagnosis and radiologic treatment of binary compli- Endoscopy. 2012;44:246-250. doi:10.1055/s-0031-1291465 PubMed
cations of liver transplantation. Semin Interv Radiol. 1992;9: PMID: 22354824.
283-289. 107. Kao D, Zepeda-Gomez S, Tandon P, et al. Managing the post–
94. Sherman S, Jamidar P, Shaked A, et al. Biliary tract complications liver transplantation anastomotic biliary stricture: multiple plastic
after orthotopic liver transplantation. Endoscopic approach to versus metal stents: a systematic review. Gastrointest Endosc. 2013;
diagnosis and treatment. Transplantation. 1995;60:467-470. 77:679-691.
95. Klingensmith III WC, Koep LJ, Fritzberg AR. Bile leak into a 108. Zajko AB, Chablani V, Bron KM, Jungreis C. Hemobilia compli-
hepatic abscess in a liver transplant: demonstration with 99m cating transhepatic catheter drainage in liver transplant recipients:
Tc-diethyl-iminodiacetic acid. AJR Am J Roentgenol. 1978;131: management with selective embolization. Cardiovasc Intervent
889-891. Radiol. 1990;13:285-288.
96. Kaplan SB, Zajko AB, Koneru B. Hepatic bilomas due to hepatic 109. Gamble P, Colapinto RF, Stronell RD, et al. Transjugular liver
artery thrombosis in liver transplant recipients: percutaneous biopsy: a review of 461 biopsies. Radiology. 1985;157:589-593.
drainage and clinical outcome. Radiology. 1990;174:1031-1035.
 CHAPTER 36

Monitoring and Care

Elizabeth J. Carey • Jorge Rakela • Hugo E. Vargas

CHAPTER OUTLINE

GENERAL MEDICAL CARE Ascites

Routine Examination, Prophylaxis, and Spontaneous Bacterial Peritonitis
Immunization Hepatorenal Syndrome
TREATMENT OF UNDERLYING LIVER DISEASES Hepatic Encephalopathy
Hepatitis B Virus Nutritional Management
Hepatitis C Virus Ammonia-Lowering Strategy
Hemochromatosis Use of Central Nervous System–Acting Drugs
Primary Biliary Cirrhosis Hepatopulmonary Syndrome and Other
Primary Sclerosing Cholangitis Pulmonary Complications
Autoimmune Hepatitis Pruritus
Management of Osteopenia and
LIVER-SPECIFIC COMPLICATIONS Osteoporosis
Portal Hypertension
PSYCHOSOCIAL ISSUES AND DEPRESSION
Esophageal Variceal Bleeding
Gastric Variceal Bleeding NUTRITION
Acute Variceal Bleeding

The worsening organ availability crisis continues to lifesaving procedures, the general medical care of these
affect liver transplantation (LT) candidates. According patients should not be overlooked. Close follow-up of
to the United Network for Organ Sharing (UNOS), these patients is a must. The Model for End-Stage Liver
there were 16,092 patients awaiting LT as of March Disease (MELD) is a useful tool that estimates the mor-
31, 2012. The number of deceased liver transplants in tality of patients awaiting LT.2,3 It was implemented on
the year 2011 was 6,094.1 The lower number of trans- February 26, 2002, by UNOS as the criterion for organ
plants coupled with longer waiting times increases the allocation in patients with chronic disease awaiting LT.
likelihood that candidates will have complications of Its implementation has been associated with an initial
their liver disease. The transplant hepatologist by reduction in LT waiting list registrations and a drop in
necessity has to be skilled in the medical management the number of deaths on the waiting list.4,5 As limitations
of candidates before LT. to the use of the MELD score have been defined, several
The aim of this chapter is to delineate the care of proposals to modify the MELD score have been commu-
patients who await LT. It focuses on clinical issues and nicated.6-9 Hyponatremia has been associated with a
complications that do not require hospitalization and higher mortality risk independently of the MELD
highlights preventive medicine measures and disease- score10; this effect was more pronounced among patients
specific measures that can maximize the survival of candi- with a lower MELD score. A modified model called
dates without LT. MELD-Na has been proposed as a more valid measure of
LT priority.6 A limitation in the use of a MELD-Na–
based allocation policy has been the concern that serum
GENERAL MEDICAL CARE sodium may be subject to laboratory variation and
manipulation.11
Routine Examination, Prophylaxis, and MELD predicts candidate mortality at different time
points with adequate accuracy. For practical purposes the
Immunization score is capped at 40, a point at which patients have vir-
Although the life-threatening complications of end-stage tual 100% mortality in 3 months. UNOS has made
liver disease require a higher acuity of care and even adjustments to the MELD score to compensate for the

478
 36 Monitoring and Care 479

patients with decompensated cirrhosis. In view of a lower

TABLE 36-1 F
 requency of Evaluations Based on
response rate, follow-up anti-HBsAg antibody levels
MELD
should be obtained after the second injection. The final
MELD Score Evaluation Frequency Age of Test injection of the series, given 6 months after the first one,
should be given even if the LT has already been per-
≥25 Every 7 days ≤48 hr
formed. In addition to hepatitis A and B vaccination,
24-19 Every 30 days ≤7 days
these patients should also receive influenza vaccine yearly
18-11 Every 90 days ≤14 days
and pneumococcal vaccination (0.5 mL intramuscularly)
≤10 Every year ≤30 days
every 5 years.19 Influenza vaccination has been shown to
MELD, Model for End-Stage Liver Disease. decrease influenza-related complications, including
hepatic decompensation, in cirrhotic patients.20 Pneumo-
coccal vaccination is recommended for cirrhotic patients
increased mortality from advancing disease in patients because Streptococcus pneumoniae infections are more
with small hepatocellular carcinoma (HCC) with long severe and accompanied with an increased fatality rate.
waiting time. The HCC patients who fulfill the so-called Tuberculin skin testing should be done yearly. The intro-
Milan criteria get a priority MELD score beyond their duction of interferon-γ release assays may improve the
degree of hepatic compensation.12 Patients with stage T2 detection of latent tuberculosis in patients with more
HCC (one lesion ≥ 2 cm but ≤ 5 cm or two or three advanced liver disease.21,22
lesions ≥ 1 cm and ≤ 3 cm) may be registered at a MELD Screening for breast, endocervical, colorectal, and
score equivalent to a 15% probability of candidate death prostate cancer should be performed as in other medical
within 3 months. This level of compensation differs based patients. A comprehensive ear, nose, and throat evalua-
on UNOS regional variations, and the impact of such an tion should be done in alcoholics with history of tobacco
adjustment, despite several modifications over time, con- use because of their increased nasopharyngeal cancer
tinues to stir strong discussion in the field.9,13,14 incidence.
Once patients are listed for LT, MELD maintenance
requires regular visits to the transplant clinic (Table
36-1). The frequency with which a patient should be TREATMENT OF UNDERLYING LIVER
monitored in clinic is based upon the MELD score. DISEASES
MELD scores of 10 or less warrant visits every 6 months
to a year, whereas patients with MELD scores of 11 to 18 In recent years great strides have been made in improving
should be seen every 3 months, those with MELD scores the management of chronic liver disease. HBV, autoim-
of 19 to 24 should be seen monthly, and patients with mune liver disease, and hepatitis C virus (HCV) have
MELD scores of 25 or higher should be evaluated weekly. newer treatment approaches that should facilitate man-
These visits should be used not only to update the param- agement. Whenever possible, treatment of the underly-
eters used for MELD scoring but also to assess electro- ing primary liver disease should be considered; in some
lyte levels, complete blood count, and coagulation profile. instances clearance of viral infection or bringing disease
As with all cirrhotic patients, assessment of subclinical into remission may resolve aspects of hepatic decompen-
portosystemic encephalopathy, ascites, and peripheral sation and make the indication of LT unnecessary.
edema are mandatory. If patients have been prescribed
β-blockers, blood pressure and pulse measurements
should be performed with the goal of adjusting medica-
Hepatitis B Virus
tions optimally. Screening for HCC should be done with In HBV-related cirrhosis, antiviral therapy should be
serum α-fetoprotein and abdominal triphasic computed considered if HBV replication is present. Successful anti-
tomography scan or magnetic resonance imaging.15 viral therapy with viral clearance may stop disease pro-
Select populations, including those with viral hepatitis B gression, reverse clinical manifestations of hepatic
and C, hemochromatosis, and alcoholic liver disease, may decompensation, and decrease significantly HBV recur-
warrant a more aggressive schedule because of elevated rence after LT. Fontana et al23 reported the outcome of
risk for HCC. lamivudine therapy in 309 patients awaiting LT for
Vaccinations for hepatitis B virus (HBV) and hepati- chronic hepatitis B; lamivudine did not improve the over-
tis A virus (HAV) have significant value. Vento et al16 all pre-LT survival or LT-free survival. Moreover, their
reported that fulminant hepatitis is associated with hep- data suggest that a subset of patients with less advanced
atitis A superinfection in chronic hepatitis C patients liver failure may derive clinical benefit from lamivudine
and recommended that these patients should be immu- treatment, thus delaying the need for LT.23 Adefovir
nized for hepatitis A. Recent publications show that therapy has also been associated with beneficial effect
hepatitis A and B vaccination rates in adult patients among pre-LT patients as well as post-LT recurrence.24
with chronic liver diseases remain low. The vaccination A vexing problem has been the need to keep treatment
rates in this patient population range between 20% and with nucleos(t)ides long term or indefinite to accomplish
30%.17,18 viral suppression. This long-term therapy has been
Patients who do not have antibodies to the HBV sur- accompanied by the emergence of resistant strains of
face antigen (HBsAg) should receive a complete vaccina- HBV.
tion schedule at the beginning of their evaluation. The Recently the combination of entecavir plus tenofovir
response rate to these vaccines is also decreased among has been used as a rescue therapy in pretreated patients
480 PART IV Special Considerations in Patient Evaluation

with chronic HBV.25 Fifty-seven patients who had previ- Hemochromatosis

ously received a median of three antiviral therapies were
treated with entecavir plus tenofovir; 51 of 57 patients The practice guidelines from the American Association
became HBV-DNA undetectable. The viral suppression for the Study Liver Diseases (AASLD) state that all
was also associated with a 23% drop in alanine amino- patients with hereditary hemochromatosis and evidence
transferase levels. There were no serious side effects asso- of iron overload should be strongly encouraged to
ciated with this combination therapy. This is a promising undergo regular phlebotomies until iron stores are
study that will have to be expanded to be able to reach depleted.35 Phlebotomies should be continued for life
more definitive conclusions.25 Seven drugs are now with the frequency of maintenance therapy determined
approved for treatment of chronic hepatitis B by the by the serum ferritin level. Patients with hereditary
Food and Drug Administration (FDA): interferon alfa- hemochromatosis have a 20-fold relative risk for deve­
2b, pegylated interferon alfa-2a, lamivudine, adefovir, loping HCC; therefore regular screening for HCC is
entecavir, telbivudine, and tenofovir. Patients with com- ­recommended. Screening of first-degree relatives with
pensated cirrhosis and evidence of HBV replication iron studies and hemochromatosis mutation analysis is
should be treated preferentially with nucleos(t)ides recommended for early diagnosis and prevention of
­
because of the possibility of serious hepatic decompensa- complications.35
tion associated with flares related to interferon-α. Ente-
cavir and tenofovir are the preferred drugs in this setting Primary Biliary Cirrhosis
because of high intrinsic barriers to resistance. Combina-
tion therapy should be considered in patients with All patients with primary biliary cirrhosis (PBC) with
decompensated disease and with a high probability of abnormal liver enzyme levels should be considered for
resistant HBV strains.26 specific therapy.36 Ursodeoxycholic acid (UDCA) treat-
ment is associated with a marked improvement in serum
biochemical markers of cholestasis (bilirubin, alkaline
Hepatitis C Virus phosphatase, and γ-glutamine transferase).37 Although
The treatment of chronic HCV has been revolutionized not a cure for PBC, treatment with UDCA slows the pro-
by the approval of two direct antiviral agents (DAAs), tela­ gression of disease, improves survival, and decreases need
previr and boceprevir.27-29 These two DAAs are inhibi- for LT.38,39 The recommended dosage for UDCA is 13
tors of the HCV nonstructural protein 3/4A (NS3/4A) to 15 mg/kg, usually in divided doses.36
serine protease. Both agents have been approved by the Osteopenia, with progression to osteoporosis, is a
FDA for chronic HCV infection with genotype1. Patients well-known complication of PBC, with a relative risk of
with compensated cirrhosis should complete therapy for 4.4.40 Both decreased osteoblastic activity and increased
48 weeks when treated with telaprevir or boceprevir, fol- osteoclastic activity contribute to the development of
lowing FDA-approved directions. Therapy consisting of osteoporosis in PBC patients.41 Patients with PBC should
pegylated interferon, ribavirin, and one DAA has not have bone mineral density testing at the time of diagno-
been evaluated in decompensated cirrhotic patients; use sis, with screening every 2 to 3 years thereafter. Calcium
in this specific patient population has to be done carefully (1000 to 1500 mg/day) and vitamin D (1000 International
and only in the context of a clinical trial and with the Units/day) supplementation should be considered for
patient approved for LT. postmenopausal women and anyone with osteopenia, and
Treatment of HCV in the setting of decompensated vitamin D levels should be checked annually. Bisphos-
cirrhosis using interferon alpha-interferon has been phonate therapy is recommended for patients with osteo-
fraught with serious and sometimes lethal complications porosis; patients with advanced fibrosis and cirrhosis
and should not be done outside a clinical trial by experi- should first have upper endoscopy to exclude esophageal
enced clinicians.30 varices.36
Everson et al31 have proposed a low accelerating dos-
age regimen (LADR) of interferon and ribavirin in Primary Sclerosing Cholangitis
patients with decompensated cirrhosis.31 Forty seven of
124 patients who were placed in LADR underwent LT; Unlike PBC, there is currently no specific medical ther-
22 of these patients had an end-of-treatment response. apy for primary sclerosing cholangitis (PSC). At the dose
Fifteen patients were HCV RNA negative before LT; 12 of 13 to 15 mg/kg/day, UDCA failed to slow the progres-
of them remained negative for at least 6 months after LT. sion of disease.42 A trial using high-dose UDCA (28 to
Genetic polymorphism in the region of the IL28B 30 mg/kg/day) was stopped early when the treatment arm
gene on chromosome 19 has been found to be associated showed higher rates of death and need for LT.43 The
with sustained viral response among patients infected AASLD practice guidelines currently recommend against
with HCV genotype 1.32 This polymorphism has also the use of UDCA in PSC.44 Other agents, including ste-
been associated with spontaneous HCV clearance33 and roids, immunosuppressants, antimetabolites, and tumor
severity of histological recurrence and treatment response necrosis factor-α antagonists, have failed to demonstrate
following LT.34 Recipient and donor TT genotype was improvements in disease activity or outcomes and are not
associated with more severe histological recurrence of recommended for treatment of PSC.44
HCV after LT. The authors suggested that CC donor Cholangiocarcinoma (CCA) is the most feared com-
livers could be preferentially allocated to recipients plication of PSC. The incidence of CCA is 7% to 9%
infected with HCV.34 over 10 years in patients with PSC, and the development
 36 Monitoring and Care 481

of this malignancy portends a dismal prognosis. Surgical treatment includes corticosteroids with or without aza-
resection should be considered in patients with limited thioprine; 80% of patients will respond to treatment.
disease, although survival after resection remains low.45 Although patients with cirrhosis and active disease are
LT for early-stage hilar CCA is now performed at likely to respond to treatment, they are more likely to
selected institutions, with overall 5-year survival of experience treatment-related side effects, especially cyto-
70%.46-49 Transplantation for CCA occurs only in a penia, compared to patients without cirrhosis.56 Although
highly selected group of patients meeting a strict diag- none have been tested in randomized trials, multiple
nostic and therapeutic protocol; therefore potential can- options exist for patients who cannot tolerate azathio-
didates should be seen at a transplant center as soon as prine, including mycophenolate mofetil, cyclosporine,
possible to maximize their candidacy (biopsy of the pri- tacrolimus, and rituximab.57
mary lesion, for example, excludes the patient from
transplantation).
The differentiation between benign and malignant
biliary strictures remains a challenge, complicating the
LIVER-SPECIFIC COMPLICATIONS
diagnosis of CCA. Any patient with clinical or biochemi- Portal Hypertension
cal deterioration should be evaluated for CCA. The
tumor marker CA 19-9 level is elevated in up to 85% of Portal hypertension is the main complication of liver cir-
patients with CCA. A cutoff of 130 units/mL yields a sen- rhosis. This syndrome develops in the majority of patients
sitivity of 79% and specificity of 98%.50 However, the CA with cirrhosis and is responsible for most life-threatening
19-9 level can also be elevated in the presence of cholan- complications of cirrhosis, including gastrointestinal
gitis, which occurs frequently in patients with PSC and bleeding from ruptured gastroesophageal varices, hepa-
extensive biliary strictures. Positive results of cytologic torenal syndrome, and hepatic encephalopathy (HE).
studies on biliary brushings have a specificity of 100%; The management of these complications in the LT can-
however, the sensitivity is limited to 18% to 40%.44 The didate will be discussed in detail.
addition of fluorescent in situ hybridization (FISH) may
increase the sensitivity of conventional cytologic exami- Esophageal Variceal Bleeding
nation.44,51 The role of [18F]fluoro-2-deoxy-D-glucose
(FDG) positron emission tomography (PET) in the diag- The average lifetime risk for variceal bleeding in patients
nosis of CCA has not yet been determined, and clinicians with cirrhosis who have had no previous bleeding is
need to be aware that inflammation can cause false-­ approximately 8% to 35%.58-60 Despite significant
positive results. Despite the clinical concern for the improvements in the early diagnosis and treatment of
development of CCA, formal surveillance protocols have esophagogastric variceal hemorrhage, the mortality rate
not been endorsed by the major hepatology societies.44,51 of first variceal hemorrhage remains high.59 Multivariate
Annual surveillance with imaging and CA 19-9 is reason- analyses of prospective studies indicate that patients at
able for most patients. Because of an elevated risk for high risk for first variceal bleeding are advanced Child-
gallbladder cancer, an annual ultrasound examination is Turcotte-Pugh class, large esophageal varices, and red
recommended in all patients with PSC. wale markings.61,62 Despite recent progress in manage-
The majority of patients with PSC also suffer from ment and improved survival, the risk to LT candidates
inflammatory bowel disease, predominantly ulcerative remains substantial, with mortality figures still greater
colitis (UC). Compared to patients with UC alone, than 20%.59,63
patients with PSC and UC have an increased risk for
colorectal cancer and dysplasia, with an odds ratio of Primary Prophylaxis
4.79.52 Some retrospective studies have suggested a che- Pharmacotherapy. Nonselective β-blockers have been
moprotective effect of UDCA in patients with PSC and shown to reduce the risk for initial variceal bleeding,
UC; however, this finding is not universal.53-55 Further- with a trend toward decreased mortality, and should be
more, high-dose UDCA is associated with adverse out- considered in all patients with large varices and red
comes in PSC.43 Routine use of UDCA for markings.58 β-blockers decrease portal pressure and col-
chemoprophylaxis in patients with PSC and UC is not lateral flow through a combination of decreased cardiac
recommended.44 Surveillance colonoscopy with biopsies output and unopposed alpha-mediated splanchnic vaso-
every 1 to 2 years is advised. constriction, resulting in decreased effective splanchnic
blood flow. Propranolol, nadolol, timolol, or carvedilol
can be used, and the dose should be titrated weekly to
Autoimmune Hepatitis decrease the resting heart rate by 25% but not to less
Autoimmune hepatitis (AIH) can present with severe than 55 beats/min and the systolic blood pressure to no
hepatic decompensation, prompting urgent evaluation lower than 90 mm Hg.58,64
for LT. With appropriate therapy, many patients will Hemodynamic studies have shown that the benefit of
have stabilization of liver disease and may not require β-blockers is noted only in patients in whom the hepatic
transplantation. Approximately 25% of patients with venous pressure gradient is reduced to less than 12 mm
AIH will have cirrhosis at the time of diagnosis, and LT Hg or 20% lower than the baseline. The risk reduction
may be warranted. Patients with inactive, or “burned- with β-blockade averages less than 50%, and the maxi-
out” AIH with normal liver enzyme levels do not need mum benefit is seen in patients with Child-Turcotte-
therapy. For patients with active disease the standard Pugh class A and B cirrhosis. More than 30% of patients
482 PART IV Special Considerations in Patient Evaluation

have no decrease in portal pressure despite adequate of randomization.73 The clinical results show that after
β-blockade.65 The addition of long-acting nitrates to 16 months of follow-up 14 patients in the standard arm
nonselective β-blockers was thought to enhance their had a rebleeding episode, compared to 1 in the TIPS arm
hemodynamic effect and reduce the risk for bleeding (P < .001). Mortality was likewise effectively decreased in
from esophageal varices and therefore was tested as a the TIPS arm during follow-up.73 Although the group
pharmacological possibility in patients who do not was highly selective, these results are highly suggestive
respond ideally to β-blockers. Large randomized studies that TIPS may play a role in LT centers with high-risk
have failed to demonstrate significant impact in this patients who can be managed aggressively until trans-
respect.66 Current AASLD guidelines discourage nitrate plantation can be accomplished.
use in this setting.67
Endoscopic Therapy. Endoscopic variceal sclerother- Gastric Variceal Bleeding
apy has been used in the primary prophylaxis of variceal
bleeding.62 However, poor results compared with phar- No specific measures are available to prevent first bleed-
macotherapy have led to the virtual displacement of this ing from gastric varices. Most of the current regimens to
modality.60 Endoscopic band ligation (EBL) has been treat gastric varices are derived from anecdotal evidence
shown to be better than β-blockers with respect to first or are extrapolated from trials of esophageal varices.58,62
bleed incidence; however, the mortality rate in this In a randomized controlled trial, endoscopic ablation
patient population is no different.58,59 These conclusions with cyanoacrylate proved more effective and safer than
were reached with meta-­analysis of 17 studies, the large band ligation in the management of bleeding gastric vari-
majority very small and heterogeneous and some stopped ces.74 However, cerebral emboli have been reported with
prematurely.58 The conclusions of the authors were the tissue adhesives, and interest has therefore been
lukewarm support of EBL in patients who would not focused on locally administered thrombin, which pro-
­tolerate β-blockers, with the distinct possibility that vides good hemostasis. There remains much heterogene-
EBL does not differ from β-blockers in well-managed ity in the approach to the management of bleeding gastric
patients.58,68 varices.58 The incidence of bleeding from gastric varices
Transjugular Intrahepatic Portosystemic Shunt. This is less than 10%, and thus no significant numbers can be
approach is associated with a high incidence of HE and accrued to perform randomized trials. TIPS placement is
with costly transjugular intrahepatic portosystemic shunt recommended early in the management of gastric vari-
(TIPS) malfunction if using bare stents. Despite effec- ceal bleeding because the rate of rebleeding after endo-
tiveness in the arrest of bleeding, TIPS cannot be recom- scopic treatment is high. Many in the field allow only one
mended as an approach to prevent the first variceal failure of endoscopic therapy.58 TIPS is very effective
bleeding (primary prophylaxis) because of the implica- with a success rate of 90% for initial hemostasis. The rate
tions of subsequent complications, overall cost benefit, of early rebleeding after TIPS procedure is 20%, and
and unexplored clinical value in this population.69 often the source of such bleeding is not variceal, but in
some instances unresolved varices may require coil
Secondary Prophylaxis embolization.69
Rebleeding is a common occurrence, with recurrence
reported as high as 70% in patients who have had at least Acute Variceal Bleeding
one prior bleeding episode. Generally this occurs within
6 weeks of the index episode.61 The use of β-blockers Patients suspected of acute variceal bleeding should be
(with EBL of varices) is the most accepted approach to managed in the intensive care setting. General principles
manage these patients. There is still debate about the of resuscitation should be followed, which include pro-
cost-effectiveness of this pharmacological approach com- tection of airway, insertion of two large-bore intravenous
bined with endoscopy, because it is not entirely clear cannulas, blood volume resuscitation with packed eryth-
whether the addition of nonselective β-blockers to endo- rocytes, correction of coagulopathy with fresh frozen
scopic therapy enhances benefit.70-72 It is probably safe plasma, and platelet transfusion if platelets are below
and of minimal cost to maintain the patient on β-blockers 30,000/ mm3. Care must be taken not to overexpand the
until variceal eradication is confirmed, after which dis- plasma volume, which may increase portal pressure and
continuation of β-blockers is safe. result in exacerbation of variceal bleeding and ascites.
TIPS remains a valid rescue method for those patients Antibiotics should be administered prophylactically,
in whom pharmacological, endoscopic, or combined especially in patients with ascites, to prevent spontaneous
measures have failed.67,69 Despite effective arrest of bacterial peritonitis. Emergency endoscopy of the upper
bleeding, HE remains a problem in this set of patients gastrointestinal tract can then be performed, and the
and may lead to the mortality seen in this patient set. A most appropriate treatment modality should be chosen at
recent highly publicized clinical trial from nine European that point.67,75
centers found improved outcomes in cirrhotic patients
who were admitted with acute variceal bleeding and upon Pharmacotherapy
admission were fast-tracked to TIPS to prevent death. In The drug classes that have been extensively studied in
this trial Child-Turcotte-Pugh class B and C patients acute variceal bleeding are vasopressin and somatostatin
were randomized to TIPS versus vasoactive agent plus and their analogues. Both somatostatin and vasopressin
EBL within 24 hours of admission, and for those assigned cause splanchnic vasoconstriction and thereby decrease
to TIPS their procedure was completed within 72 hours the portal pressure and the portal blood flow.
 36 Monitoring and Care 483

Vasopressin and Terlipressin. The efficacy of intrave- emergency setting because banding may be more chal-
nous vasopressin has been shown in several s­ tudies.59,62,76 lenging during active bleeding. This is felt to be due to
Variceal bleeding is arrested, but mortality is not reductions in the field of view by as much as 30% when
reduced. Side effects range from 32% to 64% in various the banding device is attached.60 The choice of procedure
randomized controlled trials, and these often result in should depend on the available expertise in the center
cessation of therapy. The most significant complica- managing the patient.
tions arise from coronary arterial vasoconstriction,
leading to myocardial infarction and arrhythmias. Bowel Balloon Tamponade
ischemia, cerebrovascular ischemia, and peripheral tis- This tool is a useful temporary measure to control acute
sue necrosis have been reported. The severity of com- variceal bleeding and to stabilize the patient while more
plications has led to a virtual discontinuation of this definitive procedures are being planned. Control of
pharmacological regimen.77 Hyponatremia secondary bleeding is successful in as many as 80% to 90% of cases,
to antidiuresis has also been reported with vasopressin but rebleeding occurs in up to 50% when the balloon(s)
therapy. To avoid these complications the combination are deflated. Furthermore, significant perforation risk is
of vasopressin and nitroglycerin should be used in this present, which may lead high mortality if the balloons are
clinical setting. inflated for prolonged periods of time.80
Terlipressin is a longer-acting analogue of vasopressin
and can be given as bolus infusion every 4 hours.76,77 Its Transjugular Intrahepatic Portosystemic Shunt and
efficacy is similar to vasopressin in controlling the acute Shunt Surgery
variceal bleeding and is associated with fewer side effects. In the 10% of patients in whom rebleeding cannot be
The ease of administration has allowed for paramedic controlled with two endoscopic therapeutic sessions
administration in the field with arrest of bleeding before within 24 hours, either surgery or TIPS should be
arrival to hospital. Unfortunately, terlipressin is not planned. Shunt surgery should be considered in patients
approved for use in the United States. with Child-Turcotte-Pugh class A cirrhosis.80
Somatostatin and Its Analogues. Somatostatin is TIPS could be used in patients with Child-Turcotte-
superior to vasopressin for immediate control of bleeding Pugh class B or C cirrhosis as a salvage therapy and pref-
and has less frequent and less severe side effects than erably as a bridge to LT.69 Worsening of HE after the
vasopressin, although survival benefit has not been seen TIPS procedure may impair the outcome.67,69,80
with somatostatin.62,76 Somatostatin and its analogues
can be dosed without concern for arterial vasoconstric- Ascites
tion. The complications of vasopressin with somatostatin
use and adjuvant administration of nitroglycerin are vir- Ascites is the most common major complication of portal
tually never seen. Somatostatin is usually given as an ini- hypertension. Although the development of ascites is
tial intravenous bolus of 250 μg followed by a continuous usually indicative of advanced liver disease, the clinical
intravenous infusion of 250 to 500 μg/hour. Octreotide is course of patients with cirrhosis and ascites is highly vari-
a synthetic analogue of somatostatin. When compared able. The initial evaluation of a patient with ascites should
with other vasoactive drugs, octreotide was better than include a history, physical evaluation, and abdominal
vasopressin and equivalent to terlipressin for controlling paracentesis with ascitic fluid analysis. Bleeding is suffi-
bleeding. The side effects were less frequent and less ciently uncommon to preclude the need for prophylactic
severe with octreotide than with either vasopressin or ter- fresh frozen plasma or platelets before a diagnostic para-
lipressin. It is administered intravenously as a continuous centesis.81,82 The initial ascitic fluid analysis should
infusion of 50 μg/hr for 5 days. The efficacy of octreotide include a cell count and differential and serum ascites
as a single therapy is controversial. Results from a recent albumin gradient. The culture yield increases to 80%
meta-analysis suggest that octreotide may improve the when ascitic fluid with polymorphonuclear (PMN) cell
results of endoscopic therapy but has little or no effect if count of 250 cells/mm3 or higher is inoculated into blood
used alone.76 culture bottles at bedside.81,82
The mainstay of treatment of patients with ascites
Endoscopic Therapy includes education regarding dietary sodium restriction
Endoscopic sclerotherapy controls active hemorrhage in (2000 mg/day or 88 mmol/day) and oral diuretic ther-
80% to 90% of patients.76 However, a skilled endoscopist apy.81,82 Fluid loss and weight changes are directly related
must be readily available, and the procedure is associated to sodium balance in patients with portal hypertension–
with serious complications in 10% to 20% of patients, related ascites. Primary emphasis should be placed on
with an overall mortality of 2%. The combination of sodium restriction and not fluid restriction. The mea-
sclerotherapy with somatostatin, octreotide,78 and vapre- surement of urinary sodium excretion is a helpful param-
otide79 has been reported to be superior to sclerotherapy eter to follow in these patients.83 The nonurinary sodium
alone in terms of control of bleeding and reduction of excretion in an afebrile cirrhotic patient is less than
treatment failures within 5 days.62 10 mmol/day.84 One of the goals of treatment is to
The 6-week survival of patients treated with the com- increase the urinary excretion of sodium so that it is
bination of sclerotherapy and drugs was similar to that for greater than 78 mmol/day (total daily sodium intake
sclerotherapy alone. EBL of varices was shown to be bet- minus nonurinary sodium excretion).85
ter than endoscopic sclerotherapy in controlling acute Chronic hyponatremia is commonly seen in cirrhotic
bleeding and mortality.68 However, it is limited in the patients and is seldom morbid. Rapid attempts to correct
484 PART IV Special Considerations in Patient Evaluation

hyponatremia can lead to more complications than can treatment in the absence of prostaglandin inhibitors such
the hyponatremia itself. Severe hyponatremia (serum as nonsteroidal antiinflammatory drugs.81,82 Serial thera-
sodium level < 120 mmol/L) requires fluid restriction in peutic paracentesis is effective in controlling ascites.
cirrhotic patients with ascites. Rapid correction of hypo- Serial therapeutic paracentesis should be performed as
natremia of 120 mmol/L or less results in a significant needed, approximately every 2 weeks. Postparacentesis
risk for central pontine myelinolysis.81,86 These patients albumin infusion is expensive and has not been proved to
need to be corrected with utmost care. Cirrhotic patients be necessary for paracentesis of less than 5 L. For larger-
do not usually have symptoms from hyponatremia until volume paracentesis, albumin infusion of 8 g/L of ascitic
their sodium levels fall below 110 mmol/L, or unless the fluid removed should be considered and is recommended
decline in sodium is very rapid.82,86 Gerbes et al87 showed given the ineffectiveness of volume expanders other than
that VPA-985, an orally active vasopressin V2 receptor albumin in the prevention of postparacentesis circulatory
antagonist, can correct severe hyponatremia in patients dysfunction.81
with cirrhosis and ascites. This has been corroborated by
several studies with agents in this class.88-91 Unfortu- Hepatic Hydrothorax
nately, it is still not clear what the optimal duration of Hepatic hydrothorax is defined as the accumulation of
treatment should be and what the cost analysis of these fluid in the pleural space as a consequence of liver dis-
types of intervention will bear.81,82,86,92 ease.98 The most common symptom is dyspnea without
The usual diuretic therapy consists of single morning chest pain. It can be detected with chest radiographs in as
doses of oral spironolactone and furosemide, beginning many as 13% of patients with cirrhosis.99 Right-sided
with 100 mg of the former and 40 mg of the latter.82 pleural effusion is seen in 66% of the patients with hepatic
There continues to be some discussion about single- hydrothorax.
agent spironolactone as a starting point, but hyperkale- The management options for hepatic hydrothorax
mia and the long half-life of this drug have resulted in its include medical management of ascites and therapeutic
use as a single agent only in patients with minimal fluid paracentesis for the control of shortness of breath.98,99
overload.82,93 Single-agent furosemide has been shown to Pleurodesis of the pleural space with chemical means
be less efficacious than spironolactone in a randomized such as talc, antibiotics, or chemotherapeutic agents usu-
controlled trial.94 The dose of both oral diuretics can be ally fails.99 TIPS has been successfully used to manage
increased simultaneously, maintaining the 100 mg:40 mg the symptoms of hepatic hydrothorax in the setting of
ratio, with a maximum of 400 mg/day:160 mg/day, if marked ascites.69,81,100 Video-assisted thoracoscopy with
weight loss and natriuresis are inadequate on lower doses. the repair of presumed diaphragmatic defect has been
In general this ratio maintains normokalemia.81,82 Furo- described in the literature in selected patients.99 LeVeen
semide can be temporarily withheld in patients present- or Denver shunts were popularized in the 1970s as a
ing with hypokalemia. Single morning dosing tends to physiological treatment of ascites. Shunt placement has
increase compliance and is recommended. The antian- been shown in controlled trials to decrease the duration
drogenic effects of spironolactone such as decreased of hospitalization, the number of hospitalizations, and
libido, impotence, and gynecomastia in men require dose the dose of diuretics.97,101 However, their poor long-term
reduction or discontinuation of the medicine.81,82 patency, significant complication profile, and lack of sur-
Amiloride can be substituted for spironolactone, but it is vival advantage compared with medical therapy in con-
more expensive and has been shown to be less effective in trolled trials have led to near abandonment of these
a randomized controlled trial.95 The etiology of noctur- devices. Shunt-related fibrous adhesions and even fibrous
nal muscle cramps is not well understood, and cramping cocoon formation can make subsequent LT difficult.102
may respond to the oral administration of quinine sulfate Note: The shunt must be ligated before opening the
at a dose of 325 mg in the evening.96 If cramping is limit- abdominal cavity to prevent lethal air embolus.
ing, diuretics should be discontinued or reduced. TIPS is physiologically equivalent to a side-to-side
Dietary sodium restriction and dual diuretic regimen portocaval shunt that is placed by an interventional radi-
has been shown to be effective in 90% of patients in the ologist.103 The results from the North American Study
largest, multicenter, randomized controlled trial performed for the Treatment of Refractory Ascites (NASTRA)
in patients with ascites.97 Encephalopathy, serum sodium showed that TIPS is substantially superior to conven-
level of less than 120 mmol/day despite fluid restriction, tional medical therapy but does not improve the survival
and serum creatinine level greater than 2.0 mg/dL should or quality of life.104 A recent meta-analysis confirms the
result in cessation of diuretic therapy, reassessment of the data reported by that group.105 Patients with intractable
situation, and consideration of second-line options.81,82,97 or refractory ascites will see improvement in their ascites
These patients should be monitored for daily weights, production but with minimal to no advantage in
orthostatic symptoms, and levels of serum electrolytes, survival.81,82
blood urea nitrogen, and creatinine.81,82 Random urine
sodium concentration is measured if the weight loss is not
adequate.82 The frequency of follow-up is determined by
Spontaneous Bacterial Peritonitis
response to treatment and by patient stability. Spontaneous bacterial peritonitis (SBP) is a particularly
important complication because the presence of infection
Refractory Ascites usually removes a patient from consideration of trans-
Refractory ascites is defined as ascites that is nonrespon- plantation until the infection is cleared. A diagnostic
sive to sodium-restricted diet and high-dose diuretic abdominal paracentesis must be performed, and the
 36 Monitoring and Care 485

ascitic fluid must be analyzed for cell count and bacterial albumin infusion decreases the risk for acute renal failure
culture before a confident diagnosis of ascitic fluid infec- after the paracentesis by preventing circulatory dysfunc-
tion is made. The diagnosis is made when the polymor- tion.81,82,110 The results of albumin use in this clinical
phonuclear (PMN) cell count is 250 cells/mm3 or higher setting are better than other volume expanders such as
and/or results of ascitic fluid bacterial culture are positive dextran.101,111,112
without an evident intra-abdominal or surgically correct- Patients with cirrhosis develop a specific acute renal
able source. 81,82 These patients should receive empirical failure called hepatorenal syndrome (HRS).112,113 This
treatment with broad-spectrum antibiotics. Delaying is a diagnosis of exclusion that reflects a continuum of
treatment until the ascitic fluid culture results are positive portal hypertension. HRS is an ominous complication
may result in the patient’s death from overwhelming of end-stage liver disease, as demonstrated by retro-
infection. In those patients with a PMN cell count of less spective studies indicating that HRS is present in
than 250 cells/mm3 in ascitic fluid, a repeat paracentesis is approximately 17% of patients admitted to the hospital
recommended unless there are signs or symptoms of with ascites and in more than 50% of patients with cir-
infection. Oral ofloxacin has been reported in a random- rhosis who die from liver failure.81,82,112-114 The hall-
ized controlled trial to be as effective as parenteral cefo- marks of HRS are reversible renal constriction and
taxime in the treatment of SBP in patients who are not mild to moderate systemic hypotension.112,113 The kid-
vomiting and are not in shock.106 Repeat paracentesis neys are structurally normal and at least in the early
should be performed to document a culture’s sterility and part of the syndrome, tubular function is intact, as
decrease in PMN count in patients with SBP; this step is reflected by avid sodium retention and oliguria. The
particularly important in cases in which clinical improve- cause of renal vasoconstriction is unknown but may
ment is not apparent after the first 3 days of antibiotic predominantly involve both increased vasoconstrictor
therapy.81,82 and decreased vasodilator factors in its pathogene-
Short-term inpatient quinolone should be considered sis.112,113 Two patterns of HRS are observed in clinical
in the prevention of bacterial infections in patients with practice: type 1 and type 2. Type 1 HRS is an acute
low-protein (<1 g/dL) ascites, variceal hemorrhage, and form of HRS in severe liver disease and is progressive.
prior SBP. Long-term outpatient antibiotic use probably It is associated with poor prognosis with 80% mortality
can be reserved for patients who have survived an SBP at 2 weeks. Type 2 HRS occurs in patients with
infection.81,82 diuretic-resistant ascites. The course of renal failure is
slow. It is also associated with poor prognosis, although
the survival time is longer than that of patients with
Hepatorenal Syndrome type 1 HRS.115
Patients with cirrhosis are predisposed to acute renal Although the best treatment for HRS is LT, patients
failure following complications such as variceal bleeding with HRS who are transplanted have more complica-
or administration of nephrotoxic drugs such as nonste- tions and a higher in-hospital mortality rate than those
roidal antiinflammatory drugs, aminoglycosides, and without HRS.81,82,112,116 It has been reported extensively
iodinated contrast for imaging. As with any other
patient, the cause of renal insufficiency has to be assessed
because it could be prerenal, intrarenal, or hepatorenal.
The management of renal insufficiency in patients TABLE 36-2 Systematic Review of the Patient
awaiting LT focuses on assessment of underlying renal System Symptoms/Signs
limitation, prevention of additional injury, and optimi-
zation of existing renal function. Accurate assessment of Central nervous Confusion, memory loss, reversal of
system sleep cycle, altered mental status,
baseline renal function is imperative during the initial narcotics and benzodiazepine use,
evaluation. The serum creatinine measurements may seizures, mental status changes,
not accurately reflect the underlying renal function asterixis, nystagmus, focal deficits
because muscle mass is frequently depleted in cirrhotic HEENT Signs of frequent fall, icterus, pallor,
patients. Glomerular filtration rates using iothalamate malar flush
are felt to be more accurate and are probably the gold Skin and nails Spider angiomas, pruritus, vasculitis,
standard today.107 Once the baseline renal function has clubbing, cyanosis
been established, additional insults should be avoided. Chest Cough, dyspnea, platypnea, orthodeoxia
Careful attention must be paid to volume status, which Cardiovascular Chest pain, palpitations, signs of heart
failure
is frequently tenuous in patients with marked ascites on
Gastrointestinal Abdominal pain, hematemesis, melena,
high-dose diuretic therapy. Nonsteroidal antiinflamma- constipation, tense ascites
tory drugs should be used only with close follow-up Genitourinary Signs of urinary tract infection,
because the subsequent decrease in renal prostaglandin decreased urinary output, review of
may ­precipitate acute renal failure. Radiographic imag- medications causing renal
ing studies using intravenous contrast dye also must be insufficiency
approached with caution because of the known risk for Musculoskeletal Leg cramps, frequent falls, muscle
wasting
renal injury. The use of acetylcysteine together with
Constitutional Fatigue, weight loss, signs of dehydra-
hydration is the treatment of choice to protect against tion, fever
radiographic contrast media–induced nephropathy.108,109
Large-volume paracentesis followed by intravenous HEENT, Head, eyes, ears, nose, and throat.
486 PART IV Special Considerations in Patient Evaluation

that systemic vasoconstrictor therapy may improve Most theories explaining the pathogenesis of HE accept
renal function in patients with HRS by increasing the that nitrogenous substances derived from the gut
effective arterial blood volume. A nonrandomized retro- adversely affect the brain function. These compounds
spective study in a large series of patients with HRS gain access to the systemic circulation as a result of
suggested that the vasopressin analogue, terlipressin, is decreased hepatic function or portosystemic shunts.129
an effective treatment of HRS.117 Other nonrandomized Once in the brain tissues, they produce alterations of
studies suggest that vasoconstrictive therapy with nor- neurotransmission that affect consciousness and behav-
adrenaline118 or midodrine (combined with octreotide)119 ior. Abnormalities in glutamatergic, serotoninergic,
may improve renal function in these patients. Recently, γ-aminobutyric acidergic, and catecholamine pathways,
prospective nonrandomized trials have shown that terli- among others, have been described in experimental
pressin reverses the HRS in a high proportion of HE.129 A large body of work points toward ammonia as a
patients and addition of albumin to terlipressin therapy key factor in the pathogenesis of HE.130 In acute and
markedly improves the beneficial effect of terlipres- chronic liver disease, increased arterial levels of ammonia
sin.120-122 Although the importance of vasoconstriction are commonly seen. In fulminant liver failure, elevated
in this clinical scenario is well understood, studying the arterial levels (>200 mg/dL of ammonia) have been asso-
importance of albumin infusion (comparator therapy) ciated with an increased risk for cerebral herniation.131
in these patients has created more questions than However, correlation of blood levels with mental state in
answers.120 It appears that the optimal approach is cirrhosis is often inaccurate.
aggressive fluid resuscitation, initially with albumin The approach to HE has changed in recent years. The
(approximately 100 g in the first day) followed by vaso- suspicion of HE in patients with chronic liver disease
constrictive therapy, preferably with terlipressin (if should prompt the search for the precipitating factors and
available) or midodrine/octreotide (in the United the other causes of change in mental status. The common
States) with doses adjusted to clinical response and precipitating factors include gastrointestinal bleeding,
side-effect.81 Duration of therapy can be protracted electrolyte abnormalities, renal failure, infection, recent
with reasonable median durations of 14 days. The patients placement of TIPS shunt and use of sedatives/hypnotics,
should be monitored in an intensive care unit setting development of HCC, and constipation.127,132,133 Other
because 12% have ischemic or cardiovascular compli- less likely causes of altered mental status such as intracra-
cations that warrant rapid discontinuation or dose nial bleeding or masses, hypoglycemia, and a postictal
reduction.81 Patients who have lower baseline crea­ state should also be considered. HE is the diagnosis of
tinine levels and total bilirubin levels of less than 10 exclusion and is mainly clinical. Although hyperammone-
mg/dL can be expected to have the best outcome.123 mia is associated with HE, ammonia levels do not c­ orrelate
Increase of mean arterial blood pressure during therapy with the level of encephalopathy. An electroencephalo-
is required for response.81,123 gram may be helpful in advanced stages to avoid e­ rroneous
Nonrandomized studies suggest that TIPS may diagnosis.127,128
improve renal function with HRS.124-126 Because the data In recent years a more aggressive approach to so-called
have never been obtained in controlled trials, it is difficult minimal HE has arisen, and intense clinical trial activity
to support the use of TIPS in the very ill cirrhotic patient is ongoing in this area.134,135 Clinicians should be pre-
with HRS type 1.69 There are indirect data from the pared to recognize this less apparent facet of the encepha-
NASTRA trial that patients who are treated with TIPS lopathy spectrum because it is increasingly concerning
for refractory ascites have fewer episodes of HRS than that safety and quality of life of cirrhotic patients with
their counterparts who were treated with large-volume minimal encephalopathy are decreased.134,135
paracenteses.69,104 TIPS is not a recommended therapy The treatment goals for HE are provision of support-
for HRS at this time. ive care, identification and removal of precipitating fac-
tors, and reduction of nitrogenous load from the gut.
Ultimately assessment of the need for long-term therapy
Hepatic Encephalopathy is important.127,128 The patients presenting with new-
Hepatic encephalopathy (HE) may be defined as a dis- onset or worsening HE should be evaluated for dehydra-
turbance in central nervous system function because of tion, variceal bleeding, spontaneous bacterial peritonitis,
hepatic insufficiency.127,128 This broad definition reflects and renal insufficiency. Besides these, other causes of
the existence of a spectrum of neuropsychiatric manifes- acute change in mental status such as intracranial bleed-
tations related to a normal range of pathophysiological ing, mass, drug toxicity, systemic infection, or aberrant
mechanisms. These manifestations are present in acute electrolytes should be ruled out.
as well as chronic liver failure and are potentially
reversible.127,128 Nutritional Management
Short-term memory loss, lack of concentration, sleep
cycle reversal, and irritability in the early stages can pro- The increased catabolic rate of cirrhosis leads to a recom-
foundly affect the activities of daily living; more advanced mendation of 1 to 1.5 g protein/kg/day. This should be
disease with lethargy, stupor, or coma necessitates hospi- done with the assistance of a specialty dietitian, because
talization and may be life threatening.127,128 Thus medi- patients can inadvertently decrease their protein intake to
cal management by the primary care provider is of the a dangerous level. Zinc, a cofactor of urea cycle enzymes,
utmost importance in improving the quality of life, as may be deficient in cirrhotic patients, especially if associ-
well as reversing a potentially life-threatening condition. ated with malnutrition. Zinc supplementation improves
 36 Monitoring and Care 487

the activity of the urea cycle in experimental models of clinical trial with sodium benzoate versus lactulose,
cirrhosis.136 The clinical trial data on patients supple- improvement in neuropsychiatric performance was found
mented with zinc are limited and conflicting. However, to be comparable.137
patients with zinc deficiency should receive oral zinc sup-
plements because there is enough evidence for treatment Use of Central Nervous System–Acting Drugs
and minimal downside.127
Several controlled clinical trials have been performed to
assess the efficacy of the benzodiazepine receptor antago-
Ammonia-Lowering Strategy
nist flumazenil in cirrhotic patients with various degree of
Nonabsorbable disaccharides such as lactulose are rou- severity of HE.137 Spectacular improvements in neuro-
tinely used to decrease ammonia production in the gut. psychiatric status were recorded in a subset of patients
Lactulose increases fecal nitrogen excretion by facilita- receiving flumazenil.143,144 However, the possible con-
tion of the incorporation of ammonia into bacteria and by founding effects of prior exposure to benzodiazepines
a cathartic effect. Lactulose administered orally reaches and lack of correlation between the clinical response and
the cecum, where it is metabolized by the enteric bacte- blood levels of substances have tempered enthusiasm for
ria, causing a fall in pH. This drop in pH leads to meta- this approach with benzodiazepine receptor agonist
bolic shift in bacteria favoring uptake of ammonia. The properties in these patients.137
dose is adjusted to produce two or three soft bowel move-
ments daily.127 Hepatopulmonary Syndrome and Other
Antibiotics such as neomycin are also useful for lower-
ing blood ammonia levels, mainly by an effect on ammo-
Pulmonary Complications
nia production by intestinal bacteria. However, neomycin Hepatopulmonary syndrome (HPS) is defined as the triad
therapy is associated with significant toxic side effects, of liver disease, pulmonary gas exchange abnormalities
and this has led to reluctance to using it as a first-line leading to arterial deoxygenation, and widespread pulmo-
agent.127,137 nary vascular dilatation, associated more commonly with
The introduction of a nonabsorbable antibiotic, rifaxi- cirrhosis.145 Pulmonary features include digital clubbing,
min, as an option for treatment of HE has changed the cyanosis, dyspnea, platypnea, and orthodeoxia: the later
approach to all patients with cirrhosis who may have two are defined as dyspnea and arterial deoxygenation,
HE.133,138,139 The landmark randomized controlled study respectively, induced by upright position and relieved by
enrolled 299 stable patients with documented HE, who recumbency.145
were assigned to rifaximin versus placebo.140 Patients Transplantation candidates with hypoxemia should be
were allowed to remain on lactulose (>90% of subjects screened for HPS because the syndrome has been demon-
were on lactulose). The clinical end point was time to first strated to resolve after OLT.146-148 Resolution of HPS has
hospitalization for HE in 6 months of treatment. Of the been reported in carefully selected patients after LT. These
treated patients, 22.1% developed HE, with 13.6% of changes include improvement in quality of life measures,
them requiring hospitalization. Of the placebo group which are lower in candidates for LT who have HPS.149
patients, 45.9% developed HE, with hospitalization in A diagnosis of HPS is established when three criteria
22.6%.140 Both results were highly significant, and are fulfilled. First, chronic liver disease, usually compli-
despite concerns about the high use of lactulose, the FDA cated by portal hypertension, must be present. Second,
cleared the road for approval of rifaximin in the treat- arterial hypoxemia, defined by reduced partial pressure
ment of HE. Patients should be treated with 550 mg of arterial oxygen (Pao2) or more accurately by an
orally twice per day with or without lactulose. Recent increased alveolar-arterial difference in the partial pres-
data suggest that the quality of life of cirrhotic patients sure of oxygen (AaDo2), has to be observed. The latter
increases once HE is optimally managed with the addi- includes determination of the partial pressure of arte-
tion of rifaximin.141 rial carbon dioxide (Paco2), which is often low in cir-
An alternate strategy for lowering of blood ammonia rhotic patients as a result of hyperventilation. Lastly,
levels is the stimulation of ammonia fixation. Under nor- the intrapulmonary vascular dilatation detected either
mal physiological conditions, ammonia is removed by the by two-dimensional contrast echocardiography or mac-
formation of urea in periportal hepatocytes and by gluta- roaggregated albumin lung perfusion scan has to be
mine synthesis in perivenous hepatocytes, skeletal mus- documented. Efforts have to be made to rule out intra-
cle, and brain. In cirrhosis both urea cycle enzymes and pulmonic shunting.145,150
glutamine synthetase activity are decreased in the liver. A common mistake that has to be avoided is to confuse
Strategies to stimulate residual urea cycle activities and/ this entity with portopulmonary hypertension, wherein
or glutamine synthesis have been tried over last 20 years. there may be hypoxemia, but the pathophysiology is
One of the most successful agents to be used so far is entirely different and requires a different selection
l-ornithine-l-aspartate (OA). Randomized controlled approach and a different management approach.151
clinical trials with OA demonstrate significant ammonia Pharmacological approaches have been disappointing
lowering and concomitant improvement in psychometric in providing consistent and reproducible improvement in
testing.142 hypoxemia associated with HPS.152 The largest clinical
Benzoate is also effective in reducing blood ammonia trials have involved the open-label use of vascular media-
levels both in patients with inherited urea cycle disorders tors such as almitrine bismesylate, somatostatin ana-
and in cirrhotic patients. In a randomized controlled logues, indomethacin, and garlic preparations.152-156
488 PART IV Special Considerations in Patient Evaluation

Except for garlic, marked improvement in Pao2 could not should have bone mineral density checked at baseline
be consistently demonstrated in these studies.153 and then at routine intervals thereafter (1 year if abnor-
The placement of TIPS to improve hypoxemia caused mal baseline value; 2 to 3 years if baseline bone density is
by HPS remains controversial and cannot be advised normal).
without further prospective study.69,157 Coil embolother- Treatment of osteopenia and osteoporosis is critical to
apy to occlude discrete arteriovenous communications in prevent fracture and debility. Risk factors should be mod-
patients with severe hypoxemia in type 2 HPS lesions has ified when possible: smoking cessation, weight-bearing
resulted in significant improvement in Pao2 in two exercise, and good nutrition. Although efficacy data are
adults.158 Embolotherapy is an accepted approach to the lacking, calcium (1000 to 1500 mg/day) and vitamin D
management of severe hypoxemia associated with dis- (400 to 800 International Units/day, monitoring levels)
crete arteriovenous malformation.159,160 HPS is an are recommended for all patients with cirrhosis.168,169
accepted indication for LT per pediatric and adult UNOS Patients with osteoporosis or osteopenia and history of
criteria and for which MELD exceptions are granted in fracture should be considered for specific therapy.167
the United States, although not without contro- Bisphosphonates have shown benefit in stabilizing and
versy.161,162 Pretransplantation risk factors for increased increasing bone density in patients with liver disease and
mortality are Pao2 less than 50 mm Hg and Tc 99m mac- appear to be safe in this population.170,171 Screening for
roaggregated albumin brain uptake greater than 20%. esophageal varices before initiation of bisphosphonate
Complete resolution even in the setting of severe hypox- therapy is recommended.
emia has been well documented.
PSYCHOSOCIAL ISSUES AND
Pruritus DEPRESSION
Pruritus is a common symptom of chronic cholestatic
liver diseases, particularly PBC.163 The first line of treat- Cirrhotic patients listed for LT have a poor quality of life
ment is cholestyramine, an anion exchange resin. It and a low level of perceived well-being. They have severe
should be administered at least 4 hours before or after psychopathological distress arising from the fear of wait-
taking the other medications because it binds many ing for a transplant, and the awareness of scarcity of
drugs.163 Side effects include bloating, and sometimes allografts, the potential for deterioration that will render
diarrhea. The second line of medication is rifampin.163 them nontransplantable, and death. The patients and
The mechanism of action is unclear, but it is effective in their families should be encouraged to go to support
controlling pruritus in 50% of patients with PBC. Dos- group meetings to cope with the stress and to talk about
age is 150 mg twice a day, and it is effective within their experience. DeBona et al172 showed that all post-LT
6 weeks of therapy. The drug should be taken regularly patients had improved perceived quality of life as evident
for the effectiveness of treatment. These patients should by quality of life scale scores when compared to the
be monitored closely for the possibility of drug patients listed for LT.
hepatotoxicity. High rates of depression have been demonstrated in
Several studies have demonstrated the effectiveness of patients with advanced liver disease. In one study the
opioid receptor antagonists (nalmefene, naloxone, and incidence of depression in patients with cirrhosis was as
naltrexone) in the control of pruritus.164,165 The major high as 63%.173 The depressed patients had significantly
side effects are the symptoms of opioid withdrawal. The worse adaptive coping, poorer perceived quality of life,
treatment should be started slowly, preferably in a hospi- and greater perception of bodily pain, suggesting that
tal setting.163 depression is of considerable clinical consequence and
adversely effects well-being and functioning of such
Management of Osteopenia and patients. End-stage liver disease patients should be rou-
tinely screened for depression, and early treatment with
Osteoporosis selective serotonin reuptake inhibitors should be
Osteoporosis is a common problem in cirrhosis. Although instituted.
patients with cholestatic liver disease have the highest Many cirrhotic patients will have a history of alcohol
prevalence, osteoporosis is common in cirrhosis from or other substance abuse. The transplant team should
any cause of liver disease. In transplant candidates with reinforce to these patients the importance of support
HCV-related cirrhosis, up to 37% have osteopenia and groups and abstinence from alcohol and abusive drugs.
an additional 28% have osteoporosis.166 The pathogen- Random urine drug screens should be done periodically
esis of osteopenic bone disease in cirrhosis is thought to in these patients. An ongoing assessment program is
involve an imbalance in the complex interplay between more likely to identify recidivism or problems with absti-
osteoblastic bone formation and osteoclastic bone nence than a one-time discussion or assessment during
resorption.167 Contributing factors include cholestasis, the intake process.
malnutrition, vitamin D deficiency, female sex, post-
menopausal status, immobility, corticosteroid use, and
alcohol use. Because the end point of osteoporosis—frac- NUTRITION
ture—is a painful and debilitating event, effort should be
made to screen for and treat osteoporosis before it Malnutrition is one of the most unrecognized problems
becomes clinically apparent. All patients with cirrhosis of patients with end-stage liver disease awaiting LT.
 36 Monitoring and Care 489

The prevalence of malnutrition in liver disease is diffi- Pearls and Pitfalls

cult to assess because of the lack of a standardized diag-
nosis and classification of malnutrition in this population. • As patients wait on the orthotopic liver transplantation
Fluid retention and the fact that the plasma levels of (OLT) list, the transplant physician may have to as-
most visceral proteins reflect both poor liver function sume primary care responsibilities.
and the nutritional reserve complicate nutritional • Cirrhotic patients have concurrent medical problems
assessment in cirrhosis. Protein-calorie malnutrition is that have to be addressed by the transplant medical team.
considered by some to be the most common complica- • Preventive screening for nonliver cancers is important.
tion in patients with cirrhosis.174 The prevalence of Of particular interest in the OLT candidate pool: oro-
pharyngeal squamous cell cancer, cervical cancer, co-
protein-calorie malnutrition differs according to the lon cancer, and skin cancer.
cause of cirrhosis. It has been described in 20% of • Regular screening of coronary artery disease should be
patients with compensated cirrhosis, and the incidence done in patients with cardiovascular risk factors such as
rises to 60% in patients with liver insufficiency.175 The older age, family history of premature coronary artery
pathogenesis of malnutrition in cirrhosis is unclear. disease, smoking, diabetes, and history of hyperlipidemia.
Although many patients are in a state of protein catabo- • Do not forget to monitor patients for smoking and al-
lism, these metabolic changes could not adequately cohol cessation. Also inform them about seat belt use.
explain malnutrition.175 The metabolic changes revert • Check for exposure to tuberculosis. Purified protein
back to normal within a few days after nutritional sup- derivative or preferably interferon-γ release assays
port is initiated. Nutritional status is correlated to mor- should be performed. Tuberculosis can affect liver
transplantation candidates.
tality in the total group of patients with cirrhosis and in • Inquire about human immunodeficiency virus (HIV)
Child-Turcotte-Pugh class A and B patients if analyzed testing and HIV risk factors.
separately. Malnutrition is an independent predictor for • Vaccination against hepatitis A virus (HAV), hepatitis
the first bleeding episode and the survival of patients B virus (HBV), and influenza virus is cheap and can be
with esophageal varices. It is also associated with the lifesaving. Do not let your patients die of preventable
presence of refractory ascites. Poor preoperative nutri- infections.
tional status is correlated to postoperative complica- • Oral HBV therapies have been shown to slow the rate
tions and mortality.175 of decompensation of patients who have HBV-related
Nutritional management of patients with liver disease cirrhosis.
can be a difficult task. Every effort should be made to • Sudden discontinuation of oral antivirals against HBV
(lamivudine, adefovir) in a patient with advanced liver
prevent any period of prolonged fasting. To improve disease may lead to rapid, life-threatening decompen-
nitrogen economy and to avoid undue catabolism of mus- sation.
cle protein, patients should be encouraged to eat six to • If candidates have hemochromatosis, it is important to
seven meals per day, including one late-night meal. This decrease iron stores with phlebotomy to prevent car-
should prevent depletion of glycogen stores and diminish diac, pancreatic, and pituitary involvement.
the loss of fat stores and lean body mass. If a patient has • Screen patients with primary biliary cirrhosis (PBC)
reasonable appetite, 35 to 45 kcal/kg/day should be sup- for osteopenia/osteoporosis, and treat the problem if
plied, including 0.8 to 1 g/kg/day of proteins. This may diagnosed.
need to be modified for patients with protein intolerance • Patients with ulcerative colitis and primary sclerosing
because of encephalopathy.175 cholangitis may be at increased risk for colon cancer.
Screen yearly if the patients still have their colon.
Micronutrient deficiency has been observed in 10% to • If β-blockers are started, check for baseline pulse de-
50% of patients with cirrhosis.176 Fat-soluble vitamins creases. These drugs are poorly tolerated but most fre-
may be deficient in patients with cholestatic diseases, and quently are underdosed by clinicians, and the primary
deficiency of water-soluble vitamins, vitamin B12, and physician may not know what parameters to use.
folic acid are more frequent in patients with alcoholic cir- • If a TIPS is placed, it must be followed. Ultrasound Dop-
rhosis. Multivitamin supplements may be considered in pler studies are usually insensitive to stenosis. If portal
these patients. Zinc deficiency is common in patients hypertension is clinically apparent, resort to direct angio-
with cirrhosis.176 This might be secondary to higher zinc graphic check of TIPS. In particular, pay attention to the
loss in the urine. Supplementation with zinc has been spontaneous improvement of encephalopathy or pres-
shown to improve HE and with vitamin A improves the ence of ascites or varices as clues that TIPS has failed.
• If large-volume paracentesis is performed or ordered,
sense of taste and thereby may also improve dietary intake ensure that the patient has orders for postprocedure al-
of the patients.136,177 bumin infusion. This will reduce the incidence of renal
Parenteral nutrition should be used as a second-line failure and hemodynamic compromise.
approach in those who cannot be fed adequately by the • Albumin has recently been found to decrease hepa-
oral or enteral route. In the majority of patients standard torenal syndrome if used while treatment for sponta-
amino acids are recommended.176 Solutions rich in neous bacterial peritonitis is ongoing.
branched-chain amino acids and low in aromatic acids • Rifaximin has become the standard management regi-
and tryptophane should be used in patients with encepha- men for portosystemic encephalopathy. The taste of
lopathy and with appropriate caution in those with acute lactulose and its side effects may lead to poor compli-
liver failure.178 ance. Lactulose is available in crystal form, and many
   patients improve compliance if on this regimen.
490 PART IV Special Considerations in Patient Evaluation

25. Petersen J, Ratziu V, Buti M, et al. Entecavir plus tenofovir com-

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111. Gines A, Fernandez-Esparrach G, Monescillo A, et al. Random- 136. Riggio O, Merli M, Capocaccia L, et al. Zinc supplementation
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114. Planas R, Montoliu S, Balleste B, et al. Natural history of patients cin for gastrointestinal disorders. Clin Infect Dis. 2006;42:
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118. Duvoux C, Zanditenas D, Hezode C, et al. Effects of noradrenalin 142. Kircheis G, Nilius R, Held C, et al. Therapeutic efficacy of
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145. Rodriguez-Roisin R, Krowka MJ. Hepatopulmonary syndrome–a 161. Krowka MJ, Fallon MB. Liver transplantation for hepatopulmo-
liver-induced lung vascular disorder. N Engl J Med. 2008;358: nary syndrome (HPS): what is the MESSAGE? Am J Transplant.
2378-2387. 2008;8:911-912.
146. Egawa H, Kasahara M, Inomata Y, et al. Long-term outcome of 162. Sulieman BM, Hunsicker LG, Katz DA, Voigt MD. OPTN pol-
living related liver transplantation for patients with intrapulmo- icy regarding prioritization of patients with hepatopulmonary
nary shunting and strategy for complications. Transplantation. syndrome: does it provide equitable organ allocation? Am J
1999;67:712-717. Transplant. 2008;8:954-964.
147. Krowka MJ, Porayko MK, Plevak DJ, et al. Hepatopulmonary 163. Bergasa NV. The itch of liver disease. Semin Cutan Med Surg.
syndrome with progressive hypoxemia as an indication for liver 2011;30:93-98.
transplantation: case reports and literature review. Mayo Clin Proc. 164. Bergasa NV, Schmitt JM, Talbot TL, et al. Open-label trial of
1997;72:44-53. oral nalmefene therapy for the pruritus of cholestasis. Hepatology.
148. Swanson KL, Wiesner RH, Krowka MJ. Natural history of hepa- 1998;27:679-684.
topulmonary syndrome: Impact of liver transplantation. Hepatol- 165. Wolfhagen FH, Sternieri E, Hop WC, et al. Oral naltrexone
ogy. 2005;41:1122-1129. treatment for cholestatic pruritus: a double-blind, placebo-­
149. Fallon MB, Krowka MJ, Brown RS, et al. Impact of hepatopulmo- controlled study. Gastroenterology. 1997;113:1264-1269.
nary syndrome on quality of life and survival in liver transplant 166. Carey EJ, Balan V, Kremers WK, et al. Osteopenia and osteopo-
candidates. Gastroenterology. 2008;135:1168-1175. rosis in patients with end-stage liver disease caused by hepatitis C
150. Fallon MB, Mulligan DC, Gish RG, et al. Model for end-stage and alcoholic liver disease: not just a cholestatic problem. Liver
liver disease (MELD) exception for hepatopulmonary syndrome. Transpl. 2003;9:1166-1173.
Liver Transpl. 2006;12:S105-S107. 167. Guanabens N, Pares A. Management of osteoporosis in liver dis-
151. Krowka MJ. Hepatopulmonary syndrome versus portopulmonary ease. Clin Res Hepatol Gastroenterol. 2011;35:438-445.
hypertension: distinctions and dilemmas. Hepatology. 1997;25: 168. Crippin JS, Jorgensen RA, Dickson ER, et al. Hepatic osteodys-
1282-1284. trophy in primary biliary cirrhosis: effects of medical treatment.
152. Herve P, Lebrec D, Brenot F, et al. Pulmonary vascular disorders Am J Gastroenterol. 1994;89:47-50.
in portal hypertension. Eur Respir J. 1998;11:1153-1166. 169. Van Berkum FN, Beukers R, Birkenhager JC, et al. Bone mass in
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enterol. 1998;27:232-235. 1134-1139.
154. Krowka MJ, Dickson ER, Cortese DA. Hepatopulmonary syn- 170. Guanabens N, Pares A, Ros I, et al. Alendronate is more effective
drome. Clinical observations and lack of therapeutic response to than etidronate for increasing bone mass in osteopenic patients
somatostatin analogue. Chest. 1993;104:515-521. with primary biliary cirrhosis. Am J Gastroenterol. 2003;98:
155. Soderman C, Juhlin-Dannfelt A, Lagerstrand L, et al. Ventilation- 2268-2274.
perfusion relationships and central haemodynamics in patients 171. Zein CO, Jorgensen RA, Clarke B, et al. Alendronate improves
with cirrhosis. Effects of a somatostatin analogue. J Hepatol. bone mineral density in primary biliary cirrhosis: a randomized
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156. Lange PA, Stoller JK. The hepatopulmonary syndrome. Ann 172. De Bona M, Ponton P, Ermani M, et al. The impact of liver dis-
Intern Med. 1995;122:521-529. ease and medical complications on quality of life and psychologi-
157. Corley DA, Scharschmidt B, Bass N, et al. Lack of efficacy of cal distress before and after liver transplantation. J Hepatol.
TIPS for hepatopulmonary syndrome. Gastroenterology. 1997;113: 2000;33:609-615.
728-730. 173. Singh N, Gayowski T, Wagener MM, et al. Depression in
158. Poterucha JJ, Krowka MJ, Dickson ER, et al. Failure of hepato- patients with cirrhosis. Impact on outcome. Dig Dis Sci.
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successful treatment with embolotherapy. Hepatology. 1995;21: 174. Charlton MR. Branched chains revisited. Gastroenterology.
96-100. 1996;111:252-255.
159. Ando K, Mochizuki A, Kurimoto N, et al. Coil embolization for 175. Plauth M, Merli M, Kondrup J. Management of hepatic encepha-
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 CHAPTER 37

Nutritional Aspects of
Transplantation in Adults
Jeanette M. Hasse

CHAPTER OUTLINE

THE ROLE OF THE LIVER IN NUTRIENT LONG-TERM POSTTRANSPLANT NUTRITIONAL

METABOLISM MANAGEMENT
NUTRITIONAL ASSESSMENT Obesity
Hyperlipidemia
MALNUTRITION IN TRANSPLANT CANDIDATES Hypertension
Prevalence Diabetes Mellitus
Effect of Malnutrition on Outcomes Metabolic Syndrome
OBESITY IN TRANSPLANT CANDIDATES Osteoporosis
PRETRANSPLANT NUTRITIONAL MANAGEMENT Long-Term Nutritional Goals

SHORT-TERM POSTTRANSPLANT NUTRITIONAL FUTURE

MANAGEMENT SUMMARY
Nutrient Requirements
Nutritional Support
Postoperative Complications and Nutritional
Support

THE ROLE OF THE LIVER IN NUTRIENT tryptophan) plus methionine and cysteine increase,
METABOLISM whereas levels of plasma branched-chain amino acids
(BCAAs; valine, leucine, isoleucine) decrease. The result-
The liver is a key organ in the metabolism of nutrients. ing alteration in the plasma molar BCAA/AAA ratio has
The high metabolic activity of the liver accounts for been proposed, but not proven, as a causative factor in
approximately 20% to 30% of the body’s oxygen con- hepatic encephalopathy.
sumption and energy expenditure.1 Liver dysfunction Liver disease may increase caloric requirements and
induces a catabolic state accompanied by increased energy affect energy substrate metabolism.1,2,4 The presence of
expenditure; elevated serum insulin, glucagon, epineph- ascites has been shown to elevate resting energy expendi-
rine, and cortisol concentrations; and insulin resistance.1,2 ture (REE) in patients with liver cirrhosis.5 Other studies
Because the liver is vitally involved in nutrient metabo- have found an increase in REE in patients with ESLD
lism (Table 37-1), liver disease causes alterations in pro- only when REE was expressed as energy expenditure per
tein, calorie, carbohydrate, fat, fluid, vitamin, and mineral gram of creatinine excreted.6 This measure represents
needs. REE in relation to lean body mass.6 However, another
Protein metabolism is altered in patients with end- study corrected REE for urinary creatinine excretion in
stage liver disease (ESLD). Protein catabolism and hyper- 40 alcoholic cirrhotic patients and did not find that an
ammonemia are enhanced, and synthesis of serum increase in metabolic rate was dependent on the severity
proteins, including albumin, secretory proteins, and clot- of the cirrhosis, nutritional status, or existence of alco-
ting factors, is decreased. Deamination and transamina- holic hepatitis.7
tion of amino acids, which normally takes place in the Liver failure alters energy metabolism as well. Liver
liver, can be affected. Derangement of plasma amino acid glucose transport is reduced, and peripheral glucose
concentrations also occurs.3 Concentrations of plasma metabolism decreases.8 The rate of gluconeogenesis is
aromatic amino acids (AAAs; phenylalanine, tyrosine, increased, and the body prefers noncarbohydrate fuels

494
 37 Nutritional Aspects of Transplantation in Adults 495

result from liver disease. Because vitamin E is transported

TABLE 37-1 R
 ole of the Liver in Nutrient
in lipoproteins, the hyperlipidemias associated with cho-
Metabolism
lestatic liver disease may affect vitamin E status. Vitamin
Protein
B6, vitamin B12, thiamine, folate, and niacin levels are
Synthesis of serum proteins such as albumin
often depleted as a result of alcoholism. Some vitamins,
Synthesis of blood-clotting factors
including folic acid, thiamine, pyridoxine, and vitamin D,
Formation of urea from ammonia
undergo conversion to their active form in the liver; this
Deamination/transamination of amino acids
process can be impaired when the liver is diseased. Min-
Formation of creatine
erals excreted via the biliary system, such as manganese
Oxidation of the amino acids arginine, histidine, lysine,
and copper, can be affected by an interruption in entero-
methionine, alanine, tryptophan, and tyrosine hepatic circulation.10 Magnesium, phosphorus, and zinc
stores are commonly depleted in liver disease secondary
Carbohydrate
to malnutrition, malabsorption, alcoholism, and diuretic
Glycogenesis
use. Finally, mineral bioavailability, tissue distribution,
Gluconeogenesis
and toxicity can be affected by decreased liver production
Glycogenolysis
of their protein carriers.10
Fat
Hydrolysis of triglycerides, cholesterol, and phospholipids
to fatty acids and glycerol
NUTRITIONAL ASSESSMENT
Fat storage
Cholesterol synthesis
Debility, malnutrition, obesity, encephalopathy, and
Ketogenesis
massive ascites are considered risk factors for increased
Formation of lipoproteins
morbidity before and after liver transplantation. All of
Production of bile necessary for digestion of dietary fat
these factors are nutrition related and can be treated with
Vitamins nutrition therapy. Therefore it is vital that a registered
Site of enzymatic steps in the activation of vitamins dietitian conduct a thorough nutritional assessment of all
Thiamine (thiamine pyrophosphate) liver transplant candidates to identify patients at nutri-
Pyridoxine (pyridoxal phosphate) tional risk and implement appropriate nutrition therapy.
Folic acid (tetrahydrofolic acid) Determining nutritional status in a patient with ESLD
Vitamin D (25-hydroxycholecalciferol) can be difficult because common objective nutritional
Site of synthesis of carrier proteins for vitamins such as A assessment parameters are affected by liver disease (Table
and B12 37-2). Anthropometric measurements such as arm muscle
Vitamin E is transported in lipoproteins synthesized by the circumference and handgrip strength can serve as objec-
liver
tive markers of body cell mass depletion in patients with
Storage site for vitamins A, D, E, K, B12
ESLD.11,12 As an alternative nutritional assessment tool,
Minerals the Subjective Global Assessment (SGA) method should
Storage site for copper, iron, zinc be considered.12-16 SGA nutritional ratings are based on a
thorough patient history, patient examination, and exist-
ing conditions (Table 37-3). SGA has been found to be a
such as lipids and amino acids to provide energy.2,3 valid and reliable tool to assess nutritional status.13-16 The
Plasma free fatty acids, glycerol, and ketone concentra- SGA method has shortcomings, however; there can be
tions increase in cirrhosis, and the body favors fat as a fuel interrater differences if raters are not trained similarly to
substrate.3 Gluconeogenic capacity is retained in the identify physical signs of malnutrition. In addition, it is
early stages of liver failure, but elevated blood glucose not a sensitive test to determine small improvements or
levels can develop chronically. In patients with cirrhosis, declines in nutritional status.
decreased first-pass hepatic uptake of glucose and reduced
insulin-mediated glucose uptake in peripheral tissues
increase glucose levels after an oral load.9 In addition, MALNUTRITION IN TRANSPLANT
hyperglycemia occurs as a result of the reduced insulin CANDIDATES
action.2,9 Circulating insulin levels may be increased, but
insulin sensitivity is reduced.9 In the late stages of liver Prevalence
disease, liver glycogen stores can become depleted, and
gluconeogenic capacity deteriorates. The result is fasting Figure 37-1 illustrates a malnourished patient awaiting
hypoglycemia. liver transplantation. The prevalence of malnutrition
Vitamin and mineral alterations also occur as a result among liver transplant candidates depends on the nutri-
of liver disease. Fat malabsorption is common in patients tional assessment criteria, the type of liver disease, and
with cholestatic liver disease and leads to loss of energy the severity of liver disease. For example, in a study by
and fat-soluble vitamins. Deficiencies in fat-soluble vita- Ferreira et al16 malnutrition prevalence in a group of 159
mins can also occur as a result of other mechanisms. Low liver transplant patients ranged from 6% to 80% depend-
vitamin A levels may occur because of the inability of the ing on the parameter used to define malnutrition. Malnu-
liver to synthesize retinol-binding protein. Decreased trition has been reported to occur in 53% to 74% of
biliary excretion of 1,25-dihydroxycholecalciferol can candidates based on SGA.12,13,16
496 PART IV Special Considerations in Patient Evaluation

TABLE 37-2 F
 actors That Affect the TABLE 37-3 S
 ubjective Global Assessment
Interpretation of Traditional Parameters for Nutritional
Objective Nutritional Assessment Evaluation of Liver Transplant
Tests in Patients with End-Stage Candidates
Liver Disease
History
Parameter Factors Affecting Interpretation Weight change (consider fluctuations secondary to ascites
and edema)
Body weight Affected by edema, ascites, and
diuretic use Appetite
Anthropometric Questionable sensitivity, specificity, Taste changes and early satiety
measurements and reliability Dietary recall (calories, protein, sodium)
Multiple sources of error Persistent gastrointestinal problems (nausea, vomiting,
Unknown whether skinfold measure- diarrhea, constipation, difficulty chewing or swallowing)
ments reflect total body fat Physical Examination
References do not account for variation Muscle wasting
in hydration status and skin
compressibility Fat stores
Nitrogen balance Nitrogen is retained in the body in the Ascites or edema
studies form of ammonia Existing Conditions
Hepatorenal syndrome can affect the Disease state and other problems that could influence
excretion of nitrogen nutritional status such as hepatic encephalopathy,
Visceral protein Synthesis of visceral proteins is gastrointestinal bleeding, renal insufficiency, infection
levels decreased
Nutrition Rating (Based on Results of Above Param-
Affected by hydration status, inflam- eters)
mation, malabsorption, and renal
insufficiency Well nourished
Immune function Affected by hepatic failure, electrolyte Moderately (or suspected of being) malnourished
tests imbalances, infection, and renal Severely malnourished
insufficiency
Bioelectrical Invalid with ascites and/or edema Data from references 13-15.
impedance

The prevalence of malnutrition also depends on the type

of liver disease and the severity of the liver disease.16-18
DiCecco et al17 showed that patients with alcoholic liver dis-
ease had depletion of both fat and muscle stores, patients
with primary sclerosing cholangitis lost a greater proportion
of muscle versus fat tissue, patients with primary biliary cir-
rhosis had significant losses of both lean and fat tissue, and
patients with acute hepatitis lost a greater proportion of lean
versus fat tissue. A more recent study18 also found that low
body mass index (BMI, <18.5 kg/m2) was more prevalent in
patients with cholestatic or metabolic liver disease compared
with BMI in patients with other diseases.
Disease severity also seems to be directly correlated
with degree of malnutrition. Increased Child-Turcotte-
Pugh (CTP) scores (B or C) tend to be associated with
worsened nutritional status.16,19 However, Model for
End-Stage Liver Disease (MELD) scores do not appear
to be correlated with degree of malnutrition.16
The cause of malnutrition in ESLD is multifactorial.
Nutritional depletion can result from a poor diet (in both
quantity and quality), anorexia, nausea, vomiting, meta-
bolic aberrations, hypermetabolism, malabsorption, and
psychological stress. In addition, the diet restrictions used
to control ESLD symptoms can limit food choices and
optimal nutrient intake.
FIGURE 37-1 n Severe malnutrition and ascites in a man with
Effect of Malnutrition on Outcomes end-stage liver disease. (From Hasse JM, Matarese LE. Medical
nutrition therapy for liver, biliary system, and exocrine pancreas dis-
Malnutrition is associated with increased rates of infec- orders. In Mahan LK, Escott-Stump S, eds. Krause’s Food, Nutrition,
tion,20 increased use of blood products,21 prolonged and Diet Therapy. 11th ed. Philadelphia: WB Saunders; 2004: 749.)
 37 Nutritional Aspects of Transplantation in Adults 497

length of hospital and intensive care unit (ICU) stay,12,22,23 before or during transplantation,39,40 but there have been
and reduced posttransplant survival.20,22,24,25 Low BMI no studies to evaluate if pretransplant weight loss
(<20 kg/m2) has also been associated with reduced sur- improves transplant outcomes.
vival on the transplant waiting list.26
PRETRANSPLANT NUTRITIONAL
OBESITY IN TRANSPLANT CANDIDATES MANAGEMENT
As the rate of obesity has increased in the general popula- Potential benefits of providing nutritional support to a
tion, so has it increased in the transplant population. patient include enhanced immunological defense,
Morbid obesity is often considered a relative contraindi- improved wound healing, and replacement of energy
cation for liver transplantation. Not only does morbid stores. It has been theorized that if nutritional support is
obesity present a technical challenge to transplantation provided early enough, it may help maintain quality of
surgeons, there are also concerns regarding postoperative life before transplantation, decrease perioperative mor-
complications such as infections and pulmonary prob- tality, and shorten recovery time after transplantation.41
lems or overall reduced survival. Because obesity may be While transplant candidates wait to receive a transplant,
associated with adverse transplant outcomes, many trans- malnutrition often worsens and thus warrants nutritional
plant centers have set weight limits for transplant candi- intervention. The goal of pretransplant nutrition ther-
dacy. Limits are often based on BMI, with upper limits of apy is to treat nutrition-related symptoms, prevent fur-
35 or 40 kg/m2 being considered relative or absolute con- ther depletion, and possibly replenish lost stores. A
traindications for transplantation. summary of pretransplantation nutritional needs is
Despite the concern that obesity may affect post- shown in Table 37-4.
transplant outcomes, not all studies are convincing that Oral dietary supplementation is the first intervention
obese patients (when selected carefully) will not do as that should be attempted to replenish energy stores. In a
well as nonobese patients in the postoperative period. controlled trial of oral supplementation in 51 alcoholic
Prevalence of postoperative wound infections tend to cirrhosis patients, 26 received enhanced calorie and pro-
be increased in obese versus nonobese patients.27-31 tein supplements and had shortened hospitalization
One study showed that when compared with nonobese (especially secondary to infections).42 Nutritional param-
patients, obese transplant patients had prolonged hospi- eters also improved significantly in the supplemented
talizations, increased hospital costs, and increased rates group in comparison to the 25 controls.42
of respiratory failure,30 whereas others have not.32-34 LeCornu et al43 provided oral supplements to 42 mal-
Two single-center studies demonstrated adverse mor- nourished liver transplant candidates and compared out-
tality associated with obesity18,35; but several other comes with 40 control patients not drinking supplements.
studies did not.27-31,34,36 An analysis of multicenter data Both groups improved their caloric intake, probably
from the United Network for Organ Sharing (UNOS) because of the influence of nutritional intervention and
database found reduced survival at 1, 2, and 5 years after counseling. The supplemented group had improved
transplantation in morbidly obese subjects.37 Cardio- midarm circumference, midarm muscle circumference,
vascular events accounted for reduced 5-year survival and grip strength, but outcomes were not changed, most
rates in severely and morbidly obese patients.37 In likely because there was not a difference in overall nutri-
another study evaluating obesity in liver transplant ent intake between the two groups.
patients based on the National Institute of Diabetes and In another study, malnourished pre–liver transplant
Digestive and Kidney Diseases (NIDDK) liver trans- patients with a history of encephalopathy were random-
plant database, BMI when corrected for ascites did not ized to receive either diet plus a BCAA-enriched supple-
affect mortality, graft survival, or hospital and ICU ment (n = 19), diet plus a casein-based supplement
length of stay, or other outcomes such as treated infec- (n = 21), or diet alone (n = 10).44 Each supplement was
tions and rejections.38 Despite concerns that severe dosed to provide 0.5 g protein/kg/day. Patients receiving
obesity may increase morbidity and mortality risks after supplements had significantly higher caloric intake than
transplantation, transplantation has been found to con- the control group did. Patients receiving the BCAA sup-
fer a survival benefit in these patients compared with plement had reduced frequency and length of hospitaliza-
waiting on the transplant list.26 Nevertheless, this does tions before liver transplantation.
not mean that all obese candidates are acceptable for If patients are not able to eat adequate nutrients,
transplantation. Most of the patients in these studies enteral tube feeding (TF) is the most desirable alterna-
were carefully selected; obese patients with several tive. Two studies compared a group of patients with liver
comorbidities or deconditioning are likely not be candi- disease who were receiving TF and matched groups
dates for transplantation. receiving oral diets.45,46 Thirty-one patients with alco-
Some transplant centers that have specific weight cri- holic liver disease were randomized to receive either a
teria for transplant candidacy require patients to lose regular diet alone or a diet supplemented with casein-
weight before transplantation if the patients do not meet based TF.45 The TF group had greater mean nutrient
the weight guidelines. Traditional caloric restriction and intake, an improvement in hepatic encephalopathy scores,
increased activity can be difficult to achieve when patients reduced serum bilirubin levels, and a shorter antipyrine
are deconditioned and fatigued from ESLD. There are half-life in comparison to the control group. In a similar
case studies of patients undergoing bariatric surgery study 35 cirrhotic patients were randomized to receive
498 PART IV Special Considerations in Patient Evaluation

either a low-sodium diet or TF.46 The TF group had sig-

TABLE 37-4 N
 utrition Recommendations for a
nificantly higher calorie intake, an improvement in CTP
Liver Transplant Candidate
score, and a decreased mortality rate when compared
Nutrient Recommendations with controls.
Another study47 compared effects of enteral nutri-
Calories 25-35 kcal/kg dry weight for maintenance;
35-40 kcal/kg dry weight for malnour-
tion versus corticosteroids in 71 patients with alcoholic
ished patient hepatitis and cirrhosis; treatment was administered for
120%-150% of predicted BEE (calculated 28 days, and patients were followed for 1 year. One
with the Harris-Benedict equation) group of patients was fed 2000 kcal/day of enteral nutri-
depending on nutritional status and tion via a feeding tube. The other group of patients was
current metabolic demands encouraged to eat 2000 kcal/day, but this was supple-
Protein 0.8-1.2 g/kg dry weight in compensated mented with 40 mg/day of oral prednisone. Eight
liver disease
patients dropped out of the enteral arm because of com-
1.5-2.0 g/kg dry weight in decompensated
liver disease or when patient is severely plications or repeated voluntary removal of the tube.
malnourished Mortality during treatment was no different between
There is controversy surrounding use of the groups; however, mortality occurred earlier in the
BCAA-enhanced formulas. These formulas enteral versus corticosteroid group (median 7 versus
have not consistently been shown to 23 days, P = .025). Mortality during the 1-year follow-
improve hepatic encephalopathy;
however, these formulas have been shown
up period was higher in the corticosteroid group versus
in some studies to help lessen muscle loss the enteral group, mainly because of increased infec-
Fat 25%-40% of calories tions. Because these trials did not involve transplant
Consider MCT oil when steatorrhea is patients, controlled trials are necessary to evaluate the
present effect of TF on outcomes in patients with ESLD who
Carbohydrate High complex carbohydrate; provide a undergo liver transplantation.
nighttime snack to prevent Obtaining access for a feeding tube can be problematic
hypoglycemia in patients with liver disease. A large-bore nasogastric
Carbohydrate should be controlled if feeding tube is not a feasible long-term option. A gastros-
glucose intolerance is present
tomy tube is contraindicated in patients with ascites.
Hypoglycemia can occur because of a loss of
hepatic gluconeogenesis and lack of Therefore a small-bore, nasointestinal tube is typically
glycogen; this is often seen in acute liver the best option.
failure; glucose infusion may be necessary Parenteral nutrition (PN) remains an option only in
Sodium 2 g/day for ascites or edema patients with absent gut function or significant malab-
Fluid 1000-1500 mL/day if hyponatremia is sorption. PN is costly and results in a higher incidence of
present infection and electrolyte imbalance than TF does. PN
Vitamins Monitor levels and signs of deficiency; can also potentially worsen liver function. The European
supplement to RDI
Society for Clinical Nutrition and Metabolism (ESPEN)
Give water-miscible forms of fat-soluble
vitamins if steatorrhea is present and
guidelines on parenteral nutrition for liver cirrhosis sug-
levels are low gest that patients with cirrhosis should receive early post-
Supplement thiamine especially in patients operative PN only if patients cannot tolerate adequate
with alcoholic cirrhosis oral/enteral nutrition.48
Minerals Monitor levels and signs of deficiency; Other recommendations made by ESPEN, although
supplement to RDI rated only a grade C, are to provide PN to patients who
Serum potassium, magnesium, and are moderately to severely malnourished and unable to
phosphorus levels may decrease as a eat or receive adequate enteral nutrition, or those who
result of diuretic administration or
refeeding syndrome; serum potassium have hepatic encephalopathy and unprotected airways.48
and phosphorus levels may increase in Supplementation (either enterally or parenterally)
face of renal insufficiency; some with formulas enriched with BCAAs and depleted in
diuretics are potassium sparing, whereas AAAs has been proposed to improve nutritional status
others are potassium wasting
without inducing or worsening hepatic encephalopathy.
Zinc deficiency can be caused by diuretic
use, as well as reduced intake; zinc
Some studies have supported this theory, whereas others
supplementation may help dysgeusia; have failed to show the same benefit.49-54 The use of these
zinc is often supplemented because of an formulas remains controversial.
association between zinc and hepatic
encephalopathy
Manganese excretion can be reduced
because of limited biliary excretion; SHORT-TERM POSTTRANSPLANT
manganese toxicity can manifest as NUTRITIONAL MANAGEMENT
neurotoxicity
1200 mg calcium/day; supplement at-risk
populations
Nutrient Requirements
The primary nutritional goal in the immediate posttrans-
BCAA, Branched-chain amino acid; BEE, basal energy expenditure;
MCT, medium-chain triglyceride; RDI, recommended daily intake.
plant period (generally the first 2 to 3 posttransplant
months) is to provide adequate nutrition to promote
 37 Nutritional Aspects of Transplantation in Adults 499

recovery and replenish lost nutritional stores. A post-

TABLE 37-5 N
 utritional Side Effects of
transplant catabolic state is induced by preoperative mal-
Immunosuppressive Medications
nutrition, stress of the transplant surgery, corticosteroid
administration, and in some cases renal or hepatic dys- Immunosuppressive Potential Nutritional Side
function (or both), and sepsis. Protein catabolism Medication Effect
increases markedly immediately after liver transplanta- Antithymocyte globulin, Decreased appetite
tion and necessitates a protein intake of 1.3 to 2.0 g/kg antilymphocyte
dry weight.55-59 Nitrogen loss is increased after surgery globulin
because of surgical stress and the administration of corti- Basiliximab None reported
costeroids. As much as 3.6 kg skeletal muscle mass may be Corticosteroids Hyperglycemia
lost in the first 10 days after liver transplantation.60 The- Sodium retention
oretically patients treated with corticosteroid-free immu- Osteoporosis
Hyperphagia
nosuppression regimens would lose less nitrogen than Impaired wound healing and
would those receiving traditional high-dose corticoste- increased infection risk
roid regimens. Hypertension
Serum AAA levels normalize after successful trans- Cyclosporine Hyperkalemia
plantation.61 However, Tietge et al61 demonstrated that Hypomagnesemia
Hypertension
BCAA levels remain depressed more than 6 months after Hyperglycemia
transplantation. A correlation between elevated BCAA Hyperlipidemia
levels and circulating catecholamines led the authors to Sirolimus Hyperlipidemia
conclude that insulin hypersecretion and elevations in Gastrointestinal disorders
adrenergic tone contribute to persistent BCAA metabo- (constipation, diarrhea,
lism in muscle.61 nausea/vomiting, dyspepsia)
Unlike the dramatic rise in protein catabolism, the Tacrolimus Hyperkalemia
Hyperglycemia
metabolic rate does not seem to be elevated to the same Nausea, vomiting
degree. Delafosse et al57 measured REE in eight patients Mycophenolate mofetil, Diarrhea, nausea, vomiting
on the first 2 days after transplantation. Mean REE was mycophenolic acid
only 36% to 38% above the predicted basal energy
expenditure (BEE; Harris Benedict equation). In another
study of 11 post–liver transplant patients, REE was only
7% higher than the predicted BEE, but the patient’s
actual weight was used in the BEE calculation instead of
Nutritional Support
dry weight (which increases BEE).6 REE measured in Three modalities are available to provide nutrition to
28 liver transplant patients on days 1, 3, 5, 14, and 28 patients after transplantation—oral diet, enteral TF, and
after transplantation was less than 120% of the predicted PN. A liquid diet is initiated 1 to 3 days after transplanta-
BEE.55 Mean REE in 31 liver transplant recipients mea- tion, with progression to a general diet. When hypergly-
sured on posttransplant days 2, 5, 7, and 12 was 127% of cemia persists, a carbohydrate-controlled diet is
BEE.56 Finally, REE peaked at 42% above predicted recommended. Most transplant recipients initially suffer
(with the use of a site-specific prediction equation) in from anorexia, altered taste, and early satiety. These symp-
14 liver transplant patients on day 10 after transplanta- toms hamper patients’ ability to eat, and oral nutritional
tion (2149 ± 68 kcal or 26.7 kcal/kg).60 supplements are often indicated.
A mixed-fuel system of both carbohydrate and fat is Enteral TF is the alternative method of choice to pro-
suggested to provide energy in the postoperative period. vide nutrition after transplantation. Although gastric and
Posttransplant hyperglycemia frequently occurs as a colonic ileus are common in the first few days after
result of corticosteroid administration, physiological transplantation, enteral nutrition can be administered
stress, and recovering liver function. Data regarding the successfully via a feeding tube that is inserted during sur-
most appropriate type of fatty acids for transplant patients gery.56,62-67 Figure 37-2 illustrates a decision tree for ini-
are lacking. tiation of TF after liver transplantation. TF can be started
Electrolyte alterations are common in the short-term within several hours after transplantation by infusing a
posttransplant period. Sodium is lost via urine, nasogas- moderate-osmolality formula at a low rate. Once the
tric aspiration, and abdominal drains. Serum potassium, patient begins to eat, the TF can be transitioned to noc-
phosphorus, and magnesium levels may be depleted rap- turnal feeding to enhance the patient’s appetite and allow
idly in liver transplant recipients secondary to diuretic for increased ambulation during the day. The TF infu-
use and refeeding syndrome. Calcineurin inhibitors can sion can be discontinued completely once calorie count
also accelerate magnesium loss. In contrast, cyclosporine, results confirm the adequacy of a patient’s oral intake.
tacrolimus, and renal insufficiency can lead to hyperkale- An early study by Wicks et al63 compared enteral
mia and other electrolyte disturbances. Table 37-5 nutrition via a nasojejunal tube (n = 14) with PN (n = 10)
reviews additional nutritional side effects of immunosup- in patients after liver transplantation. Intestinal permea-
pressive medications. Finally, although not specifically bility, infection rates, and anthropometric measurements
defined in liver transplant patients, vitamin and mineral did not differ between groups, nor did the number of days
stores must be replenished, especially in malnourished to reach 70% of requirements with oral intake (4 days for
patients. TF versus 5 days for PN).
500 PART IV Special Considerations in Patient Evaluation

Patient
undergoes
transplantation

Patient able to
eat adequately
within 2 to 3 days
after transplantation

No Yes

Is gut
functional?

Yes No

Immediate Wait until Begin TPN

posttransplantation oral diet is
tube feeding begun

When oral diet Adequate oral Inadequate oral Gut function Gut function
is begun intake intake returns does not return

Inadequate oral Adequate oral Offer oral Continue TPN

intake intake supplements

Continue Discontinue Intake

tube feeding tube feeding remains
inadequate

Initiate tube
feeding
FIGURE 37-2 n Nutritional support algorithm for organ transplant recipients. TPN, Total parenteral nutrition. (From Hasse JM, Roberts S:
Transplantation. In: Rombeau JL, Rolandelli RH, eds. Clinical Nutrition: Parenteral Nutrition. 3rd ed. Philadelphia: WB Saunders; 2001: 533.)

Another early retrospective review evaluated 108 patients during surgery) within 12 hours after liver transplanta-
fed via a jejunal tube after liver transplantation and showed tion (TF group) or maintenance intravenous fluid until
that TF was tolerated.65 However, complications with this oral diets were initiated (control group). Feeding was well
type of tube may be unacceptable for short-term TF tolerated in the TF group (n = 14). The TF group had
(mechanical obstruction of tubes in six, reoperation for significantly greater 12-day cumulative calorie and pro-
infection in six, small bowel obstruction in two, catheter tein intake than the control group did. The TF patients
displacement in two, and requirement for surgical removal also had better nitrogen balance on posttransplant day 4
of the tube in one).66 and quicker recovery in grip strength than the control
A prospective, randomized study was performed to patients did. Viral infections occurred in 17.7% of the
determine the effects of early posttransplant TF on control patients versus 0 of the TF patients (P = .05). In
­outcomes of liver transplant recipients.56 Liver transplant addition, there was a trend for other infections to occur
patients were prospectively randomized to receive either more frequently in the control group than in the TF
an enteral formula via nasointestinal feeding tubes (placed group (bacterial, 29.4% versus 14.3%; overall infections,
 37 Nutritional Aspects of Transplantation in Adults 501

47.1% versus 21.4%; not significant). This study con- elemental diet was given to 36 patients. All patients
cluded that early TF after liver transplantation was received a product supplemented with glutamine, dietary
well tolerated and promoted improvement in patient fiber, and oligosaccharide as well as a probiotic drink con-
outcomes. taining Lactobacillus casei Shirota strain. Bacteremia
A similar feeding protocol was implemented by Ikeg- occurred in only 15% of the patients receiving the whey
ami and associates.62 Nasointestinal feeding tubes were formula versus 47% in patients receiving the elemental
placed in liver transplant recipients and TF begun 12 to formula. In-hospital mortality and rejection rates were
24 hours after surgery. The authors performed a retro- not different between the groups.
spective analysis of bacterial sepsis in 346 adult trans- With the shortened hospital stay and frequent occur-
plant recipients of living donors. A multivariate analysis rence of transplantation in severely compromised
identified lack of enteral feeding within 48 hours of sur- patients, the use of home TF after discharge is becoming
gery and blood loss of greater than 10 L to be significant more frequent. Additional outpatient monitoring of the
risk factors for bacterial sepsis. Patients with bacterial TF access device, gastrointestinal symptoms, laboratory
sepsis had only a 45.7% 2-year survival rate compared values (especially electrolytes), and oral intake is required
with a 2-year survival rate of 88.7% in noninfected to determine tolerance and continued need for TF. Insur-
patients and 79.8% in patients with only local infection. ance coverage for home TF can sometimes be difficult to
Upon further analysis, for patients who received early obtain if TF is not the only source of nutrition and will be
TF (within 48 hours), bacterial sepsis occurred in 5.9% needed for less than 3 months.
of patients versus 21% of patients who received TF after TF is favored over PN, but PN is indicated when a
48 hours. In addition, graft loss was eightfold higher in malnourished patient’s gut cannot be used for a mini-
patients who had more than 10 L blood loss and did not mum of 5 to 7 days. One study evaluated the effect of PN
receive early TF (P < .001). after transplantation surgery.70 Twenty-eight patients
Rayes et al64 compared different types of TF formula were randomly assigned to one of three groups: (1) no
plus addition of a probiotic in liver transplant patients. nutritional support, (2) PN (35 kcal/kg/day) with a stan-
Group 1 underwent small bowel decontamination and dard amino acid solution (1.5 g/kg/day), or (3) total PN
was fed a standard formula, group 2 received a fiber-con- (35 kcal/kg/day) with a BCAA-enriched amino acid solu-
taining formula plus Lactobacillus plantarum 299, and tion (1.5 g/kg/day). PN was administered for 1 week.
group 3 received a fiber-containing formula plus heat- The PN groups had improved nitrogen balance and a
killed L. plantarum 299. The addition of a probiotic significantly shorter length of stay in the ICU than the
(L. plantarum 299) resulted in reduced infection rates. group that received no nutrition. The BCAA-enriched
The study design provided patients with TF for 12 days, solution was not found to be superior to the standard
which is unlikely in a scenario in which patients can meet amino acid group. These data are difficult to apply in
needs with an oral diet and are discharged from the hos- today’s practice, when TF is available and ICU and hos-
pital in less than a week. It does raise an interesting con- pital stays can be very brief. However, when PN is
cept of using oral probiotics after transplantation. administered, a concentrated solution containing a
The same group of researchers then evaluated the mixed-fuel system is generally required. Electrolyte lev-
effect of TF, fiber, and a synbiotic on liver transplant out- els should be monitored carefully and adjusted in the PN
comes.67 Thirty-three liver transplant patients received accordingly (Table 37-6).
postoperative TF via a nasointestinal tube and a synbiotic
containing four lactobacillus organisms and four fibers. A Postoperative Complications and
control group of 33 patients received TF and fiber only.
There were no differences between the groups with
Nutritional Support
respect to hospital and ICU length of stay, operating Potential postoperative complications include rejection,
time, blood transfusion, or diarrhea. However, the synbi- infection, renal insufficiency, intestinal complications
otic group had a 3% infection rate compared with a 48% (ileus, diarrhea, ulcers), abdominal bleeding, biliary compli-
rate in the control group. cations, vascular complications, pancreatitis, and metabolic
Two studies have evaluated immunomodulating for- complications. The onset of any of these complications or
mulas after ransplant.68,69 Plank et al68 compared outcomes their treatment may necessitate a change in the nutrition
from 15 patients who received perioperative nutritional care plan for an individual.
support with an immunomodulating formula with those of Treatment of rejection with additional corticosteroids
17 historical controls who received standard perioperative results in heightened protein catabolism and hyperglyce-
nutrition. Infectious complications occurred in 33% of the mia. Treatment with antithymocyte globulin may cause
group who received the immunomodulating formula and anorexia, nausea, vomiting, and diarrhea. Adequate nutri-
71% of the control patients, but the difference was not tion is required to prevent infection, and treatment of an
­statistically different (P = .074) in this nonrandomized, ret- infection with antibiotics can decrease appetite and cause
rospective study. gastrointestinal upset. Renal insufficiency may require
In a later study the effect of a formula containing limitation of potassium, phosphorus, sodium, or fluid.
hydrolyzed whey protein was retrospectively compared Complications requiring surgical treatment or bowel rest,
with effects of an elemental TF given via a surgical jeju- or both, indicate a need for nutritional support. An altera-
nostomy.69 Tube feeding was begun in the first 24 hours tion in bile excretion can affect fat and fat-soluble vitamin
after surgery via jejunostomy. A formula containing absorption. Finally, metabolic complications may require
hydrolyzed whey peptide was given to 40 patients, and an alterations in nutritional substrates or electrolytes.
502 PART IV Special Considerations in Patient Evaluation

Monitoring of nutrition in immediate posttransplant

TABLE 37-6 C
 onsiderations for a Posttransplant
patients should include measurement of weight, labora-
Parenteral Nutrition Regimen
tory values, and nutrient intake. For patients receiving
Amino acids Use standard amino acid solutions nutritional support, REE and nitrogen balance studies
May use a 15% initial concentration of amino may be useful.
acids when volume must be restricted
Dextrose Provide 50%-70% of nonprotein calories as
glucose LONG-TERM POSTTRANSPLANT
Decrease final glucose concentration or NUTRITIONAL MANAGEMENT
provide insulin when serum glucose
> 150 mg/dL
Liver transplantation usually results in correction of
May use a D70W initial concentration when
volume must be restricted malnutrition (Fig. 37-3). The goal of long-term post-
Lipid Provide about 30% of nonprotein calories as transplant nutrition is improvement in nutritional status
lipid and avoidance of long-term nutrition-related complica-
May want to limit lipid if patient is septic or tions. Many liver transplant recipients suffer from prob-
may need additional lipid if glucose lems of “overnutrition” as early as a few months after
control difficult transplantation. Common long-term posttransplant
Electrolytes Monitor and supplement as needed nutritional problems include excessive weight gain,
Potassium, magnesium, and phosphorus hypertension, hyperlipidemia, diabetes mellitus (DM),
can become depleted rapidly
and osteoporosis. Many of these comorbid conditions
Vitamins Administer daily recommended dose of
multivitamin supplement
contribute to the risk for cardiovascular and fatty liver
Provide vitamin K weekly unless provided in
disease and can adversely affect a patient’s medical con-
the multivitamin supplement dition and quality of life.
Can supplement with individual vitamins as

Trace
needed
Administer daily recommended dose of a
Obesity
elements standard trace element supplement Liver transplant patients may lose weight before trans-
Can supplement with individual trace plantation, but it is usually regained after transplantation.
elements as needed However, posttransplant weight gain does not always
Medications Depending on compatibility, may be able to reflect a gain in total body mass; instead, it often reflects
administer medication in PN (e.g., H2
blockers) sarcopenia—a gain of fat tissue with low muscle mass.71
In addition, much of the weight gain tends to be abdomi-
D70W, 70% dextrose in water; PN, parenteral nutrition. nal.72 In one study of 143 liver transplant recipients who

A B
FIGURE 37-3 n Correction of malnutrition in a patient who underwent liver transplantation. A, Male patient awaiting liver transplanta-
tion. B, Same patient 1 year after liver transplantation.
 37 Nutritional Aspects of Transplantation in Adults 503

were a median of 4 years posttransplant, 88% had some recipients who underwent bariatric surgery before, after,
degree of abdominal obesity.72 and even concurrently with transplantation.80-86 This
The cause of posttransplant obesity is multifactorial. procedure is an extreme measure that should be evaluated
Obesity before the onset of liver disease predicts post- cautiously.
transplant obesity. Some patients have a good appetite
after transplant recovery and may develop an attitude of
“I can eat anything I want.” This mindset can be coupled
Hyperlipidemia
with the false hunger created by the corticosteroids. Hyperlipidemia has been reported in liver transplant survi-
Patients who experienced pretransplant malabsorption vors.87-90 The prevalence depends on the immunosuppres-
are no longer excreting valuable nutrients. Many patients sion regimen, the definition of hyperlipidemia, and the
are forced to adopt a sedentary lifestyle during their ill- time since transplantation. Factors contributing to post-
ness as a result of uncontrolled fatigue and weakness. transplant hyperlipidemia include weight gain, corticoste-
After transplantation they increase their dietary intake but roids, cyclosporine, sirolimus, proteinuria and kidney
continue a sedentary lifestyle. Finally, once these patients insufficiency, DM and insulin resistance, and antihyper-
recover, they often resume old eating habits, which may tensive medications (thiazides and β-blockers).91,92 The
have been the cause of these same problems before the possible causative mechanisms of hyperlipidemia by corti-
onset of their liver disease. Other factors that may influ- costeroids, cyclosporine, and sirolimus are reviewed in
ence weight gain after transplant include the type of liver Table 37-7.91,93 Conversion from cyclosporine to tacroli-
disease, posttransplant complications, and sex. mus has been shown to reduce hyperlipidemia.76,94 When
Patients maintained on a cyclosporine-based immuno- hyperlipidemia is refractory to dietary alterations and
suppression regimen tend to have a greater prevalence of changes in immunosuppression cannot be made (i.e.,
obesity than do patients receiving a tacrolimus-based regi- reduce or discontinue corticosteroids or sirolimus),
men.73,74 The body mass index 1 year after liver transplan- 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)
tation in the U.S. FK506 trial was lower in the tacrolimus
group (25.5 kg/m2) than in the cyclosporine group (27.7
kg/m2); 18.2% of cyclosporine patients were more than TABLE 37-7 E
 ffects of Immunosuppressive
140% of their ideal body weight versus 10.9% in the tacro- Medications on Serum Lipid
limus group.74 One would theorize that the total dose of Levels91,93
corticosteroids contributes to this effect.74 When cortico-
Corticosteroid's • Stimulates hepatic lipoprotein
steroid therapy was discontinued in 51 liver transplant effects on production
recipients, weight loss occurred in 88% of the patients.75 cholesterol • Stimulates adipocyte hormone-­
The mean weight loss was 9.5 lb (4.3 kg). In another small sensitive lipase, resulting in release of
study of 26 patients, when immunosuppression was stored triglycerides as free fatty acids,
which are used for further hepatic
switched from cyclosporine to tacrolimus, there was a mean lipoprotein synthesis
weight loss of 3.3 kg over a 1-month period.76 Many newer • Causes insulin-potentiating activity,
immunosuppressive regimens use lower or no doses of cor- which may increase activity of
ticosteroids. Theoretically the risk for excessive weight gain lipoprotein lipase and interfere with
would be decreased. In addition, use of sirolimus as part of LDL-cholesterol receptor function
• Enhances hepatic secretion of VLDL
an immunosuppression regimen seems to reduce posttrans- cholesterol and conversion to LDL
plant gain.77 In a study by McKenna and colleagues,77 cholesterol
patients receiving sirolimus (n = 777) versus those who Corticosteroid's • Increases peripheral free fatty acid
never received sirolimus (n = 777) had significantly lower effects on production
body weight at 2 and 5 years posttransplant despite having triglycerides • Increases hepatic lipoprotein synthesis
similar baseline weights. Cyclosporine's • CyA is transported in blood in
effects on association with lipoproteins; an
However, overall obesity rates continue to rise in the cholesterol abnormal interaction between LDL
United States, and this trend is probably reflected in receptors and their ligands may occur
transplant patients as well. Traditional therapy for post- because of the presence of CyA
transplant obesity includes caloric restriction and exer- • May inhibit bile acid production,
cise. No prospective study to date has evaluated the which may decrease excretion of free
cholesterol
effectiveness of dietary interventions on posttransplant • Binds to LDL receptors and increases
weight. Even though exercise performance (as defined by circulation levels of LDL
maximum oxygen consumption [Vo2max]) improves after Sirolimus’s • Alters insulin signaling pathway,
liver transplantation,78 it remains impaired.78,79 effects on which reduces lipoprotein lipase and
Other more aggressive therapy available for weight triglycerides increases adipose tissue lipase; this
increases hepatic synthesis of
management includes pharmacological and surgical triglycerides and VLDL secretion
interventions. Orlistat is contraindicated in patients tak-
ing cyclosporine because the medication would reduce Data from Perez R. Managing nutrition problems in transplant
absorption of cyclosporine. Other weight loss drugs have patients. Nutr Clin Pract. 1993;8:28-32; and Morrisett JD,
recently been made available but have not been evaluated Abdel-Fattah G, Hoogeveen R, et al. Effects of sirolimus on
plasma lipids, lipoprotein levels, and fatty acid metabolism in
in the transplant population. Bariatric surgery is reserved renal transplant patients. J Lipid Res. 2002;43:1170-1180.
for individuals with morbid obesity. Case reports demon- CyA, Cyclosporine A; LDL, low-density lipoprotein; VLDL, very-low-
strated weight loss in morbidly obese liver transplant density lipoprotein.
504 PART IV Special Considerations in Patient Evaluation

reductase inhibitors have been used to treat hyperlipidemia recipients, a recommended sodium intake after trans-
(Table 37-8).95 HMG CoA reductase inhibitors may affect plantation is 2 g/day.
calcineurin inhibitor levels through interaction with the
cytochrome P-450 system. Ezetimibe also has been used
successfully in liver transplant recipients to lower serum
Diabetes Mellitus
total cholesterol and low-density lipoprotein (LDL)-cho- There are conflicting data regarding the effect of preex-
lesterol levels, but liver function should be monitored isting DM on transplant outcomes. One small study did
closely.92 not demonstrate an association with pretransplant DM
and rates of infection, rejection, or hypertension.100
Another study showed that preexisting DM was linked
Hypertension with increased cardiovascular, infectious, renal, respira-
Calcineurin inhibitors cause sodium retention and tory, neurological, hematological, musculoskeletal, and
increase systemic vascular resistance by means of arterial malignancy complications after liver transplantation.101
vasoconstriction.96 Hypertension is a frequent finding in Several studies have shown that there is reduced post-
posttransplant patients and occurs more frequently in transplant survival in patients with preexisting DM,101-
patients treated with cyclosporine than in those treated 104 but another group did not find that pretransplant

with tacrolimus* and in those patients who receive corti- DM affected survival.105 With regard to new-onset
costeroids versus no corticosteroids.98 One study in a posttransplant diabetes, some studies showed increased
group of 77 liver transplant patients with acute liver fail- morbidity106 and increased mortality105,107 in patients
ure (no long-standing liver disease), 71% had hyperten- in whom posttransplant DM developed. Finally, in a
sion requiring treatment after transplantation compared study of patients with hepatitis B, DM in patients did
with 12% before transplant, suggesting a role of post- not influence their posttransplant survival or complica-
transplant factors such as immunosuppressive drugs in tions unless blood glucose level was not well
the development of hypertension.99 Although no clinical controlled.108
trials have substantiated the effectiveness of a sodium- The rate of posttransplant DM is difficult to ascertain
restricted diet in controlling hypertension in transplant because the definition of DM has varied in published
reports. However, a study of 20,172 liver transplant
recipients in the Organ Procurement and Transplant
*References 73, 76, 89, 90, 97. Network (OPTN)/UNOS database transplanted between

TABLE 37-8 P
 otential Adverse Effects of Lipid-Lowering Agents and Drug Interactions
in Transplant Recipients
Class of Lipid-
Lowering Agent Examples Possible Adverse Effects Comments
Bile acid resin Cholestyramine May prevent absorption of fat-soluble May inhibit absorption of cyclosporine and
vitamins; poor compliance because of absorption of other fat-soluble drugs;
constipation and bloating space dose by 2 hr with interacting drug;
may increase triglyceride concentrations
Nicotinic acid Nicotinic acid, Flushing, pruritus, increase in liver Concomitant cyclosporine and prednisone
extended- enzyme levels, increased uric acid use may exacerbate adverse effects
release concentrations, altered glucose
formulations tolerance, and exacerbation of peptic
ulcer disease
Fibric acid Gemfibrozil Gallstones, myositis (especially in Increased risk for myositis with concomitant
derivative patients with decreased renal func- HMG-CoA reductase inhibitors and
tion), nausea, gastrointestinal upset immunosuppressive drugs
Antioxidant Probucol Flatulence, loose stools, prolonged QT May interact with cyclosporine and cause
interval on electrocardiogram, fluctuation in cyclosporine concentrations
decreased HDL
HMG-CoA Statin drugs Abdominal pain, flatulence, increase in May increase liver function enzyme levels;
reductase transaminase concentration, myositis, increased risk for myositis with high-dose
inhibitor sleep disturbances HMG-CoA reductase inhibitors and fibric
acid derivatives with cyclosporine
Ezetimibe Zetia Headache; dizziness; diarrhea; sore Inhibits dietary and biliary cholesterol
throat; runny nose; sneezing; joint absorption; does not affect fat-soluble
pain; risk for myositis and rhabdomy- vitamins; can be used in combination with
olysis, especially when given with statin drugs but must monitor liver
statin drugs or in the presence of other function tests; has little cytochrome
risk factors such as advanced age, P-450–mediated metabolism; need to
hypothyroidism, or renal impairment monitor cyclosporine levels if drugs are
being coadministered

Modified from Kobashigawa JA, Kasiske BL. Hyperlipidemia in solid organ transplantation. Transplantation. 1997;63(3):331-338.
HDL, High-density lipoprotein; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A.
 37 Nutritional Aspects of Transplantation in Adults 505

2004 and 2008 showed a 26.4% rate of new-onset diabe- insufficiency may help improve long-term survival.
tes mellitus after transplantation (NODAT).109 Factors A long-term study from a single center looking at 1000
that predicted NODAT included the following: age 50 consecutive liver transplants also identified cardiopul-
years or older, African American race, BMI of 25 kg/m2 monary events in addition to recurrence of liver disease
or higher, hepatitis C diagnosis, history of cirrhosis, and malignancy as main causes of death more than 1
donor age 60 years or older, diabetic donor, use of tacro- year from transplantation.130
limus versus cyclosporine, and use of corticosteroids at Hyperhomocysteinemia is another risk factor for car-
discharge. Decreased risk for NODAT was associated diovascular disease that may be present in liver transplant
with living donor transplantation and use of induction patients as a result of cyclosporine therapy89 and renal
therapy.109 Another study from a single center found sim- dysfunction.131 Hyperhomocysteinemia responds to folic
ilar results with presence of hepatitis C and pretransplant acid supplementation.131
fasting serum glucose level predicting NODAT and liv-
ing donor transplantation being protective of develop-
ment of NODAT.110 Obesity, advanced age, a family
Osteoporosis
history of DM, pretransplant glycemia, and ethnicity Chronic liver disease and liver transplantation are associ-
(Hispanic, African American, Native American) are ated with bone disease; bone mineral density is low before
strong risk factors for the development of NODAT. liver transplantation and may decrease after transplanta-
Cyclosporine, tacrolimus, and corticosteroids are poten- tion.132 Bone loss is greatest in the first 6 months post-
tial diabetogenic agents. Hepatitis C virus is also associ- transplant with the greatest incidence of fracture
ated with increased rates of DM both before and after occurring in the first 6 to 12 months posttransplant.133
transplantation.103,111-117 Vertebral and rib fractures are the most common post-
Calcineurin inhibitors decrease insulin secretion, transplant fractures.133
increase insulin resistance, and alter beta cell function.118 Risk factors for posttransplant bone loss include the
Some studies suggest that tacrolimus may be more diabe- cause of the liver disease (especially cholestasis and alco-
togenic than cyclosporine.74,113,115,119-122 Corticosteroids hol abuse), immunosuppressive medications, vitamin D
also cause insulin resistance.118 Other potential effects of deficiency, hypogonadism, impaired absorption or inad-
corticosteroids on glucose metabolism include decreased equate intake of calcium, reduced physical activity, mal-
insulin receptors and affinity, impaired peripheral glu- nutrition, DM, advanced age, smoking, postmenopausal
cose uptake in muscle, deactivation of glucose/free fatty status, and preexisting bone disease.
acid, and faulty suppression of endogenous insulin pro- Careful monitoring of bone mineral loss and treat-
duction.118 Prevalence of posttransplant DM is higher in ment is warranted for liver transplant patients. Calcium
patients treated with corticosteroids than those who do and vitamin D intake should be considered, as well as
not receive corticosteroids.98,123 Serum glucose and gly- other osteoporosis risk factors such as decreased estro-
cosylated hemoglobin levels have been reported to gen levels in women, lack of exercise, and smoking.
decrease in liver transplant patients in whom corticoste- Treatment with bisphosphonates would seem logical,
roid use was discontinued.124-126 although this effect has not been seen in all studies.134-140
However, a recent meta-analysis concluded that
bisphosphonates or vitamin D analogues can reduce
Metabolic Syndrome posttransplant fractures.141
Obesity, hyperlipidemia, hypertension, and diabetes
mellitus are risk factors for metabolic syndrome and
coronary artery disease. There is also concern for
Long-Term Nutritional Goals
patients with posttransplant metabolic syndrome devel- Long-term nutritional guidelines focus on preventive
oping fatty liver disease. Metabolic syndrome was iden- measures. Moderate intake of fat, sugar, and salt should
tified in 5.4% of 252 patients before liver transplant and be accompanied by exercise. Table 37-9 summarizes
51.9% of patients after transplant.127 Metabolic syn- posttransplant dietary goals. It must be emphasized that
drome was also associated with a higher cumulative rate most transplant recipients require ongoing nutritional
of cardiovascular morbidity.127 Other single-center counseling to incorporate healthy eating practices and a
studies have also reported increased cardiovascular risk regular exercise program into their lives. Compliance is
among liver transplant patients.73,89,97,128 At least two variable, and it is difficult for the transplant team because
studies suggest that cardiovascular risk in liver trans- it is the patient’s decision to either follow or disregard the
plant patients is higher than that in the general popula- nutrition and exercise guidelines prescribed to the patient.
tion,127,128 whereas another suggests that 5 years after Patients with a history of obesity are at greatest risk for
transplantation the risk is similar to that in the general gaining excess weight, but these long-term complications
population.89 An evaluation of data from the NIDDK can develop in all patients and affect their physical and
liver transplant database looked at causes of late death psychological quality of life.
following transplantation.129 Cardiovascular disease was
one cause, along with graft failure, malignancy, and
renal failure. Those patients who had the lowest rate of FUTURE
survival were those with older age, DM, and renal insuf-
ficiency, again suggesting that management of meta- Liver transplantation is a relatively new field of medi-
bolic symptoms such as DM, hypertension, and renal cine, and transplant nutrition is in its infancy. There
506 PART IV Special Considerations in Patient Evaluation

TABLE 37-9 Posttransplant Nutritional Guidelines

Nutrient Short-Term Recommendations Long-Term Recommendations
Calories 120%-140% of BEE (30-35 kcal/kg) or measure REE Maintenance: 120%-130% BEE (20-30 kcal/kg)
depending on activity level
Protein 1.3-2 g/kg/day 1 g/kg/day
Carbohydrate ≈50% of calories ≈50% of calories
Restrict simple sugars if glucose level elevated Restrict simple sugars and encourage high-fiber
complex carbohydrate choices
Fat 30% of calories (or higher with severe ≤30% of total calories
hyperglycemia) <10% of calories as saturated fat
Calcium 1200 mg/day 1200-1500 mg/day (consider the need for estrogen or
vitamin D supplements)
Sodium 2 g/day 2 g/day
Magnesium and Encourage intake of foods high in these nutrients Encourage intake of foods high in these nutrients
phosphorus Supplement as needed Supplement as needed
Potassium Supplement or restrict based on serum potassium Supplement or restrict based on serum potassium
levels levels
Other vitamins Multivitamin/mineral: supplement to RDI levels Multivitamin/mineral: supplement to RDI levels
and minerals May need additional supplements to replete May need additional supplements to replete
suspected or confirmed deficiencies suspected or confirmed deficiencies
Other Avoid complementary or alternative products Avoid complementary or alternative products
without proven safety and effectiveness in without proven safety and effectiveness in
transplant patients transplant patients

BEE, Basal energy expenditure; RDI, recommended daily intake; REE, resting energy expenditure.

are many applications of nutrition in other fields that Pearls and Pitfalls
may one day prove to be helpful in transplantation. For
example, could nutrients such as arginine or n-3 fatty Nutritional intervention is required throughout all stages of
acids affect rejection or infection after liver transplan- liver transplantation to achieve optimal short- and long-term
tation? Because grapefruit interferes with drug metab- outcomes. To practice the best medical nutrition therapy,
follow the following points:
olism, are there other foods that may exert harmful
effects? What role will complementary medicine have Do
in transplantation? Some herbal products are known to • Involve a registered dietitian in all phases of the treatment
be harmful in transplant recipients142; for that reason, of patients.
despite the surge in interest and production of herbal • Assess and reassess nutritional status throughout the con-
products, they should be avoided until their safety in tinuum of transplantation.
liver transplant patients is determined. Will probiotics • Individualize nutritional recommendations for calories,
be found to have benefit in transplant patients? Probi- protein, fat, carbohydrates, vitamins, minerals, fluids, and
otics have been reported to reduce antibiotic-associ- electrolytes based on nutritional status, current nutrient
ated diarrhea, recurrent Clostridium difficile infection, intake, goals for medical and nutrition therapy, current
conditions, and medications.
and symptoms of inflammatory bowel disease. At lease
• Be aware of drug-nutrient interactions.
two studies showed benefit of probiotic supplementa- • Initiate nutritional interventions early (e.g., postoperative
tion in liver transplant patients,64,67 but the full spec- tube feeding).
trum of safety and the benefits of probiotics are not yet • Achieve tight glucose control.
known. • Consider changing the immunosuppression regimen if
metabolic problems ensue (e.g., hypertension, hyperlip-
idemia, diabetes).
SUMMARY • Monitor bone density, and consider prophylactic treat-
ment in patients at high risk for osteoporosis.
Nutrition is a central issue throughout the transplant Don’t
process. Malnutrition is common in the pretransplant
• Use a “one-size-fits-all” nutrition prescription.
period, and the nutritional goal is to prevent further • Initiate protein restriction in pretransplant patients.
depletion. A catabolic state exists in the immediate post- • Give directives (such as “lose weight”) without providing
transplant period, so nutrition is administered to replen- specific action steps and follow-up.
ish stores. The long-term posttransplant period may be • Hesitate to provide tube feeding if patients are not able to eat.
the most difficult because patients suffer from chronic • Ignore comorbid conditions (such as diabetes, obesity,
“overnutrition” problems; therefore long-term nutri- hyperlipidemia, or hypertension) that can be treated in
tional guidelines emphasize prevention or minimization part with nutritional interventions.
of these problems.
 37 Nutritional Aspects of Transplantation in Adults 507

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102. Yoo HY, Thuluvath PJ. The effect of insulin-dependent diabetes orthotopic liver transplant recipients. Transplant Proc.
mellitus on outcome of liver transplantation. Transplantation. 1996;28:2247-2249.
2002;74:1007-1012. 126. De Carlis L, Belli LS, Rondinara GF, et al. Early steroid with-
103. Oufroukhi L, Kamar N, Muscari F, et al. Predictive factors for drawal in liver transplant patients: final report of a prospective
posttransplant diabetes mellitus within one-year of liver trans- randomized trial. Transplant Proc. 1997;29:539-542.
plantation. Transplantation. 2008;85:1436-1442. 127. Laish I, Braun M, Mor E, et al. Metabolic syndrome in liver trans-
104. Samuelson AL, Lee M, Kamal A, et al. Diabetes mellitus increases plant recipients: prevalence, risk factors, and association with car-
the risk of mortality following liver transplantation independent diovascular events. Liver Transpl. 2011;17:15-22.
of MELD score. Dig Dis Sci. 2010;55:2089-2094. 128. Johnston SD, Morris JK, Cramb R, et al. Cardiovascular morbid-
105. Steinmuller TH, Stockmann M, Bechstein WO, et al. Liver ity and mortality after orthotopic liver transplantation. Transplan-
transplantation and diabetes mellitus. Exp Clin Endocrinol Diabetes. tation. 2002;73:901-906.
2000;108:401-405. 129. Watt KDS, Pedersen RA, Kremers WK, et al. Evolution of causes
106. John PR, Thuluvath PJ. Outcome of patients with new-onset and risk factors for mortality post-liver transplant: results of the
diabetes mellitus after liver transplantation compared with those NIDDK long-term follow-up study. Am J Transplant.
without diabetes mellitus. Liver Transpl. 2002;8:708-713. 2010;10:1420-1427.
107. Moon JI, Barbeito R, Faradji RN, et al. Negative impact of new- 130. Jain A, Singhal A, Fontes P, et al. One thousand consecutive pri-
onset diabetes mellitus on patient and graft survival after liver mary liver transplants under tacrolimus immunosuppression: a
transplantation: long-term follow up. Transplantation. 2006;82: 17- to 20-year longitudinal follow-up. Transplantation. 2011;91:
1625-1682. 1025-1030.
108. Ling Q, Xu X, Wei Q, et al. Impact of preexisting diabetes mel- 131. Herrero JI, Quiroga J, Sangro B, et al. Hyperhomocysteinemia in
litus on outcome after liver transplantation in patients with hepa- liver transplant recipients: Prevalence and multivariate analysis of
titis B virus-related liver disease. Dig Dis Sci. 2011;56:889-893. predisposing factors. Liver Transpl. 2000;6:614-618.
109. Kue H-T, Sampaio MS, Ye X, et al. Risk factors for new-onset dia- 132. Chauhan V, Ranganna KM, Chauhan N, et al. Bone disease in
betes mellitus in adult liver transplant recipients, an analysis of the organ transplant patients: pathogenesis and management. Post-
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Organ Sharing database. Transplantation. 2010;89:1134-1140. 133. Kulak CA, Borba VZ, Kulak Jr J, et al. Osteoporosis after trans-
110. Carey EJ, Aqel BA, Byrne TJ, et al. Pretransplant fasting glucose plantation. Curr Osteoporos Rep. 2012;10:48-55.
predicts new-onset diabetes after liver transplantation. J Trans- 134. Dodidou P, Bruckner T, Hosch S, et al. Better late than never?
plant. 2012. Experience with intravenous pamidronate treatment in patients
111. Bigam DL, Pennington JJ, Carpentier A, et al. Hepatitis-C with low bone mass or fractures following cardiac or liver trans-
related cirrhosis: a predictor of diabetes after liver transplantation. plantation. Osteoporos Int. 2003;14:82-89.
Hepatology. 2000;32:87-90. 135. Pennisi P, Trombetti A, Giostra E, et al. Pamidronate and osteo-
112. Baid S, Cosimi AB, Farrell ML, et al. Posttransplant diabetes mel- porosis prevention in liver transplant recipients. Rheumatol Int.
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mortality. Transplantation. 2001;72:1066-1072. bone mineral density and bone metabolic markers in patients with
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Influence of immunosuppression and effect of hepatitis C virus on 137. Crawford BA, Kam C, Pavlovic J, et al. Zoledronic acid prevents
new onset of diabetes mellitus in liver transplant recipients. bone loss after liver transplantation: a randomized, double-blind,
Transplant Proc. 2008;40:2994-2996. placebo-controlled trial. Ann Intern Med. 2006;144:239-248.
114. Delgado-Borrego A, Liu Y-S, Jordan SH, et al. Prospective study 138. Millonig G, Graziadei IW, Eichler D, et al. Alendronate in com-
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115. Saliba F, Lakehal M, Pageaux G-P, et al. Risk factors for new- 139. Guadalix S, Martínez-Díaz-Guerra G, Lora D, et al. Effect of
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 CHAPTER 38

Management of Portal
Hypertensive Hemorrhage
Jayme E. Locke • Andrew M. Cameron • Ronald W. Busuttil

CHAPTER OUTLINE

MANAGEMENT STRATEGIES Transjugular Intrahepatic Portosystemic

Resuscitation and Medical Management Shunt
Endoscopic Diagnosis and Directed Therapy Surgical Shunts

PORTOSYSTEMIC SHUNTS SUMMARY

Portal hypertension is most commonly a manifestation of

underlying liver parenchymal disease and worsens with
Resuscitation and Medical Management
increasing severity of cirrhosis. It is responsible for com- When severe, acute variceal hemorrhage can be associated
plications, such as the development of varices and variceal with hemorrhagic shock. Therefore resuscitation should be
hemorrhage, among chronic liver disease patients and prompt and aggressive, including airway protection, large-
often portends the need for liver transplantation. Fifty bore intravenous access, and crystalloid and colloid product
percent of patients with cirrhosis have gastroesophageal infusion, with a goal of maintaining hemodynamic stability.
varices, and approximately one third of these patients will Although resuscitation of the acutely bleeding patient is of
go on to develop variceal hemorrhage.1-3 The continuum primary importance, if possible the central venous pressure
of gastroesophageal varices to variceal hemorrhage is lin- should be kept less than 10 mm Hg with a target hemoglo-
early correlated with hepatic function and mortality.4-7 bin level of 7 to 8 ng/dL.12,17 In addition, octreotide and
Although advances in the management of acute variceal Protonix drips should be initiated. Octreotide is a synthetic
bleeding over the last decade have resulted in a reduction analogue of somatostatin and serves as a splanchnic vaso-
in overall mortality, acute variceal hemorrhage continues constrictor through inhibition of glucagon and other vaso-
to have high morbidity and mortality.8-15 In fact mortality dilatory peptides. Protonix suppresses gastric acid secretion
from variceal bleeding ranges from 5% to 68% among through inhibition of the parietal cell hydrogen-potassium
Child-Turcotte-Pugh class A and C cirrhotic patients, adenosine triphosphate (ATP) pump. Interestingly, bacte-
respectively.2 This correlation highlights the need for an rial infection has been associated with variceal bleeding and
algorithmic approach to caring for patients with cirrhosis is an independent risk factor for failure to control bleed-
with advanced portal hypertension and variceal bleeding. ing,18 early rebleeding, and death.19,20 Intravenous ceftriax-
one or oral norfloxacin should be administered in the
setting of an acute variceal hemorrhage.17,21-24
MANAGEMENT STRATEGIES
Endoscopic Diagnosis and Directed
The presence of portal hypertensive varices is not reliably
correlated with bleeding. More than 50% of patients with
Therapy
varices will not experience bleeding, and therefore varices Esophagogastroduodenoscopy (EGD; upper endoscopy)
are generally medically managed. Avoidance of hepatotox- is the primary modality used for diagnosis and initial treat-
ins and the use of β-blockers are the mainstays of therapy. ment of variceal hemorrhage. EGD should be performed
β-blockers reduce portal hypertension by constriction of on an urgent basis, because a delay more than 15 hours
splanchnic vasculature. Endoscopic therapies, such as after presentation is associated with increased mortality.25
injection sclerotherapy and banding, have been associated Through a combination of injection sclerotherapy and
with a reduction in bleeding but have not been shown to variceal band ligation, bleeding is controlled in more than
improve mortality.16 Acute variceal hemorrhage, however, 90% of patients. EGD-directed sclerotherapy is associ-
requires an algorithmic approach that involves emergent ated with esophageal ulceration, and therefore patients
resuscitation, optimization of medical management, endo- should be watched closely and repeat EGD should be per-
scopic diagnosis, and directed therapy (Fig. 38-1). formed within a week of the initial variceal hemorrhage.

510
 38 Management of Portal Hypertensive Hemorrhage 511

Bleeding splenorenal shunt, provide selective decompression of

varices the portal-azygous system while preserving portal inflow
into the liver. These shunts are often limited by technical
difficulty and gradual development of pancreatic collaterals.
Nonselective shunts, such as portacaval, mesocaval, and
Resuscitation TIPS, reduce portal pressure without preservation of
Medical measures portal inflow into the liver. As a result, these shunts are
often associated with encephalopathy and worsening liver
function. Multiple studies have compared selective and
nonselective shunts and demonstrated that rates of survival
EGD and recurrent bleeding are similar but the incidence of
Sclerotherapy banding postoperative encephalopathy is lower with selective
shunts.27-34 Independent of type, the goal of intervention
is to reduce the portal pressure, because hepatic venous
Bleeding Bleeding not pressure gradients greater than 20 mm Hg are associated
controlled controlled with increased rates of rebleeding and mortality.35-37

Repeat EGD Balloon tamponade Transjugular Intrahepatic Portosystemic

Shunt
Recurrent TIPS is performed percutaneously by guiding a needle
bleeding from the right or middle hepatic vein into a portal vein
CTP class C branch. A guidewire is subsequently passed into the main
Assess TIPS portal vein, the tract is balloon dilated, and then following
Bleeding
portography, an expandable stent is inserted. Major com-
stops
CTP class A or B plications following TIPS include shunt stenosis (33% to
66%), hepatic encephalopathy (15% to 30%), technical
Surgical shunt
failure (5% to 10%), portal or splenic vein thrombosis
(<5%), worsening liver function (<5%), and chronic
hemodialysis (<5%).2 TIPS has rapidly become the first-
Stable Decompensation line therapy for the treatment of portal hypertension after
endoscopic control of variceal hemorrhage. However,
studies have demonstrated that surgical shunts are often
Observe OLT
more durable and cost-effective options in patients with
FIGURE 38-1 n Algorithm for management of acutely bleeding Child-Turcotte-Pugh class A and B cirrhosis,16,38 suggest-
esophageal varices. CTP, Child-Turcotte-Pugh; EGD, esophago- ing that TIPS should be reserved as primary therapy for
gastroduodenoscopy; OLT, orthotopic liver transplantation; patients with advanced liver disease awaiting imminent
TIPS, transjugular intrahepatic portosystemic shunt.
liver transplantation.39-42 Liver transplantation after TIPS
is safe and effective, because TIPS has not been associated
Failure of endoscopic therapy is most common in patients with longer operative time, increased blood loss, or early
with Child-Turcotte-Pugh class C cirrhosis. Therapeutic mortality.43
options for ongoing variceal hemorrhage despite optimal
endoscopic therapy include placement of a Sengstaken- Surgical Shunts
Blakemore tube (esophageal balloon tamponade), tran-
sjugular intrahepatic portosystemic shunt (TIPS), surgical Surgical shunts are not typically performed for acute
shunt, and/or liver transplantation. Surgical shunts are con- variceal bleeding but rather are reserved for chronic or
traindicated in patients with Child-Turcotte-Pugh class C recurrent variceal hemorrhage44-48 or as a salvage procedure
cirrhosis, and the choice of shunt is determined by portal after failed TIPS.49 There are selective and nonselective
anatomy and the likelihood of liver transplantation. Liver surgical shunts, including splenorenal (selective),50 por-
transplantation is rarely used as a therapeutic option in the tocaval,51,52 mesocaval,53 and the Rex procedure.54,55 In
setting of an acute variceal bleed and can realistically be general, mesocaval shunts, also known as H-grafts, serve
offered to only those patients stable enough to undergo as a surgical shunt bridge to liver transplantation. These
the procedure. Recently, covered metal stents have been shunts are relatively easy to construct, avoid dissection in
used as an alternative to esophageal balloon tamponade the porta hepatis, and can be ligated at the time of liver
for the control of acute variceal hemorrhage in the setting transplantation.53
of an endoscopic treatment failure.26

SUMMARY
PORTOSYSTEMIC SHUNTS
Acute variceal hemorrhage is a known complication of
Portosystemic shunts are typically categorized as either portal hypertension and is associated with high morbidity
selective or nonselective. Selective shunts, such as the and mortality. Initial management centers around
512 PART IV Special Considerations in Patient Evaluation

aggressive volume resuscitation, antibiotic prophylaxis, 11. D’Amico G, De Franchis R. Upper digestive bleeding in cirrhosis.
and endoscopic directed therapy. Patients who fail endo- Post-therapeutic outcome and prognostic indicators. Hepatology.
Sep 2003;38(3):599-612.
scopic therapy may require the temporary placement of 12. de Franchis R. Evolving consensus in portal hypertension. Report
an esophageal balloon tamponade or covered metal stent of the Baveno IV consensus workshop on methodology of diagnosis
until TIPS or surgical shunt can be performed. Once the and therapy in portal hypertension. J Hepatol. Jul 2005;43(1):
acute bleeding has been controlled, patients should be 167-176.
13. El-Serag HB, Everhart JE. Improved survival after variceal hem-
evaluated for placement of a portosystemic shunt with orrhage over an 11-year period in the Department of Veterans
the goal of maintaining a hepatic venous pressure less Affairs. Am J Gastroenterol. Dec 2000;95(12):3566-3573.
than 10 mm Hg. 14. McCormick PA, O’Keefe C. Improving prognosis following a first
variceal haemorrhage over four decades. Gut. Nov 2001;49(5):
682-685.
Pearls and Pitfalls 15. Thomopoulos K, Theocharis G, Mimidis K, et al. Improved sur-
vival of patients presenting with acute variceal bleeding. Prognostic
• Over the last decade, advances in the management of indicators of short- and long-term mortality. Dig Liver Dis. Dec
2006;38(12):899-904.
acute variceal bleeding have resulted in a reduction in 16. Rikkers LF. The changing spectrum of treatment for variceal
the overall mortality associated with acute bleeding. bleeding. Ann Surg. Oct 1998;228(4):536-546.
• Mortality from acute variceal bleeding is correlated 17. de Franchis R. Revising consensus in portal hypertension: report
with the underlying degree of liver dysfunction. of the Baveno V consensus workshop on methodology of diag-
• Resuscitation with blood products should be undertak- nosis and therapy in portal hypertension. J Hepatol.
en promptly with a goal of maintaining hemodynamic Oct;53(4):762-768.
stability and a target hemoglobin level of 7 to 8 ng/dL. 18. Goulis J, Armonis A, Patch D, et al. Bacterial infection is indepen-
• Antibiotic prophylaxis should be administered to dently associated with failure to control bleeding in cirrhotic
all cirrhotic patients presenting with acute variceal patients with gastrointestinal hemorrhage. Hepatology. May
1998;27(5):1207-1212.
bleeding. 19. Bernard B, Cadranel JF, Valla D, et al. Prognostic significance of
• Portal venous pressure gradients greater than 20 mm bacterial infection in bleeding cirrhotic patients: a prospective
Hg are associated with increased rates of rebleeding study. Gastroenterology. Jun 1995;108(6):1828-1834.
and mortality. 20. Garden OJ, Motyl H, Gilmour WH, et al. Prediction of out-
• Nonsurgical management strategies, including endo- come following acute variceal haemorrhage. Br J Surg. Feb
scopic and pharmacological therapies, are the first line 1985;72(2):91-95.
of treatment in acute variceal hemorrhage. 21. Allison MC, Sandoe JA, Tighe R, et al. Antibiotic prophylaxis in
• Covered metal stents may be an alternative to gastrointestinal endoscopy. Gut. Jun 2009;58(6):869-880.
Sengstaken-Blakemore balloon in temporary control 22. Banerjee S, Shen B, Baron TH, et al. Antibiotic prophylaxis for GI
endoscopy. Gastrointest Endosc. May 2008;67(6):791-798.
of bleeding after treatment failures. 23. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and man-
• Selective shunts are indicated only in well-compensated agement of gastroesophageal varices and variceal hemorrhage in
cirrhosis. cirrhosis. Hepatology. Sep 2007;46(3):922-938.
• Transjugular intrahepatic portosystemic shunt is indi- 24. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and man-
cated for patients in imminent need of liver transplan- agement of gastroesophageal varices and variceal hemorrhage in
   tation. cirrhosis. Am J Gastroenterol. Sep 2007;102(9):2086-2102.
25. Hsu YC, Chung CS, Wang HP. Application of endoscopy in
improving survival of cirrhotic patients with acute variceal hemor-
rhage. Int J Hepatol. 2011:893973.
26. Escorsell A, Bosch J. Self-expandable metal stents in the treat-
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 CHAPTER 39

Portopulmonary Hypertension
and Hepatopulmonary Syndrome
Randolph H. Steadman • Michael A.E. Ramsay

CHAPTER OUTLINE

THE PULMONARY VASCULAR ENDOTHELIUM Endothelial Dysfunction

HEPATOPULMONARY SYNDROME Pathological Changes
Clinical Features and Prevalence Screening Pretransplant, Including
Characterization of Pulmonary
Pathophysiology Hemodynamics and Right Ventricular
Screening Pretransplant Function
Perioperative Management Through Surgery, Pharmacotherapy
Including Liver Transplantation Risk Management
Risk Management, Postoperative Care, and Perioperative Management Through Liver
Outcomes Transplantation, Including Acute Elevations
PORTOPULMONARY HYPERTENSION in Portopulmonary Hypertension and Right
Overview Ventricular Dysfunction
Clinical Features and Incidence Postoperative Care, Including Long-Term
Pharmacotherapy
Pathophysiology

Pulmonary disease is common in patients with end-stage vessel lumen and the vascular wall. The integrity of the
liver disease, and as many as 50% to 70% of patients with endothelium is vital for vasoregulation, antithrombosis,
end-stage liver disease complain of shortness of breath.1 laminar blood flow, selective permeability to hematopoi-
The differential diagnosis includes obstructive airway dis- etic cells and nutrients, and the regulation of growth of
ease, infection, fluid retention with hydrothorax, and the surrounding smooth muscle tissue. The intact vascu-
decreased lung capacities secondary to ascites.2 Other con- lar endothelium produces nitric oxide (NO), which is
ditions such as α1-antitrypsin deficiency and cystic fibrosis vital for the regulation of vasomotor tone, vascular per-
can affect both the lung and liver. This chapter focuses on meability, and protection from inflammatory mediators
the pulmonary vascular complications of liver disease. and provides a powerful antioxidant capacity.4 In patients
There are two clinical and pathophysiological pulmonary with portal hypertension, exposure to inflammatory cyto-
abnormalities usually associated with portal hypertension, kines and stress forces caused by high cardiac output ren-
and often liver cirrhosis. These are hepatopulmonary syn- der the pulmonary vascular endothelium dysfunctional.
drome (HPS) and portopulmonary hypertension (POPH). As a result, several responses may occur. Vasodilatation,
These syndromes appear to be paradoxical responses by with the formation of aneurysms and shunts, results in
the pulmonary vascular endothelium to the adverse effects HPS. Vasoconstriction, with proliferation of smooth
of portal hypertension often associated with liver disease. muscle and microthrombosis, causes an increase in pul-
Both entities can have a significant effect on survival and monary vascular resistance (PVR) and POPH (Fig. 39-1).
liver transplantation (LT) candidacy. It is likely that these These two pathological changes may be seen in the same
entities are underdiagnosed and undertreated worldwide.3 lung, but one entity usually predominates.5
This chapter will describe the different presentations,
pathophysiology, distinct treatment, and unique responses
of these conditions to LT. HEPATOPULMONARY SYNDROME
THE PULMONARY VASCULAR Clinical Features and Prevalence
ENDOTHELIUM The relationship between the lung and liver was first
noted in 1884 when Flückiger described a female patient
The pulmonary vascular endothelium is a dynamic organ with cyanosis, clubbing, and cirrhosis.6 In 1935 Snell
that provides the interface between the blood in the reported a series of three patients with “hypoxemia of

514
 39 Portopulmonary Hypertension and Hepatopulmonary Syndrome 515

Liver Liver injury

Portal hypertension

Endothelin-1
shear stress
bacterial translocation/TNF-
other
?Inflammation
ETB Macrophage ?Vasoactive
receptors iNOS HO-1 mediators
VEGF ?Genetic factors
eNOS Endothelial cell

NO CO
NO Smooth muscle cell

Vasodilatation Lung Vasoconstriction

angiogenesis remodeling

HPS POPH
FIGURE 39-1 n Pathophysiology of hepatopulmonary syndrome (microvascular dilatation and angiogenesis) and portopulmonary
hypertension (vasoconstriction and remodeling in resistance vessels). CO, Carbon monoxide; eNOS, endothelial nitric oxide syn-
thase; ETB, endothelin B; HO-1, heme oxygenase-1; HPS, hepatopulmonary syndrome; iNOS, inducible nitric oxide synthetase;
NO, nitric oxide; POPH, portopulmonary hypertension; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor.
(From Kochar R, Nevah Rubin MI, Fallon MB. Pulmonary complications of cirrhosis. Curr Gastroenterol Rep. 2011;13[1]:34-39.)

cirrhosis.”7 The term hepatopulmonary syndrome was first

used in 1977 by Kennedy and Knudson, who accurately TABLE 39-1 D
 iagnostic Criteria for
suggested that intrapulmonary vascular dilatations were Hepatopulmonary Syndrome
responsible for the hypoxemia.8 These early reports Portal hypertension
described the association of hypoxemia with cirrhosis. Arterial hypoxemia
However, the significant prevalence and the prognostic Intrapulmonary vascular dilatations
importance of HPS are only now being appreciated. The Positive contrast-enhanced echocardiography
remarkable therapeutic impact of LT has led to intense
interest in the role of transplantation in the management From Rodríguez-Roisin R, Krowka M, Hervé P, Fallon M. Highlights
of HPS. of the ERS Task Force on pulmonary-hepatic vascular disorders
(PHD). J Hepatol. 2005;42(6):924-927.
HPS is defined as the triad of liver disease and increased
alveolar-arterial (A-a) oxygen gradient in the presence of
intrapulmonary vascular dilatations (IPVDs).9 The Euro- occur commonly in HPS but are not specific, because they
pean Respiratory Society HPS diagnostic criteria are are seen in patients with cirrhosis without HPS. Clubbing
similar except for the addition of positive contrast- and cyanosis should raise suspicion for HPS2 (Fig. 39-2).
enhanced echocardiography10 (Table 39-1). Early defini- HPS is the most common pulmonary vascular abnor-
tions emphasized the need to exclude other causes of A-a mality, with 15% to 20% of patients undergoing evalua-
gradient; however, now it is recognized that HPS can tion for liver transplantation.17 The prevalence of HPS
coexist with other conditions that cause hypoxemia.1 Age depends on the predictive cutoff used to define the condi-
correction of the normal A-a gradient criteria to less than tion. In a study of 33 HPS patients diagnosed by contrast-
20 mm Hg in patients over 64 years of age, instead of less enhanced echocardiography, a Pao2 of less than 70 mm Hg
than 15 mm Hg in younger adults, will avoid overdiagno- had a higher positive predictive value for HPS than an A-a
sis of HPS.1,3,11 gradient of more than 15 mm Hg (positive predictive value
Thus the hallmark of HPS is impairment in oxygen- of 93% and 34%, respectively).18 HPS appears to be as
ation, with or without dyspnea. Orthodeoxia, a decrease in prevalent in pediatric patients as adults, although less data
the partial pressure of arterial oxygen (Pao2) of 5% or are available.19
more or 4 mm Hg or more upon standing, is a unique The natural history of HPS patients is progressive
feature of HPS.12,13 This is caused by preferential perfu- worsening over time, with a Pao2 decline of approxi-
sion of the lung bases in a standing patient.14,15 Platypnea, mately 5 mm Hg per year.20 Improvement in the absence
shortness of breath worsened by sitting, results from the of LT is rare but has been reported.21 As recently as 2010,
same mechanism.14 Orthodeoxia can occur in other set- severe hypoxemia was considered a contraindication to
tings, such as after pneumonectomy, pulmonary thrombo- LT.20,22
emboli, and patent foramen ovale, but it is highly specific However, over time an increasing number of reports
for HPS in the presence of liver disease.16 Spider angiomas described a reversal of hypoxemia after successful LT.23-27
516 PART IV Special Considerations in Patient Evaluation

levels of exhaled NO in HPS patients, which normalize

after LT in parallel with resolution of HPS.41-44 Further
support for this mechanism is reports of transient
improvement in HPS by inhibitors of NO production
such as N-nitro-L-arginine methyl ester (L-NAME) or
methylene blue, which inhibits cyclic guanosine mono-
phosphate (cGMP).45-47 However, other mechanisms
may be responsible, because inhaled L-NAME adminis-
tration does not consistently improve HPS.48 The coexis-
tence of HPS and POPH may be explained by differential
effects of endothelin A and B receptors, the former being
associated with vasoconstriction and the latter, after stim-
ulation by endothelin-1, is associated with upregulation
of endothelial NO synthase (eNOS)5 (Fig. 39-4).
The only established experimental model capable of
reproducing human HPS is chronic common bile duct
ligation in the rat.49,50 Other rodent models of cirrhosis
FIGURE 39-2 n Clinical features of severe hepatopulmonary syn- (thioacetamide induced) and portal hypertension (partial
drome in a 38-year-old man. (From Rodríguez-Roisin R, Krowka M. portal vein ligation) do not produce HPS. Bile duct
Hepatopulmonary syndrome—a liver-induced lung vascular disorder.
N Engl J Med. 2008;358[22]:2378-2387.) ligation–produced HPS results in increased production of
NO via eNOS. Endothelin-1 appears to be responsible
for eNOS increases and overexpression of endothelin-B
The reversibility of hypoxemia in HPS patients has been receptors.51,52 The association between elevated endo-
compared to the improvement of hepatorenal syndrome thelin-1 levels and intrapulmonary vasodilatation has
that occurs with recovery of liver function.28 Currently been shown in humans.53 In experimental HPS, macro-
LT is the treatment of choice for HPS, and in the United phages accumulate and produce inducible NO synthetase
States patients with Pao2 of less than 60 mm Hg are given (iNOS) and heme oxygenase-1 (HO-1).54,55 This
priority for organ allocation.29 Interestingly, HPS can enhances vasodilatation through the production of NO
coexist with POPH in the same patient.5 and HO-1 derived carbon monoxide. Angiogenesis, stim-
ulated by increased levels of vascular endothelial growth
factor, appears to play a role in experimental HPS.56
Pathophysiology Norfloxacin inhibits both bacterial translocation and
Intrapulmonary arterial oxygenation can be impaired by tumor necrosis factor-α (TNF-α), which decreases the
alveolar ventilation-perfusion imbalance, increased intra- iNOS response. This suggests that bacterial transloca-
pulmonary shunt, and diffusion defects,30 and all of these tion, which stimulates TNF-α, is responsible for macro-
mechanisms may be present in HPS.3,31-39 However, the phage accumulation.57 Nonspecific phosphodiesterase
response to the administration of 100% oxygen is typi- inhibition with pentoxifylline increases intracellular
cally preserved; shunts appear to be functional rather cyclic adenosine monophosphate (cAMP) levels and
than anatomical. Diffusion limitation and ventilation- inhibits TNF-α, resulting in prevention or attenuation of
perfusion mismatch appear to be predominant factors. HPS.58,59 In humans, gene polymorphism that results in
The common finding of a low diffusing capacity of lung increased monocyte migration is associated with HPS.60
for carbon monoxide (DLCO) supports diffusion impair-
ment. This most likely results from the increased distance Screening Pretransplant
between the alveoli and the red blood cells in the central
stream of the dilated pulmonary capillary (Fig. 39-3). Interestingly, the severity of HPS, as determined by the
The hyperdynamic circulation (high rate of blood flow) Child-Turcotte-Pugh classification, does not mirror the
found in cirrhotic patients decreases the exposure time of degree of hepatic dysfunction.1,12,17,40 This, coupled with
the red blood cell to the alveolus, further worsening the the fact that dyspnea is a common, nonspecific symptom
diffusion impairment. in patients with end-stage liver disease, makes screening
The pathophysiological hallmark of HPS is the pres- important.
ence of IPVDs. The diameter of pulmonary capillaries is Pulse oximetry is commonly used to diagnosis hypox-
normally between 8 and 15 μm. Red blood cells, which emia. However, the oxygen saturation as measured by
possess a similar diameter, travel through the capillaries pulse oximetry (Spo2) has been shown to overestimate
in single file. This configuration minimizes the distance arterial oxygen saturation (Sao2), both in patients with
required for oxygen diffusion and facilitates oxygen trans- cirrhosis and controls.61 To reliably detect a Pao2 of less
fer to red cells. In HPS pulmonary capillaries dilate to a than 70 mm Hg, patients with an Spo2 of 98% or less
diameter of 50 to 500 μm, impeding oxygenation.40 Occa- warrant arterial blood gas (ABG) analysis. Obtaining
sionally a single large shunt may be found that bypasses ABG levels based upon an Spo2 of 98% or less is 100%
the pulmonary vasculature; this may be amenable to coil- sensitive for hypoxemia (defined as Pao2 <70 mm Hg)
ing by the interventional radiologist. but has a low specificity (a significant number of ABG
Elevated levels of vascular vasodilators, including NO, analyses will reveal a Pao2 >70 mm Hg). In a study of
are responsible for IPVD. This is supported by increased 200 patients who were LT candidates, approximately
 39 Portopulmonary Hypertension and Hepatopulmonary Syndrome 517

A Homogeneous lung

Mixed venous
blood Uniform
ventilation

Alveolus Alveolus

Oxygenated
arterial blood

Uniform perfusion

B Hepatopulmonary syndrome

Mixed venous
blood Uniform
ventilation

Right-to-left
shunt Alveolus
Diffusion limitation

Hypoxemic
arterial
Nonuniform perfusion blood

Ventilation-perfusion mismatch

FIGURE 39-3 n The mechanism of hypoxemia in hepatopulmonary syndrome (HPS). A, Uniform ventilation and pulmonary perfusion
in a healthy patient. B, Ventilation and perfusion in a patient with HPS. In HPS capillaries are dilated and blood flow is not uniform.
Ventilation-perfusion mismatch predominates, whereas shunt and diffusion limitation also contribute to the hypoxemia of HPS.
(From Rodríguez-Roisin R, Krowka M. Hepatopulmonary syndrome—a liver-induced lung vascular disorder. N Engl J Med. 2008;358[22]:
2378-2387.)

one third were referred for ABG analysis based upon an met standard A-a gradient criteria; however, after age
Spo2 of less than 97%, which preserved sensitivity correction 35% met criteria.2
(96%) and was moderately specific (75%).61 The cost Chest x-ray examination and pulmonary function
effectiveness of ABG analysis in the presence of Spo2 of tests are frequently obtained to assess for other causes of
less than 97% compares favorably to screening using a cardiopulmonary disease. However, these tests have a
validated dyspnea questionnaire.62 ABG analysis per- low specificity for HPS and should not be used to exclude
formed while the patient is supine and standing, while (or diagnosis) HPS. The DLCO is commonly impaired
breathing room air, is helpful,63 although desaturation in HPS patients.65 One study found the predicted
upon standing may be present in as many as one third of DLCO was less than 80% in 15 of 18 HPS patients.66
cirrhotic patients.64 The A-a gradient should be age cor- However, a number of other conditions, such as intersti-
rected to avoid inappropriately diagnosing older tial lung disease, vasoocclusive disease, and severe ane-
patients. The normal A-a gradient is less than 10 + 0.43 mia, can lower diffusing capacity, so this finding is
(age − 20). In a study of 207 patients with HPS, 66% nonspecific.67
518 PART IV Special Considerations in Patient Evaluation

CBDL Bile acids

Cholangiocyte proliferation
? TGF-1
Other Lung

Normal
ETB receptor
ET-1 eNOS

ETA receptor
Bile duct NO
Stellate cell
?
Bacterial ?
translocation Endotoxin ET-1 Macrophage
TNF- iNOS HO-1
ETBR

Hyperdynamic state eNOS Endothelial cell

Gut Vascular shear stress NO CO
?
NO Smooth muscle
cell
Angiogenesis Vasodilatation
Vasculogenesis
Remodeling

HPS
FIGURE 39-4 n Proposed mechanisms of hepatopulmonary syndrome. CBDL, Common bile duct ligation; CO, carbon monoxide; eNOS,
endothelial nitric oxide synthase; ET-1, endothelin-1; ETA, endothelin A; ETB, endothelin B; ETBR, endothelin B receptor; HO-1, heme
oxygenase-1; iNOS, inducible nitric oxide synthetase; NO, nitric oxide; TGF-β1, transforming growth factor-β1; TNF-α, tumor necrosis
factor-α. (From Palma D, Fallon M. The hepatopulmonary syndrome. J Hepatol. 2006;45[4]:617-625.)

Contrast-enhanced echocardiography (CEE) and per- time. Radionuclide perfusion scanning is useful to quan-
fusion lung scanning using technetium Tc 99m-labeled tify the magnitude of the shunt, which may help distin-
macroaggregated albumin are the most common guish the contribution of HPS to hypoxemia in patients
approaches for IPVD assessment.1,13,68,69 During CEE with HPS and coexisting respiratory conditions.71
agitated saline is injected intravenously. Echogenic shad- Other diagnostic tests, such as high-resolution com-
ows are normally visible only in the right heart, because puted tomography scanning and angiography, may pro-
they are filtered by the pulmonary microcirculation. vide useful information about the appearance of
Visualization in the left heart implies an intracardiac or pulmonary vessels. However, these tests have not been
intrapulmonary shunt. With an intracardiac shunt, studied sufficiently to warrant their use to detect IPVD.
microbubbles appear in the left heart within three heart- Computed tomography is helpful when pulmonary arte-
beats of their appearance in the right heart. In contrast, riovenous malformation is suspected.72,73 The combina-
intrapulmonary shunts result in the delayed (four to six tion of hypoxemia, liver disease, and IPVD is sufficiently
beats) appearance of microbubbles in the left heart (Fig. unique that it is diagnostic for HPS even in the presence
39-5). Transesophageal echocardiography with contrast of other conditions (such as chronic lung disease) that
enhancement may be more sensitive than transthoracic might worsen hypoxemia.10 Cirrhosis is the most com-
CEE but requires sedation and carries a theoretical risk mon liver disease associated with HPS, although HPS
to patients with esophageal varices.3 has occurred in the setting of acute and noncirrhotic
Technetium 99m labeled macroaggregated albumin, liver diseases such as Budd-Chiari syndrome, hepatitis A,
approximately 20 μm in diameter, is filtered in the pul- hypoxic hepatitis, and chronic hepatitis without
monary capillary bed. In the presence of intrapulmonary cirrhosis.33,74-76,77
vasodilatation, albumin aggregates pass through to the The severity of HPS is not easily quantified via CCE
systemic circulation. Shunting of more than 6% reflects or lung perfusion scans. Instead, Pao2 on room air is use-
an intracardiac or intrapulmonary shunt.40 However, ful for this purpose, with very severe HPS defined by the
CEE is generally the screening test of choice, because it European Respiratory Society Task Force as a resting,
has been shown to be more sensitive than lung perfusion room air Pao2 of less than 50 mm Hg (<300 mm Hg on
scan, and CEE can differentiate intracardiac from intra- 100% O2), whereas a Pao2 greater than or equal to
pulmonary shunts.12,13 CEE in the standing position has 50 mm Hg and less than 60 mm Hg defines severe HPS.3
been shown to increase the number and size of shunts The severity of HPS is an important prognostic tool for
compared with supine injection and may detect early predicting survival and determining the timing of
HPS before changes are apparent via ABG analysis.70 LT.33,78,79 All patients presenting for LT should be
Because echocardiography is routinely used to screen for screened with pulse oximetry while breathing room air in
POPH, some centers elect to perform CEE at the same both the sitting and supine positions.
 39 Portopulmonary Hypertension and Hepatopulmonary Syndrome 519

these may traverse through the shunts to the systemic cir-

culation. This may be a factor when considering the use of
venovenous bypass, because the risk for air emboli is a rec-
ognized complication. However, unique postoperative
complications have been described, including pulmonary
hypertension,87,88 cerebral embolic hemorrhage,89 and
RV LV postoperative desaturation requiring prolonged mechani-
cal ventilation.27,90
RA LA There are case reports of improvement in hypoxemia
after transjugular intrahepatic portosystemic shunt
(TIPS) placement in patients with HPS91 and some case
reports without convincing evidence for improvement.92
However, in a report that described improved oxygen-
A ation in an HPS patient after TIPS, intrapulmonary
shunting persisted.93 Thus the mechanism of improve-
ment may not be related to reversal of intrapulmonary
vasodilatation but perhaps changes in cardiac output. In
other cases HPS developed in the presence of a functional
TIPS.94 Because of the uncertainty surrounding the
response to TIPS, it should be reserved for experimental
trials1 or as a bridge to LT.95
Few data exist in children, although single-center
reports of small series of pediatric patients with HPS sug-
gest that treatment of the underlying cause of liver fail-
ure, such as splenectomy for splenic vein thrombosis or
antiviral therapy for hepatitis C, may result in resolution
of HPS.96

B Risk Management, Postoperative Care,

FIGURE 39-5 n Transthoracic echocardiographic features of the
and Outcomes
hepatopulmonary syndrome. The chambers of the right heart Initial postoperative care should include keeping the
are initially opacified with microbubbles (A), followed by
delayed opacification of the left heart (B). LA, Left atrium; LV, left patient dry so that the lung function in particular may be
ventricle; RA, right atrium; RV, right ventricle. (From Rodríguez- optimized. This may need aggressive diuresis or, if there
Roisin R, Krowka M. Hepatopulmonary syndrome—a liver-induced is significant renal dysfunction, the institution of short-
lung vascular disorder. N Engl J Med. 2008;358[22]:2378-2387.) term continuous venovenous hemodialysis.
In a series of 61 HPS patients wait-listed for trans-
plant, the mean partial pressure of oxygen declined by 5 ±
Perioperative Management Through 2 mm Hg per year.20 Oxygen supplementation is com-
Surgery, Including Liver Transplantation monly used for patients with Pao2 of less than 60 mm Hg
or those with exercise-induced desaturation. This prac-
LT is indicated for patients with HPS. LT offers a sur- tice is derived from the benefits of oxygen therapy in
vival advantage compared to HPS patients who do not other pulmonary disorders. Anecdotal evidence suggests
undergo transplantation. The American Association for that exercise tolerance and quality of life are improved.1
the Study of Liver Diseases recommends that patients Hypoxemia during sleep may be common in HPS
with HPS, regardless of the degree of hepatic dysfunc- patients. In one study 7 of 10 HPS patients spent more
tion, undergo evaluation for LT.80 than 10% of sleeping hours with Sao2 of less than 90%.97
Although a number of medical therapies have been Hypoxemia during sleep directly correlated with the
tried in an attempt to improve oxygenation in HPS, no severity of HPS, as determined by A-a gradient, but was
therapies have been proven to be effective for long-term not predicted by the severity of hypoxemia during waking
treatment. Mixed results or temporary improvement has hours.
been achieved with methylene blue,46,81 garlic,82,83 pent- In a study of 111 patients, 24% of whom had HPS,
oxifylline,84,85 L-NAME,47,48 norfloxacin, and other anti- the median pretransplant survival of HPS patients was
microbial agents.86 A single case report describes 11 months shorter than patients without HPS. Mortality
complete resolution of HPS after methadone withdrawal remained higher after adjusting for underlying liver dis-
and postulates NO signaling by opiates as a contributing ease severity.78 The cause of death in HPS patients
factor.21 was primarily due to complications of liver disease and
Intraoperative management focuses on the provision of portal hypertension, rather than from hypoxic respira-
adequate oxygenation. Given that HPS is typically respon- tory failure.
sive to supplemental oxygen, this goal is usually attainable. In the absence of LT, HPS patients’ 5-year mortality
The prevention of embolic material, especially air bubbles, is 77% compared to 24% mortality in HPS patients
from entering the venous circulation is imperative because who underwent transplantation.20 This suggests that LT
520 PART IV Special Considerations in Patient Evaluation

offers a decided survival advantage for HPS patients and of less than 50 mm Hg and a macroaggregated albumin
is the only effective therapy for HPS. Improvement in gas shunt fraction greater than 20% were strong predictors
exchange occurs in over 85% of patients, although the of postoperative mortality.79 In another large, single-cen-
length of time for hypoxemia to normalize is variable and ter study 61 patients with HPS had a 5-year post-LT sur-
may be more than a year in some patients.98 Noninvasive vival of 76%, a rate not significantly different from LT
pulmonary ventilation has been used successfully in the recipients without HPS.20 However, patients with a Pao2 of
immediate postoperative management of HPS patients.99 50 mm Hg or less had worse survival than HPS patients with
However, mortality after LT is higher in patients with less severe hypoxemia (Fig. 39-6). A multicenter database
HPS than patients without HPS.88,100,101 A room air Pao2 from 10 centers reported a 16% mortality (5 of 32) during
post-LT hospitalization.102 All nonsurvivors had a Pao2
of less than 50 mm Hg. Twenty percent (8 of 40) of the
1.0 OLT  PaO2  50 mm Hg** HPS patients evaluated for LT were denied. No denials
were for pulmonary reasons. Although statistically different,
0.8 the Pao2 of patients denied transplant was not clinically
dissimilar to that of patients who underwent transplant
(47 versus 52 mm Hg, respectively).
0.6 OLT  PaO2  50 mm Hg* Recent data from 21 patients with HPS (11 of whom
Survival

had Pao2 of less than 50 mm Hg) suggest that LT, even

0.4
No OLT
 PaO2  50 mm Hg**
in patients with severe HPS (defined as Pao2 of less than
50 mm Hg), can be performed safely without increased
mortality27 (Fig. 39-7).
0.2 However, a fourth of these patients required oxygen
No OLT
 PaO2  50 mm Hg* for 11 to 31 days, and some hospitalizations exceeded
0.0 3 months, suggesting both high acuity and a considerable
commitment to long-term critical care.103
0 40 80 120 160
Increased waiting-list mortality has led the United
Months to outcome Network for Organ Sharing to increase priority for
FIGURE 39-6 n Survival based upon initial determinations of par- HPS patients with severe hypoxemia by awarding
tial pressure of arterial oxygen (Pao2) at the time of hepatopulmo- Model for End-Stage Liver Disease (MELD) exception
nary syndrome diagnosis. OLT, Orthotopic liver transplantation.
(*P = .001; **P = .002) Pao2 measurements were taken in the points.20,29,78,104 To qualify for MELD exception for
standing position. (From Swanson K, Wiesner R, Krowka M. Natural HPS, ABG determinations should be performed in the
history of hepatopulmonary syndrome: impact of liver transplantation. sitting position.29 To receive prioritization for organ
Hepatology. 2005;41[5]:1122-1129.) allocation a Pao2 of less than 60 mm Hg is required.

100 100
PaO2 (mm Hg)
PaO2 (mm Hg)

80 80
60 60
40 40
20 20
0 0
Pretransplant Posttransplant Pretransplant Posttransplant
A B
100 100
AaDO2 (mm Hg)

AaDO2 (mm Hg)

80 80
60 60

40 40

20 20

0 0
Pretransplant Posttransplant Pretransplant Posttransplant
C D
FIGURE 39-7 n Changes in gas exchange after liver transplant. First points represent pre–liver transplant (LT) values, and second points
represent the most recent post-LT value, performed between 4 months and 2.6 years after LT. Error bars represent the standard error
of the mean. A, Pre- and post-LT partial pressure of arterial oxygen (Pao2) values for 17 patients. B, Mean pre- and post-LT Pao2 values
(12 patients). C, Pre- and post-LT alveolar-arterial oxygen gradient (AaDo2) values in 12 patients. D, Mean pre- and post-LT AaDo2
values (12 patients). (From Gupta S, Castel H, Rao R, et al. Improved survival after liver transplantation in patients with hepatopulmonary
syndrome. Am J Transplant. 2010;10[2]:354-363.)
 39 Portopulmonary Hypertension and Hepatopulmonary Syndrome 521

The exception points provide a reasonable probability of upon the severity of POPH as determined by catheteriza-
being transplanted within 3 months.105 tion. Patients with moderate (MPAP 35 to 50 mm Hg)
In an analysis of 255 patients with HPS who received and severe (MPAP >50 mm Hg) POPH are at increased
exception points, pre- and post-LT survival in HPS risk for perioperative mortality and should be referred for
patients was approximately half that of non-HPS medical treatment, if feasible, before liver transplantation.
patients.106 This suggests that the exception policy for This chapter reviews the clinical presentation, pathophys-
HPS favors these patients. However, this analysis did not iology, treatment, and risk for POPH.
take into account the severity of hypoxemia or the post-
LT improvement in survival in HPS patients awarded
exception points compared to the predicted survival in
Clinical Features and Incidence
these patients in the absence of exception points.107 For the past 50 years hepatologists have been aware that
Regional geographical differences in exception points pulmonary hypertension has an association with portal
awarded for HPS suggest inconsistencies in diagnosis and hypertension.112 POPH appears to be less common than
policy implementation that are likely to be addressed in HPS. The initial reports linking pulmonary hypertension
the future. to cirrhosis were based upon autopsies. One such report
In summary, HPS results from intrapulmonary vascu- suggested a prevalence of pulmonary hypertension of
lar dilatations and is diagnosed by the presence of liver 0.13% in all 17,000 autopsies, but a prevalence of 0.73%
disease, hypoxemia, and positive results with CEE. In the in patients with cirrhosis.113 In 1991 the prevalence of
absence of liver transplantation the condition progresses POPH in 507 patients hospitalized for portal hyperten-
and is associated with increased mortality. Transplanta- sion was 2%.114 In a more recent series from the same
tion is the only definitive therapy. After transplantation, hospital the prevalence of POPH was 6%, albeit in
hypoxemia resolves over a variable time period. Trans- patients with more severe liver dysfunction being evalu-
plantation before hypoxemia is severe (Pao2 <50 mm Hg) ated for liver transplantation. Studies in POPH patients
may improve outcomes and result in less need for postop- undergoing evaluation for liver transplant have shown
erative ventilator support. varying prevalences: 6%,115 9%,116 and 12%.117 Finally,
in a large series of patients with refractory ascites under-
going right heart catheterization, the prevalence of
POPH was even higher, 16% to 20%.118 Whether the
PORTOPULMONARY HYPERTENSION prevalence of POPH has increased or screening methods
Overview are more sensitive is unclear. The definition of POPH
varies among case series. One report noted isolated eleva-
POPH is defined as the presence of pulmonary hyperten- tions of the pulmonary artery pressure in 20% of patients
sion in a patient with portal hypertension.3,40 Hemody- presenting for liver transplantation; however, only 4%
namic criteria on right heart catheterization include (1) a had concurrent elevations of PVR (>120 dynes·sec·cm-5)
mean pulmonary artery pressure (MPAP) greater than and met criteria for POPH. Those with normal PVR had
25 mm Hg, (2) PVR of greater than 240 dynes·sec·cm-5, volume overload or hyperdynamic circulation-related
and (3) pulmonary capillary wedge pressure (PCWP) of MPAP elevations, which do not have the same prognostic
less than 15 mm Hg or a transpulmonary gradient greater significance.
than 12 mm Hg108-111 (Table 39-2). The important The most common presentation in patients with
parameters are the transpulmonary gradient and the PVR, POPH includes fatigue, exertional dyspnea, syncope,
because the PCWP may be elevated above 15 mm Hg if chest pain, and sudden death.40,119 However, as many as
there is accompanying volume overload, high cardiac out- 60% of POPH patients may be asymptomatic.114 On
put, or cirrhotic cardiomyopathy. Transthoracic echocar- cardiopulmonary evaluation a pansystolic tricuspid
diography is an effective, noninvasive method of screening regurgitation (TR) murmur may be present, and there
for POPH. Positive screening results necessitate right may be signs of right ventricular (RV) failure. Chest
heart catheterization for definite diagnosis. The implica- x-ray examination can have normal results, or it may
tions of POPH for liver transplant mortality are based demonstrate cardiomegaly, prominent pulmonary arter-
ies, and peripheral pruning of vessels. The electrocar-
diogram may demonstrate RV hypertrophy, right axis
deviation, a right bundle branch block, and evidence of
TABLE 39-2 D
 iagnostic Criteria for
right heart strain.40
Portopulmonary Hypertension
POPH appears to affect all age groups, including pedi-
Portal hypertension atric patients. Similar to adult patients with POPH, the
MPAP >25 mm Hg presentation in pediatric patients is subtle and can be eas-
Pulmonary vascular resistance >240 dynes·sec·cm-5 ily overlooked. The prognostic implication in pediatric
Transpulmonary gradient >12 mm Hg patients is similar to that of adults based upon a limited
number of published reports.120 Children with congenital
From Krowka M. Evolving dilemmas and management of portopul- malformations such as heterotaxy with polysplenia are
monary hypertension. Semin Liver Dis. 2006;26(3):265-272. known to be at high risk for congenital extrahepatic por-
Pulmonary vascular resistance = (MPAP − PAOP) × 80/CO;
transpulmonary gradient = MPAP − PAOP. CO, Cardiac output;
tosystemic shunts, which can cause POPH. The presence
MPAP, mean pulmonary artery pressure; PAOP, pulmonary artery of patent portal and hepatic veins allows percutaneous
occlusion pressure. shunt closure.121
522 PART IV Special Considerations in Patient Evaluation

Recent consensus reports from the American College include vasoactive intestinal peptide, serotonin, throm-
of Cardiology/American Heart Association and the Euro- boxane A2, interleukin-1, glucagon, and secretin.3,136,137
pean Society of Cardiology/European Respiratory Soci- The beneficial effect of thromboxane synthesis inhibition
ety provide classifications of pulmonary hypertension, of has been reported in a patient with POPH. This patient
which POPH is one subtype.111 Both reports highlight had improved exercise tolerance and survived 7 years
evolving evidence and opinion regarding diagnosis and without liver transplantation.138 Prostacyclin synthase,
treatment. which results in the production of the potent vasodilator
Although portal hypertension is a perquisite for the prostacyclin, is decreased in the lungs of patients with
diagnosis of POPH, cirrhosis is not. POPH has POPH. The dysfunctional endothelium also promotes
been reported in patients with portal vein thrombosis and vasoconstriction that is reversible with the administration
idiopathic portal hypertension with preserved liver of vasodilators such as inhaled NO and prostacyclin.
function.114 In addition, evidence exists that the transforming
growth factor (TGF)-β receptor family is involved in the
pathogenesis of pulmonary hypertension.139 TGF-β2
Pathophysiology receptor mutations have been found in the endothelial
Initially the pathogenesis of POPH was thought to be cells of pulmonary arterioles in patients with sporadic
secondary to pulmonary thromboembolic phenomena primary pulmonary hypertension. TGF-β is thought to
originating from portal vein thrombosis, propagated via play a key role in the pathogenesis of hepatic fibrosis140
portopulmonary collaterals. However, subsequently case and may be responsible for the fibrosis of POPH.
reports appeared describing nonembolic pulmonary Mutations in the gene for bone morphogenetic pro-
hypertension associated with portal hypertension.122 tein receptor II are responsible for idiopathic and familial
Increased portal venous inflow is a factor in the patho- POPH but have not been found in other patients with
genesis of portal hypertension in rodent models.123 POPH.139 In the first study to show genetic variation as a
Whether increased pulmonary blood flow, in a similar risk factor for POPH, 29 of 1000 single nucleotide poly-
fashion, is a causative factor in POPH has received con- morphisms coding for estrogen and other pathways were
siderable attention but has been largely discounted. The associated with POPH.141
pulmonary circulation has a substantial capacity for
recruiting normally closed vessels. As a result, MPAP Pathological Changes
rarely rises above 30 mm Hg even in the presence of
extremely high cardiac outputs.124 In 17 cirrhotic patients The pathological changes seen in the pulmonary vascula-
undergoing TIPS insertion, a model for increased pul- ture are similar to those found in pulmonary arterial
monary flow, patients initially experienced an exacerba- hypertension from other causes. POPH is thought to
tion of an underlying hyperdynamic circulation. The progress from an initial vasodilatory, high-flow state to
cardiac output increased from an average of 8 to 12 L/ one with endothelial/smooth muscle proliferation,
min, with an associated increase in MPAP from 15 to accompanied by plexogenic arteriopathy, intimal fibro-
26 mm Hg, a PVR increase from 140 to 167 dynes·sec·cm-5, sis, and in situ thrombosis3 (Fig. 39-8). These changes
and a rise in PCWP from 10 to 19 mm Hg.125 However, have an impact on the reversibility of the condition and
only 9 hours after the TIPS procedure, MPAP had fallen have led some authors to question whether vasodilator
to 19 mm Hg. In another report with similar findings, therapy alone (for instance, calcium channel blockers), in
pulmonary artery pressures remained slightly elevated the absence of agents with antiproliferative and anti-
over baseline 1 month after TIPS.126 Because elevated platelet properties, will successfully treat all patients with
pulmonary artery pressure is a recognized consequence POPH.142
of TIPS, this procedure should be avoided in POPH
patients.3,127,128
Screening Pretransplant, Including
Endothelial Dysfunction
Characterization of Pulmonary
Hemodynamics and Right Ventricular
The pathogenesis of pulmonary hypertension is currently
thought to involve an excess of vasoconstrictors, such as
Function
endothelin-1 and vasoactive intestinal peptide.40,129 Ele- Because of the absence of symptoms specific for POPH,
vated circulating levels of endothelin-1 have been the diagnosis is frequently missed.3,119 In a series of 43
described in patients with primary pulmonary hyperten- patients from 18 studies, 65% of POPH patients were
sion and POPH.116,130 In contrast to healthy individuals in first diagnosed in the operating room at the time of liver
whom the lungs clear endothelin-1,131 patients with pul- transplantation.143 Chest x-ray examination and electro-
monary hypertension exhibit increased local production cardiography are not sufficiently sensitive screening tools
of endothelin-1 in pulmonary vascular endothelial cells.132 for POPH.120
Cirrhotic patients are known to have elevated circulating Transthoracic echocardiography is the most com-
levels of endothelin-1 because of increased production monly used screening examination. The RV systolic pres-
both in the liver and in other splanchnic organs.133,134 sure (RVSP) is estimated based upon the velocity of
Interleukin-6, a potent stimulator of smooth muscle, tricuspid regurgitation (TR) using the Bernoulli equa-
fibroblasts, and endothelium, is also increased in patients tion, RVSP (in mm Hg) = 4 × (TR m/sec)2 + right atrial
with POPH.116,135 Other possible vasoactive substances pressure109 (Fig. 39-9).
 39 Portopulmonary Hypertension and Hepatopulmonary Syndrome 523

The right atrial pressure is typically estimated from the catheterization should be performed.145 More severe
echocardiographic assessment of the inferior vena cava POPH may manifest as bowing of the septum away from
size and the degree of collapse with respiration.144 How- the pressure-overloaded right ventricle146 (Fig. 39-10).
ever, TR is not present in every patient. In one study It is vital that both right and left ventricular anatomy
more than 60% of patients (102 of 165) had an absent or and function are well characterized. The assessment of RV
inadequate tricuspid systolic peak velocity signal on echo- function by transesophageal echocardiography (TEE) is
cardiograpy,115 whereas in another series the TR velocity challenging because the right ventricle does not have the
was not detected in 22% of patients.109 In patients with- symmetrical structure of the left ventricle, which makes the
out TR an evaluation of RV size and function is particu- cross-sectional view more difficult to interpret. The typical
larly important. If concerns remain, right heart patient with liver cirrhosis has a hyperdynamic circulation

A B

C D

E
FIGURE 39-8 n Pulmonary arterial changes in portopulmonary hypertension. A and B, Intimal thickening as a result of fibrosis and cel-
lular thickening. C, D, and E, Pentachrome stain illustrates the black elastic demarcation separating the thickened intima from the
medial layer of the vessel. Asymmetrical intimal thickening is seen in E. (From Koch D, Caplan M, Reuben A. Pulmonary hypertension
after liver transplantation: case presentation and review of the literature. Liver Transpl. 2009;15[4]:407-412.)
524 PART IV Special Considerations in Patient Evaluation

with a low systemic vascular resistance that can give the

impression of a dynamic functioning heart, which masks a
significant cirrhotic cardiomyopathy. Any dilatation of the
right heart chambers must be noted as a risk factor for liver
transplantation. Right heart dysfunction or failure may
result in graft congestion and malfunction. Most patients
with liver cirrhosis will have a downregulation of the
β-receptors or more overt manifestation of cirrhotic car-
diomyopathy.147 Therefore close examination by echocar-
diography for systolic and particularly diastolic dysfunction
should be made. The diagnostic features are an early to late
diastolic filling ratio (E/A ratio) of less than 1, a prolonged
deceleration time of greater than 200 msec, a prolonged
isovolumetric relaxation time of greater than
80 msec, enlarged left and right atria, an abnormal pattern
FIGURE 39-9 n Pulmonary artery pressure determination using of contractility, decreased wall motion, increased wall thick-
Doppler echocardiography. The tracing illustrates a tricuspid ness, resting ejection fraction of less than 55%, and a pro-
regurgitant velocity of 3.12 m/sec. Using an estimated right longed ratio of preejection period to left ventricular ejection
atrial pressure of 10 in the Bernoulli equation, pulmonary artery
pressure (PAP) = 4 × (3.12)2 + 10 = 49 mm Hg. (From Bozbas S, time of greater than 0.44 seconds (rate corrected).148
Eyuboglu F. Evaluation of liver transplant candidates: a pulmonary A more accurate screening test has been reported by
perspective. Ann Thorac Med. 2011;6[3]:109-114.) measuring an increased PVR using the ratio of peak tri-
cuspid regurgitant velocity to RV outflow tract velocity
time. This value has been demonstrated as a more accu-
rate test for PVR greater than 120 dynes·sec·cm-5. In one
report the sensitivity and negative predictive value of this
test was 100%.149
Many institutions consider RV systolic pressures of
greater than 50 mm Hg an indication for right heart
catheterization, which is necessary to confirm the diag-
nosis of POPH and assess the severity.109,119,150,151 A
quarter or more patients with a RV systolic pressure
above 50 mm Hg will not have POPH on right heart
catheterization because elevated RV pressures can occur
because of the hyperdynamic state common in end-stage
liver disease. This state is characterized by elevated car-
diac output and pulmonary pressures in the presence of a
normal (or low) PVR.119 Patients with fluid overload may
A also present with elevated pulmonary artery pressure,
particularly in the presence of hepatorenal syndrome and
oliguria. However, these patient also have normal (or
low) PVR and therefore do not fulfill POPH criteria119
(Table 39-3).
The diagnosis of POPH is made in the presence of
portal hypertension, MPAP greater than 25 mm Hg, and

TABLE 39-3 P
 ulmonary Hypertension
and Hemodynamics
Type of Pulmonary
Hypertension MPAP PVR CO PCWP
High flow/hyperdynamic ↑ ↓ ↑ ↓
B circulation
Volume related ↑ ↑ ↑ ↑
FIGURE 39-10 n Echocardiographic images from a patient with
Vasoconstriction (PPH) ↑ ↑ ↑↓ ↓
portopulmonary hypertension. A, The left ventricle is D-shaped
(parasternal short axis view). B, The right ventricle is dilated.
From Krowka M. Hepatopulmonary syndrome versus portopulmo-
(From Giusca S, Jinga M, Jurcut C, Jurcut R, Serban M, Ginghina C.
nary hypertension: distinctions and dilemmas. Hepatology.
Portopulmonary hypertension: from diagnosis to treatment. Eur J Int
1997;25(5):1282.
Med. 2011;22[5]:441.)
CO, Cardiac output; MPAP, mean pulmonary artery pressure;
(systolic − diastolic) × 1⁄3 + diastolic; PCWP, pulmonary capillary
wedge pressure; PPH, portopulmonary hypertension; PVR,
pulmonary vascular resistance; (MPAP − PCWP) ÷ CO.
 39 Portopulmonary Hypertension and Hepatopulmonary Syndrome 525

an elevated PVR (>120 dynes·sec·cm-5).40,129 Some inves- is required or if an isolated improvement in PVR is suf-
tigators substitute a PVR greater than 240 dynes· ficient is less clear.109 The current recommendation of
sec·cm-5.109 Many definitions require a normal PCWP; the European Respiratory Society Task Force is to target
however, fluid overload can coexist with POPH. This has a MPAP of less than 35 mm Hg and PVR of less than
led to the use of the transpulmonary gradient (MPAP 400 dynes·sec·cm-5.3 There is evidence that a portion of
minus PCWP), which is normal in patients with increased POPH patients respond to treatment and that subsequent
intravascular volume and elevated (>12 mm Hg) in LT can be performed without additional risk if these
POPH.109,110 treatment goals are reached. However, the course of
In a prospective study of 165 patients evaluated for POPH after successful transplant is, unlike HPS, not one
LT, two-dimensional TEE was compared to right heart of progressive improvement. Thus POPH monitoring
catheterization. TEE was not associated with false nega- and treatment is indicated after successful transplanta-
tives but had a poor positive predictive value, meaning tion. The key to how well the patient will tolerate LT
that positive findings required confirmation by right may rest with RV function more than any other parame-
heart catheterization.115 Interestingly, three patients ter. If the RV has accommodated the increase in PVR and
developed POPH between the time of initial screening has hypertrophied, contracting well and is no longer
and liver transplantation, over a period ranging from 2.5 dilated, this may facilitate a successful outcome.110
to 5 months, which suggests that repeat echocardio- Continuous intravenous epoprostenol (prostacyclin)
graphic screening may be necessary in patients with has long been considered the drug of choice with which
longer wait times. other drugs are compared.160-163 Vasodilatation, antiplate-
Type B natriuretic peptide has not been extensively let aggregation, inotropic effects, and vascular remodeling
evaluated as a marker for POPH (or RV failure) in LT are responsible for an improvement in pulmonary hemo-
candidates. One study showed only a weak correlation dynamics. More recently case reports have highlighted
with MPAP (r = 0.3) as determined by right heart improvements in pulmonary hemodynamics with the use
catheterization.152 of epoprostenol and other prostanoids,160,164-166 endothe-
Although POPH is indistinguishable from primary lin receptor antagonists such as bosentan,167-173 and phos-
pulmonary hypertension,153 other conditions that can phodiesterase inhibitors such as sildenafil.174,175
cause pulmonary hypertension should be considered. In a single-center series of 19 patients with moderate
These include cardiac valvular disease, pulmonary emboli, and severe POPH, epoprostenol-treated (median dura-
collagen vascular disease, human immunodeficiency tion 15 months) patients had similar survival to a cohort
virus, schistosomiasis, oral ingestion of appetite suppres- with POPH that was not treated.176 The group that did
sants, and toxic oil ingestion.154 not receive epoprostenol contained patients that were not
LT candidates, so the two groups may not have been
comparable. Notably, of the 13 patients in the epopros-
Pharmacotherapy tenol group, 5 met hemodynamic targets (MPAP <35
Over the last decade a number of therapeutics advances mm Hg and PVR < 240 dynes·sec·cm-5), but only 2
have occurred in the treatment of idiopathic pulmonary underwent LT. Three patients that met hemodynamic
arterial hypertension (IPAH).155-157 However, many of targets died awaiting LT. Epoprostenol appeared to have
these therapies have not been as extensively evaluated in no significant effect on liver biochemical profiles. In
patients with POPH, where case-series level of evidence another series of 30 patients with moderate to severe
predominates.158 Clinical trial enrollment favors patients POPH, 14 patients treated acutely (over 1 to 2 hours)
with idiopathic and connective tissue disease–associated with intravenous epoprostenol showed marked improve-
pulmonary hypertension over POPH patients. Although ment in hemodynamics, whereas 10 patients treated for a
POPH is a subtype of pulmonary arterial hypertension median of 5 months showed further improvement,
based upon the World Health Organization classifica- though the additional change was not statistically signifi-
tion,108 there is little evidence to suggest that the response cant.160 The largest series of POPH patients was a data-
to medical treatment is unique among these conditions.159 base evaluation of 66 POPH patients from 10 centers. Of
However, there are side effects of some treatments that the 66 patients, 36 underwent LT. Thirteen of these died
limit their usefulness in patients with POPH. Calcium postoperatively (5 died in the operating room). Only one
channel blockers have some, albeit limited, usefulness in of the 13 that died was treated preoperatively with epo-
IPAH but are avoided in POPH because of their effects prostenol (for 3 months).102
on portal hypertension. Other therapies, including epo- The side effects of epoprostenol (headache, nausea/
prostenol and bosentan, can cause hepatic injury as evi- vomiting, diarrhea, myalgia, jaw pain, and hypotension),
denced by hepatocellular enzyme level elevations.155 along with the need for continuous intravenous adminis-
However, they have been frequently used without appar- tration (because of a 2 to 3-minute half-life), have led to a
ent ill effect. The advantage of bosentan is that it can be search for other agents. Three epoprostenol analogues
administered orally. have been evaluated (iloprost, beraprost, and treprostinil).
Another issue is the definition of successful treatment. Treprostinil is a stable prostanoid with pharmacological
In IPAH the 6-minute walk test is commonly used to effects similar to those of epoprostenol, with the exception
evaluate functional capacity and monitor improvement. of an elimination half-life of 4.5 hours. In a report of
This is less useful in patients with POPH, where evidence intravenously administered treprostinil in three POPH
of improved pulmonary hemodynamics is more com- patients, it appeared effective.165 In patients with IPAH,
monly sought. Whether a reduction in MPAP and PVR subcutaneous administration of treprostinil is associated
526 PART IV Special Considerations in Patient Evaluation

with erythema or pain at the injection site and may be New antiproliferative therapies that block platelet-
associated with a high rate of gram-negative catheter derived growth factor receptors are under review. They
infections.157 The complexity of administration limits its may reverse vascular remodeling and reduce MPAP.190
use to centers with experience with this agent. Iloprost can
be delivered by an aerosol device. It has been shown to
improve functional capacity in patients with IPAH.177 In a
Risk Management
trial of acute and chronic administration to POPH POPH is unrelated to the severity of the underlying liver
patients, iloprost appears to be tolerated and effective for disease or portal hypertension, with one study documenting
the treatment of POPH without altering portal hemody- a distribution of 51% Child-Turcotte-Pugh class A, 38%
namics.178 However, another report was less favorable.179 Child-Turcotte-Pugh class B, and 11% Child-Turcotte-
Given the putative role of endothelin-1 in the patho- Pugh class C patients among a population of patients sent to
genesis of POPH, endothelin receptor blockade is a a referral center.191,192 Female patients and patients with
promising approach to treatment. Bosentan, a nonselec- underlying autoimmune hepatitis are at increased risk for
tive receptor blocker, has been shown to improve func- POPH, and patients with chronic hepatitis C are at
tional status in a double-blind, placebo-controlled trial of decreased risk.191,193
213 patients with IPAH. Side effects included liver Large portosystemic shunts, greater than 10 mm in
enzyme level elevations, syncope, and flushing.177 A diameter as measured by computed tomography or mag-
small, nonrandomized observational study was reported netic resonance imaging, are more likely to be associated
in 31 POPH patients. The 18 patients who received with moderate or severe POPH and less likely to respond
bosentan had higher 1-, 2- and 3-year survival rates com- to pharmacological treatment.194 Whether percutaneous
pared with 13 patients treated with inhaled ilioprost.179 occlusion of large shunts should be considered is unclear.
Pulmonary hemodynamic improvements were significant Theoretically portal pressures could increase with shunt
only in the bosentan group; however, hemodynamic mea- occlusion, worsening ascites and increasing the likelihood
surements were not performed in all patients. Liver of variceal bleeding. However, the effects of shunt occlu-
enzyme level elevations were seen in one patient in the sion on pulmonary blood flow are likely to be beneficial
bosentan group but normalized after a dose reduction. by two mechanisms, through both a decrease in total pul-
Selective endothelin-A receptor blockers sitaxsentan monary blood flow and the diversion of blood to the liver,
and ambrisentan have undergone trials in patients with where vasoactive mediators may be metabolized.
IPAH. Transaminase level elevations with these drugs β-blockers, commonly used in end-stage liver disease
appear to be less frequent than with bosentan, 3% to 5% patients as primary and secondary prophylaxis for variceal
versus 11%, respectively.180,181 bleeding, have been shown to worsen exercise tolerance
Sildenafil is another oral drug that has shown efficacy and pulmonary hemodynamics in POPH patients, so
in treating POPH.182,183 This drug selectively inhibits they should be avoided.195 Calcium channel blockers,
cGMP-specific phosphodiesterase type 5 enzymes that which are recommended in IPAH in patients with a posi-
are found in the pulmonary vascular endothelium. This tive response to an acute vasodilator challenge, are not
enhances the effects of locally produced NO. In an recommended in POPH patients because of their unfa-
uncontrolled study of 12 patients with moderate and vorable effects on portal hypertension.196,197
severe POPH, sildenafil (≤0 mg three times per day) as TIPS should be avoided in patients with POPH
monotherapy (n = 6) or in combination with prostacyclin because of increases in preload and MPAP, which worsen
(n = 6) appeared beneficial at 3 months, but the results hemodynamics and place additional stress on the right
were not sustained at 12 months.184 In another report of ventricle.3,127,128
10 patients treated with sildenafil, three became trans- In 19 POPH patients who did not receive medical ther-
plant eligible.183 Interestingly, none of these patients apy or undergo LT, 5-year survival was 14%.198 In 43
responded to acute vasodilator therapy with inhaled NO. patients who received medical therapy but not LT, 5-year
In another series of POPH patients, four of nine patients survival was 45%. Patients who received both medical
became transplant eligible (MPAP <35 mm Hg).182 How- treatment and LT (n = 12) had a 5-year survival of 67%
ever, one patient who initially responded was found to (25% if medical therapy was not provided before LT).
have progression of POPH at the time of LT, and the The authors concluded that medical therapy should be
procedure was aborted. considered for all patients with POPH. They also noted
Inhaled NO has met with mixed therapeutic success in that mortality did not correlate with the severity of liver
POPH. In one study five of six POPH patients responded disease, a finding supported by other reports.191,193 Based
with decreases in PAP and PVR greater than 10%.185 upon improved outcomes, MELD exception points,
However, another series of 10 patients failed to show which lead to earlier allograft allocation, were proposed
beneficial effects.186 Chronic inhalation of NO has been for POPH in 2006.199 Criteria for exception points include
used in the treatment of primary pulmonary hyperten- MPAP above 35 mm Hg, 12 weeks of U.S. Food and
sion and also to reverse acute elevations in MPAP during Drug Administration–approved pulmonary arterial hyper-
liver transplantation.185,187 tension therapy that results in MPAP below 35 mm Hg,
Because various treatment options target different pro- and PVR below 400 dynes·sec·cm-5 with satisfactory RV
cesses, combination therapy is viewed as an attractive function. Five years later many but not all regional review
option to enhance suboptimal responses and limit toxicity. boards had implemented them.200
Although some reports of combination therapy have shown In the multicenter REVEAL (Registry to EValuate
mixed results, a number of reports show benefits.188,189 Early And Long-term Pulmonary Arterial Hypertension
 39 Portopulmonary Hypertension and Hepatopulmonary Syndrome 527

MPAP  35 PVR  240 Good QT and right

TRANSPLANT
mm Hg dynes.sec.cm5 ventricular function

MPAP 35-40 PVR  240 Good cardiac function

TRANSPLANT
mm Hg dynes.sec.cm5 determined by TEE

Attempt to reduce MPAP 35 Irreversible

mm Hg and PVR 240
dynes.sec.cm5

Poor ventricular function

Irreversible, but right ventricular

function is good (dobutamine and fluid
challenge OK) DEFER SURGERY

TRANSPLANT

DEFER SURGERY
MPAP 40 mm Hg PVR 240 dynes.sec.cm5
Initiate vasodilator therapy

FIGURE 39-11 n The decision algorithm for portopulmonary hypertension. MPAP, Mean pulmonary artery pressure; PVR, pulmonary
vascular resistance; QT, cardiac output; TEE, transesophageal echocardiography. (From Ramsay M. Liver transplantation and pulmonary
hypertension: pathophysiology and management strategies. Curr Opin Organ Transplant. 2007;12:274-280.)

Management) study, outcomes of POPH patients were vasodilator testing is used to identify POPH patients with
compared with those of patients with IPAH.201-203 POPH responsiveness to therapy. This indicates a degree of
patients (n = 174) were found to have worse 2-year reversibility resulting from vascular reactivity and is asso-
postenrollment survival (67% and 85%, respectively), ciated with an improved prognosis in IPAH.157,208 Drugs
and worse 5-year postdiagnosis survival (40% and 64%, used for vasodilator testing include intravenous epopros-
respectively) despite better pulmonary hemodynamics at tenol,209 intravenous adenosine,210 and inhaled NO.211
the time of diagnosis. POPH patients were less likely to NO is commonly preferred; doses of 20 to 40 ppm are
be on medical therapy at the time of enrollment, suggest- used for a 5-minute trial. The definition of a positive
ing treatment delays in this group. response has been debated. In IPAH a response is defined
Successful LT can be performed in the presence of as a MPAP decrease of at least 10 mm Hg, to a MPAP of
mild POPH (MPAP <35 mm Hg).204 For patients with 40 mm Hg or less, with an unchanged or increased car-
moderate or severe POPH (MPAP ≥35 mm Hg) the peri- diac output.157 A study using a different definition of
operative risk is high. In one study 40% of 30 patients responsiveness (MPAP and PVR decline of >20%) found
with severe POPH died.102 Even with active screening only 13% of patients (70 of 557) were responders.212 Oth-
efforts that include denial of LT to patients with severe ers have reported higher response rates, up to 55%.213,214
POPH, intraoperative and postoperative mortality In 19 POPH patients intravenous epoprostenol and
remains a concern.142 However, as previously empha- oral isosorbide more effectively reduced MPAP and PVR
sized, the prognosis for untreated POPH is dismal, with during vasodilator testing when compared with inhaled
the mean survival (for 78 patients with POPH) 15 months NO.215 Overall one third of the patients responded with
and the median survival 6 months.205 Fortunately, treat- a reduction in MPAP to less than 35 mm Hg and would
ment of moderate or severe POPH that achieves treat- have been considered LT candidates. In IPAH patients
ment targets can lead to successful LT206,207 (Fig. 39-11). approximately 10% respond to acute vasodilator test-
ing.216 NO use has met with mixed reviews, one report
showing favorable effects in a single patient217 and
Perioperative Management Through Liver another reporting no beneficial effects in a series of 10
Transplantation, Including Acute patients under evaluation for LT.186
Elevations in Portopulmonary Hypertension The primary risk for POPH patients is right heart fail-
ure after perfusion of the allograft or in the early postop-
and Right Ventricular Dysfunction erative period.110,218,219 (Fig. 39-12). In a nonadapted right
Up to 65% of POPH patients are diagnosed in the oper- ventricle, MPAP above 40 mm Hg can result in ventricular
ating room at the time of transplantation.92 Acute failure.220 During reperfusion, unclamping of the inferior
528 PART IV Special Considerations in Patient Evaluation

100 15.7 12.6

Cardiac output L/m
80

Pressure (mm Hg)

PA2-S
60 PA2-D
5.9
PA2-M
40

20

Reperfusion
0
15:50 16:04 16:19 16:33 16:48 17:02 17:16
Time (h:min)
FIGURE 39-12 n Acute elevation in pulmonary artery pressure on reperfusion of the liver allograft. PA2-D, Pulmonary artery pressure–
diastolic; PA2-M, pulmonary artery pressure–mean; PA2-S, pulmonary artery pressure–systolic. (From Ramsay M. Portopulmonary
hypertension and right heart failure in patients with cirrhosis. Curr Opin Anaesth. 2010;23[2]:145-150.)

vena cava results in a significant volume challenge, along dysfunction, volume overload, and graft congestion. If
with an influx of vasoactive substances from the portal cir- renal dysfunction is significant, then continuous venove-
culation and the graft into the pulmonary circulation.221 nous hemodialysis should be considered.
Techniques to mitigate the volume changes include the Acute treatment of POPH with intravenous epopro-
use of venovenous bypass and use of the piggyback tech- stenol improved pulmonary hemodynamics by 20% or
nique, both of which help maintain preload during the more in nearly 80% of 15 patients.160 Further improve-
anhepatic phase.163 Milrinone was used in a case report to ments, including nearly a 50% reduction in PVR,
mitigate the effects of POPH on RV function.222 occurred with long-term infusion, probably a result of
Balloon atrial septostomy is a rarely used treatment pulmonary vascular remodeling. However, the need for
option to lower MPAP. Support for the procedure comes long-term therapy increases the risk for progression of
from the fact that IPAH patients with a patent foramen underlying liver disease. Six of 10 patients on l­ ong-term
ovale have a survival advantage over those with an intact epoprostenol died while awaiting liver transplant.160
atrial septum.223 It is used as a palliative or bridging pro- In a report of 38 POPH patients, 4 of 5 patients with
cedure in patients with recurrent syncope and an accept- MPAP above 40 mm Hg survived a year or more. At the
able peripheral oxygen saturation (>95%). It should not time of reevaluation at 12 months, MPAP and PVR in
be performed emergently in patients with acute right one patient were still elevated at 32 mm Hg and 390
heart failure. However, mortality is as high as 30%.224,225 dynes·sec·cm-5, respectively.229 However, a diverse range
Combined heart, lung, and liver transplantation of outcomes has been reported, including intraoperative
(CHLLT) and combined lung and liver transplantation death,23 immediate postoperative death,230 late postop-
(CLLT) have been performed in POPH patients that do erative death,231-233 unchanged pulmonary hemodynam-
not qualify for isolated liver transplant because of severe ics,234 improvement of POPH,90,235-237 and new-onset
elevations in MPAP that do not respond to medical treat- POPH after LT.87,88,100,238-240
ment.226 Of the 10 POPH patients reviewed in a 2011 In a single-center series of 86 patients with RV sys-
report, 6 received CLLT and 4 CHLLT. In a series of 13 tolic pressure above 40 mm Hg, 30 cases of POPH were
patients (5 with POPH) who underwent CLLT, survival confirmed by right heart catheterization.207 Sixteen of
was 69% after 1 year, 62% after 3 years, and 49% after 20 with moderate to severe POPH were otherwise LT
5 years.227 These survival rates compared favorably to candidates and were treated with vasodilators. Twelve
isolated lung transplant but are inferior to isolated liver of 16 (75%) reached the target MPAP of less than
transplant. Several reports of mortality from right heart 35 mm Hg. Eleven underwent LT, and 9 were able to
failure have been reported in the postoperative period ­discontinue vasodilator therapy a median of 9 months
following CLLT.227,228 This emphasizes the preoperative after LT.
assessment of cardiac function, which is critical to the In summary, POPH is a progressive condition that
decision of whether to include heart transplantation in can shorten survival. It is underrecognized because of an
the procedure. Combined organ transplant should be insidious onset and a lack of symptoms. Screening is
reserved for patients who are not expected to survive an imperative for early diagnosis and assessment of severity.
isolated organ transplant. LT can be safely undertaken in mild POPH. Early med-
ical therapy should be initiated for moderate and severe
Postoperative Care, Including Long-Term POPH (MPAP >35 mm Hg), with the specific treatment
goals of lowering the MPAP to less than 35 mm Hg and
Pharmacotherapy PVR to less than 400 dynes·sec·cm-5. Future improve-
Initial postoperative fluid management should be aimed ments in therapy and outcomes require multicenter
at keeping the patient as dry as possible to prevent RV cooperation.200
 39 Portopulmonary Hypertension and Hepatopulmonary Syndrome 529

10. Rodríguez-Roisin R, Krowka MJ, Hervé P, Fallon MB. High-

Pearls and Pitfalls lights of the ERS Task Force on pulmonary-hepatic vascular dis-
orders (PHD). J Hepatol. Jun 2005;42(6):924-927.
Hepatopulmonary Syndrome 11. Harris EA, Kenyon AM, Nisbet HD, et al. The normal alveolar-
• Liver disease, intrapulmonary shunts, and varying de- arterial oxygen-tension gradient in man. Clin Sci Mol Med. Jan
grees of hypoxemia are present. 1974;46(1):89-104.
12. Krowka MJ, Wiseman GA, Burnett OL, et al. Hepatopulmonary
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syndrome: a prospective study of relationships between severity of
room air. liver disease, PaO(2) response to 100% oxygen, and brain uptake
• Check pulse oximetry in the sitting and supine posi- after (99m)Tc MAA lung scanning. Chest. Sep 2000;118(3):
tions. Hepatopulmonary syndrome (HPS) patients im- 615-624.
prove on lying down. 13. Abrams GA, Jaffe CC, Hoffer PB, et al. Diagnostic utility of con-
• Test for delayed passage (four to six heartbeats) of trast echocardiography and lung perfusion scan in patients with
ecogenic material (agitated saline) passing from right hepatopulmonary syndrome. Gastroenterology. Oct 1995;109(4):
heart to left heart with echocardiography. 1283-1288.
• The more severe the hypoxemia associated with HPS, 14. Gomez FP, Martinez-Palli G, Barbera JA, et al. Gas exchange
mechanism of orthodeoxia in hepatopulmonary syndrome. Hepa-
the greater the risk for liver transplantation and the
tology. Sep 2004;40(3):660-666.
longer the postoperative intensive care. 15. Krowka MJ, Cortese DA. Hepatopulmonary syndrome: an evolv-
• Liver transplantation will reverse HPS over a variable ing perspective in the era of liver transplantation. Hepatology. Jan
amount of time. 1990;11(1):138-142.
16. Seward JB, Hayes DL, Smith HC, et al. Platypnea-orthodeoxia:
Portopulmonary Hypertension clinical profile, diagnostic workup, management, and report of
• Liver transplantation may not reverse portopulmonary seven cases. Mayo Clin Proc. Apr 1984;59(4):221-231.
hypertension (POPH). 17. Martinez GP, Barbera JA, Visa J, et al. Hepatopulmonary syn-
• Right ventricular (RV) function is key to the success of drome in candidates for liver transplantation. J Hepatol. May
2001;34(5):651-657.
liver transplantation in patients with POPH.
18. Schenk P, Fuhrmann V, Madl C, et al. Hepatopulmonary syn-
• Careful assessment of RV function should occur in the drome: prevalence and predictive value of various cut offs for arte-
preoperative and intraoperative periods using trans- rial oxygenation and their clinical consequences. Gut. Dec
esophageal echocardiography. 2002;51(6):853-859.
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192. Castano G, Sookoian S. Female sex and autoimmune hepatitis monary vascular reactivity in portopulmonary hypertension. Liver
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2008;48(6):2090-2090. 216. Swanson KL. What might be learned from acute pulmonary vaso-
193. Kawut SM, Krowka MJ, Trotter JF, et al. Clinical risk factors for dilator testing in portopulmonary hypertension? Liver Transplant.
portopulmonary hypertension. Hepatology. Jul 2008;48(1):196-203. Nov 2007;13(11):1498-1499.
194. Talwalkar JA, Swanson KL, Krowka MJ, et al. Prevalence of 217. Mandell MS, Duke J. Nitric oxide reduces pulmonary hyperten-
spontaneous portosystemic shunts in patients with portopulmo- sion during hepatic transplantation. Anesthesiology. Dec
nary hypertension and effect on treatment. Gastroenterology. Nov 1994;81(6):1538-1542.
2011;141(5):1673-1679. 218. Acosta F, Sansano T, Palenciano CG, et al. Portopulmonary hyper-
195. Provencher S, Hervé P, Jais X, et al. Deleterious effects of beta- tension and liver transplantation: hemodynamic consequences at
blockers on exercise capacity and hemodynamics in patients with reperfusion. Transplant Proc. Nov 2005;37(9):3865-3866.
portopulmonary hypertension. Gastroenterology. Jan 2006;130(1): 219. Afifi S, Shayan S, Al-Qamari A. Pulmonary hypertension and
120-126. right ventricular function: interdependence in pathophysiology
196. Ota K, Shijo H, Kokawa H, et al. Effects of nifedipine on hepatic and management. Int Anesthesiol Clin. Winter 2009;47(1):97-120.
venous pressure gradient and portal vein blood flow in patients with 220. Sibbald WJ, Driedger AA. Right ventricular function in acute dis-
cirrhosis. J Gastroenterol Hepatol. Mar-Apr 1995;10(2):198-204. ease states: pathophysiologic considerations. Crit Care Med. May
197. Navasa M, Bosch J, Reichen J, et al. Effects of verapamil on 1983;11(5):339-345.
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222. Fukazawa K, Poliac LC, Pretto EA. Rapid assessment and safe 231. Taura P, Garcia-Valdecasas JC, Beltran J, et al. Moderate primary
management of severe pulmonary hypertension with milrinone pulmonary hypertension in patients undergoing liver transplanta-
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2010;24(4):515-519. 232. Gillies BS, Perkins JD, Cheney FW. Abdominal aortic compres-
223. Rozkovec A, Montanes P, Oakley CM. Factors that influence the sion to treat circulatory collapse caused by severe pulmonary
outcome of primary pulmonary hypertension. Br Heart J. May hypertension during liver transplantation. Anesthesiology. Aug
1986;55(5):449-458. 1996;85(2):420-422.
224. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diag- 233. Ramsay MA, Simpson BR, Nguyen AT, et al. Severe pulmonary
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2009;34(6):1219-1263. Sep 1997;3(5):494-500.
225. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diag- 234. Prager MC, Cauldwell CA, Ascher NL, et al. Pulmonary hyper-
nosis and treatment of pulmonary hypertension: the Task Force tension associated with liver disease is not reversible after liver
for the Diagnosis and Treatment of Pulmonary Hypertension of transplantation. Anesthesiology. Aug 1992;77(2):375-378.
the European Society of Cardiology (ESC) and the European 235. Yoshida EM, Erb SR, Pflugfelder PW, et al. Single-lung versus
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226. Scouras NE, Matsusaki T, Boucek CD, et al. Portopulmonary 236. Koneru B, Ahmed S, Weisse AB, et al. Resolution of pulmonary
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CHAPTER 40

Donor Selection
and Management
Sherilyn Gordon Burroughs • Burnett “Beau” S. Kelly, Jr. • R. Mark Ghobrial

CHAPTER OUTLINE

BRAIN DEATH EXTENDED CRITERIA DONORS

Historical Perspective and Definition Older Donors
CONFIRMATORY TESTS OF BRAIN DEATH Hepatic Steatosis
Bioelectrical Activity Testing Hepatic Trauma or Other Lesions
Electroencephalography Bacterial or Fungal Infections
Evoked Cerebral Potentials Viral Infections
Cerebral Circulatory Testing Hepatitis B
Doppler Ultrasonography Hepatitis C
Scintigraphy Human Immunodeficiency Virus
Angiography Malignancy

BIOETHICAL ISSUES SPECIAL CONSIDERATIONS: INCREASING THE

DECEASED DONOR POOL
ORGAN DONOR IDENTIFICATION AND CONSENT Split-Liver Transplantation
DONATION AFTER BRAIN DEATH ORGAN Domino Transplantation
RECOVERY PROCESS: THE NATIONAL Machine Perfusion
RESPONSE
ABSOLUTE CONTRAINDICATIONS TO ORGAN
THE PHYSIOLOGICAL EFFECTS OF BRAIN DEATH DONATION
DONOR-RECIPIENT MATCHING Infectious Diseases
Donor Risk Index Malignancy
Organ Inspection
Donor Liver Biopsy

It is estimated that each year in the United States BRAIN DEATH

approximately 20,000 potential brain-deceased donors
are not properly identified as such; furthermore, of Historical Perspective and Definition
those unquestionably opting to donate lifesaving
organs, 17% to 25% of donors are lost due to errors in Before the passage of the first brain death law in Kansas in
management.1 With the persistent disparity of donor 1970,2 non–heart-beating donation (discussed in detail in
organsrelative to patients awaiting liver transplanta- another chapter) was the primary mode of organ donation
tion (LT), the full potential impact of liver transplan- in the United States. Donation after brain death policy
tation has gone unrealized due to the lack of access to was first proposed at a 1965 CIBA Foundation meeting
donor liver grafts (Fig. 40-1).2 Optimization of donor following report of a successful kidney transplant from a
selection and management has thus become a priority brain-dead donor3 and subsequently endorsed with for-
in the effort to reduce this disparity. With an increased mal diagnostic criteria by Harvard Medical School in
understanding of brain-deceased donor physiology 1968.4 Those core criteria—complete apnea, brainstem
and application of ethical and humane donor manage- areflexia, and cerebral ­unresponsiveness—taken together
ment protocols, the supply of viable organs available with evidence of irreversible and permanent loss of
for transplantation can be effectively increased to central nervous system (CNS) function have withstood
match the increasing demand for transplantable liver years of clinical and legal scrutiny and remain fundamen-
grafts. tally unchanged (Table 40-1).

536
 40 Donor Selection and Management 537

The clinical presentation of brain death is a conse- death to radically change the definition of patient death
quence of brain edema resulting in neuronal ischemia and with continued cardiac circulation and ultimately the face
death, generally following traumatic brain injury, cere- of organ donation.
brovascular event, growth of CNS neoplasm, or CNS
infection. The impact of confounding clinical states such
as hypothermia, shock, drug intoxication, severe meta- CONFIRMATORY TESTS OF
bolic derangement, and effects of neuromuscular block- BRAIN DEATH
ade must be considered before making the final diagnosis
of brain death. Methods used to confirm the clinical diagnosis of brain
Intense debate over the concepts of futility of care, the death are categorized based upon assessment of bioelec-
precise timing of brain death, and the ultimate pro- trical brain activity or cerebral circulation.
nouncement of patient death prompted the 1981 Report
of the Medical Consultants on the Diagnosis of Death to
the U.S. President’s Commission. The commission’s rec- Bioelectrical Activity Testing
ommendation was that fulfillment of the criteria for brain Electroencephalography
death should be considered synonymous with meeting
criteria for death of the patient as a whole. The Uniform Electroencephalographic (EEG) recordings have been
Determination of Death Act (UDDA) arose from this shown in experimental models to become irreversibly
recommendation.5 As physicians and hospitals adopted isoelectric after as little as 8 minutes of complete cerebral
this recommendation, optimization of organ function anoxia6; however, continuous recording demonstrating a
with end-organ and nutritional support in patients with lack of activity for at least 30 minutes is required to dem-
no chance of recovery from irreversible CNS insults onstrate irreversible bioelectrical silence and to confirm
became an acceptable goal of care and allowed clinicians clinical brain death.7
to certify death while simultaneously and legally perfus-
ing potential donors with oxygenated blood. This land-
mark recommendation, made in an era of relatively
Evoked Cerebral Potentials
unsophisticated confirmatory testing, prompted the med- Evoked cerebral potentials, elicited after adequate stim-
ically, philosophically, and legally novel concept of brain ulation of peripheral receptors, are undetectable in the
presence of brain death. Though both EEG and evoked
2500 cerebral potentials are noninvasive and can be per-
formed at bedside, evoked cerebral potentials are inde-
pendent of the potential CNS effects of sedatives,
2000 whereas EEG activity is not; in fact serum sedative lev-
els are should be obtained before EEG examination to
prevent an inaccurate or premature brain death
1500 diagnosis.8

1000 Cerebral Circulatory Testing

Doppler Ultrasonography
500
Transcranial Doppler ultrasonography demonstrates
the presence or absence of arterial blood flow at the base
0 of the brain; moreover, as brain perfusion decreases,
2002 2004 2006 2008 2010 2012 characteristic transcranial Doppler ultrasonographic
flow patterns indicating impending circulatory arrest
FIGURE 40-1 n Number of U.S. wait-listed registrants removed
from liver transplant waiting list because of death by year can be detected. The accuracy of transcranial Doppler
(2002-2012). (From UNOS Data Website Query of Annual US Wait- ultrasonographic testing has been reported to be as high
List Mortality. http://www.unos.org. Accessed December 15, 2012.) as 95%.9

TABLE 40-1 Current Guidelines for Determination of Brain Death

Cessation of Life Irreversibility
Absent cerebral Absent brainstem function (loss Cause of coma Possibility of Cessation of all brain
function and of pupillary, corneal, oculoce- established and recovery of any function persists
receptivity phalic, oculovestibular, sufficient to account residual brain for an appropriate
oropharyngeal, respiratory for loss of brain function is ruled period of
reflexes)* function out observation
Failed apnea test

*Spinal cord reflexes may persist after death, but true decerebrate or decorticate posturing or seizures are inconsistent with the diagnosis
of death.
538 PART V Operation

organ recovery, (2) passage of required request legisla-

Scintigraphy
tion, whereby hospitals are required to ask families of
Cerebral perfusion is assessed by performing a nuclear deceased patients to consider organ donation, (3) estab-
medicine brain flow scan with either Tc 99m diethylenetri- lishment of state-sponsored motor vehicle registries, and
amine pentaacetic acid or Tc 99m hexamethylpropyle- (4) implementation of OPO-promoted local grassroots
neamine oxime tracers. Loss of cerebral perfusion is initiatives. Despite tremendous effort and numerous col-
confirmed by lack of intracranial uptake of the intrave- laborative initiatives, the number of deceased donors
nously injected tracer. Scintigraphy is available as a bedside available annually has not increased by even 10% over the
examination at some institutions and is reportedly greater year of peak donor numbers (2007; 8065 donors) in the
than 98% accurate.10 last decade.13 It is thus imperative that all donor candi-
dates, regardless of cause of death, be evaluated.
Angiography
Though not a bedside modality, four-vessel angiography DONATION AFTER BRAIN DEATH ORGAN
is the most accurate means of demonstrating absence of
cerebral blood flow and is considered the diagnostic gold RECOVERY PROCESS:
standard.11 At least two injections of contrast, 20 minutes THE NATIONAL RESPONSE
apart, must show no filling of intracranial arteries to con-
firm loss of cerebral perfusion. In 1980 a national network of local OPOs was developed
in the United States in response to the need for equitable
and efficient coordination of the organ donation and
BIOETHICAL ISSUES recovery process. OPOs serve as a link between donor
hospitals and transplantation centers and provide a vari-
Although over the last 5 decades the medical commu- ety of functions to facilitate organ donation, including
nity has come to accept and better understand the physi- education of families and health care workers on dona-
ological characteristics and diagnosis of brain death, tion and transplantation, assistance in obtaining the
ethical questions and controversy remain, largely in the diagnosis of brain death and family consent, donor resus-
lay arena. Misperceptions and ethical conflicts sur- citation and management, identification of appropriate
rounding the diagnosis of brain death manifest from two organ recipients, and coordination of various surgical
recurring issues surrounding the care of brain-injured recovery teams. A trained coordinator is present at the
patients: (1) the concept of differentiating persistent donor hospital to oversee the process and promote con-
vegetative state from brain death, and (2) our increasing sensus between the multiple teams involved to optimally
ability to successfully provide cardiopulmonary support manage the donor and ensure recovery of all potential
in the critically ill brain-dead patient. Both scenarios organs.
present seemingly paradoxical concepts grieving fami-
lies may find difficult to grasp. Though the UDDA pro-
vides the guiding principles for physicians in the United THE PHYSIOLOGICAL EFFECTS OF
States to pronounce death when brain death criteria are BRAIN DEATH
met, use of independent input from palliative care and
ethics colleagues may assist intensive care unit teams The physiological derangements caused by the process of
caring for potential donors in conveying and helping brain death and the subsequent loss of integrated neuro-
patients’ families understand the implications of a diag- logical function in the potential organ donor can produce
nosis of brain death. profound hemodynamic and metabolic abnormalities
with potential loss of valuable organs. The process is pre-
cipitated by a profound and sustained proinflammatory
ORGAN DONOR IDENTIFICATION cytokine release (“autonomic storm”) and can negatively
AND CONSENT affect the function of multiple systems (Table 40-2).14
The cardiovascular effects of brain death often culmi-
As stated, successful organ recovery occurs in less than nate in a profound reduction in sympathetic outflow with
one third of potential donors; the majority are lost due to vasodilatory and hypovolemic shock (failure of cerebral
inadequate identification processes, donor mismanage- mechanisms to maintain effective peripheral vascular
ment, or family or coroner refusal to allow donation. resistance), dysrhythmia, impaired inotropic and chrono-
Whereas several European nations such as Portugal, tropic response, hypoperfusion, and consequent hemo-
Norway, and Belgium have adopted presumed consent dynamic instability. The release of fibrinolytic factors15
(implied organ donor status unless otherwise declined as a result of neuronal necrosis can induce a significant
before death),12 this concept has not gained favor in the coagulopathy with spontaneous hemorrhage that may
United States. Other venues have thus been created to further exacerbate hypovolemic shock. Ultimately 80%
promote organ donation: (1) passage of the 1986 Omni- to 85% of donors will progress to requiring invasive
bus Reconciliation Act requiring Medicare and Medicaid hemodynamic monitoring and vasopressor support to
recipient facilities to participate in a donor referral sys- maintain organ perfusion.14
tem in connection with local organ procurement organi- Potential respiratory complications are numerous and
zations (OPO) for evaluation of all in-hospital deaths for may include pulmonary artery hypertension with capillary
 40 Donor Selection and Management 539

protecting the patient’s damaged brain to maintaining

TABLE 40-2 B
 rain Death Pathophysiology—
viability of all organs; thus while adjunctive donor ther-
Common Complications
apy is instituted, organ recovery should proceed as expe-
Encountered in Brain-Dead Donors
ditiously as possible to avoid potential donor loss.
Complication Etiology
Hypotension Hypovolemia from osmotic
agents used to decrease ICP
DONOR-RECIPIENT MATCHING
DI
Left ventricular dysfunction When faced with donors demonstrating deranged physi-
Arrhythmias Electrolyte derangements ological or less than ideal characteristics, selection of an
Hypotension with cardiac appropriate recipient for that given donor is critical to the
ischemia successful outcome. Once a potential donor is identified,
Hypothermia
Inotropic effect criteria include patient age, size, blood type, and social/
Increased ICP medical/surgical history, with particular emphasis on
Hyponatremia Alcohol intoxication substance or alcohol use history, hepatobiliary disease,
Hyperglycemia infection, and malignancy. The cause of death, length of
Renal dysfunction hospitalization, results of liver function studies, hemody-
Cardiac failure
Adrenal insufficiency
namics, and pulmonary function should be assessed.
Hypothyroidism Donors possessing all or nearly all “ideal" parameters
Other electrolyte derange- DI such as age less than 50 years, hemodynamic stability with
ments: hypernatremia, minimal or no vasopressor requirement, and absence of
hypomagnesemia, abdominal trauma, systemic infection, malignancy, or
hypokalemia, chronic disease are infrequently encountered. To this
hypocalcemia,
hypophosphatemia end LT donor assessment has evolved into an analysis of
Hyperglycemia Infusion of dextrose-containing how suitable a donor may be for a specific recipient. This
fluid process involves a two- or three-pronged approach that
Catecholamine release includes use of the methods discussed in the following
Inotrope infusion sections.
Hypothermia Infusion of large volumes of
crystalloid or blood products
Loss of thermoregulation Donor Risk Index
Exposure
Coagulopathy Tissue malperfusion with The Donor Risk Index (DRI, Table 40-3) was con-
release of fibrinolytic factors ceived21 to assist clinicians with formulating an objective
determination of donor-recipient pairing suitability. This
Data from Jenkins DH, Reilly PM, Schwab CW. Improving the concept takes into consideration the recipient’s severity
approach to organ donation: a review. World J Surg.
1999;23:644-649; and Karcioglu O, Ayrik C, Erbil B. The brain- of illness (i.e., metabolic needs) and underlying disease
dead patient or a flower in the vase? The emergency department and allows an assessment of donor attributes and comor-
approach to the preservation of the organ donor. Eur J Emerg bidities as they may affect that specific recipient. Use of
Med. 2003;10:52-57. this tool allows for the possibility that a donor deemed
ICP, Intracranial pressure; DI, diabetes insipidus. inappropriate for one recipient may be suitable for
another and therefore decreases the likelihood that any
wall disruption and leakage of protein-rich fluid into the liver graft will be discarded.
pulmonary interstitium, resulting in neurogenic pulmo-
nary edema, aspiration pneumonitis, and ventilator-­ Organ Inspection
associated pneumonia.16
Neuroendocrine changes often occur with relation to Despite employing the DRI in conjunction with surro-
hypothalamic-pituitary axis dysfunction. Diabetes insipi- gate indicators of graft suitability, assessment of the
dus, a consequence of brain injury–related antidiuretic donor is not complete until the liver graft is inspected.
hormone deficiency, can further exacerbate low vascular Information such as laboratory data, history of substance
resistance hypovolemia.17 Anterior pituitary dysregula- abuse, donor body mass index, and surgical history may
tion with impairment of thyroid- and cortisol-dependent give insight into quality; however, only visual inspection
pathways can result in mitochondrial dysfunction, anaer- allows the surgeon to make a final determination.
obic metabolism, and lactic acidosis. Although several
authors have demonstrated that intravenous thyroxine, Donor Liver Biopsy
insulin, and steroid replacement may stabilize donor
physiological characteristics,18-20 central pathophysiolog- Lastly, a preprocurement percutaneous biopsy or intra-
ical changes characterized by thermodysregulation may operative procurement biopsy may assist physicians in
result in irreversible hypothermia, which, along with aci- determining the suitability of a graft. The most common
dosis, can exacerbate coagulopathy, arrhythmia, and car- indications include ruling out malignancy within ques-
diac arrest. In sum, brain-dead donors are very tionable lesions, evaluating degree of steatosis, or grading
physiologically fragile, requiring meticulous care. Once fibrosis in the context of viral hepatitis. A trained pathol-
organ donation is considered, the emphasis expands from ogist should be available on site or at the recipient
540 PART V Operation

TABLE 40-3 D
 onor Risk Index According to Recipient Characteristics for Transplants Performed
Between April 2002 and December 2003
95% Confidence Limits for Donor
Difference from
Recipient Parameter Reference Group P Value Upper Lower

Recipient Age
0-10 0.332 <0.0001 1.65 1.74
11-17 -0.052 0.024 1.24 1.34
18-39 -0.012 0.362 1.30 1.36
40-49 1.343 Ref
50-59 0.033 <0.0001 1.36 1.40
60-69 0.041 <0.0001 1.36 1.41
70+ 0.116 <0.0001 1.41 1.52
Race
Black -0.010 0.385 1.35 1.39
White 1.380 Ref
Other 0.039 0.004 1.39 1.45
Sex
Male -0.041 <0.0001 1.35 1.38
Female 1.408 Ref
Diagnosis
AHN -0.011 0.427 1.34 1.40
Noncholestatic 1.381 Ref
Cholestatic -0.009 0.437 1.35 1.40
Metabolic disease -0.023 0.224 1.32 1.40
Malignant neoplasms 0.000 0.990 1.35 1.41
Other 0.023 0.047 1.38 1.43
Hepatitis C
Positive -0.027 0.001 1.35 1.38
Negative 1.391 Ref
Medical Condition
Not in hospital 1.377 Ref
Missing 0.008 0.894 1.26 1.54
In hospital 0.018 0.069 1.38 1.42
In ICU 0.008 0.536 1.36 1.41
Medical Urgency
Status 1 -0.058 0.007 1.29 1.38
MELD <10 1.399 Ref
MELD 10-14 0.044 0.026 1.40 1.49
MELD 15-19 0.008 0.657 1.37 1.45
MELD 20-24 -0.020 0.256 1.34 1.41
MELD 25-29 -0.031 0.090 1.33 1.40
MELD 30-34 -0.026 0.180 1.33 1.41
MELD ≥35 -0.044 0.027 1.31 1.39

From Feng S, Goodrich NP, Bragg-Gresham JL, et al. Characteristics associated with liver graft failure: the concept of a donor risk index.
Am J Transplant. 2006;6:783-790.
AHN, Acute hepatic necrosis; ICU, intensive care unit; MELD, Model for End-Stage Liver Disease; Ref, reference.

institution to evaluate the biopsy specimen before graft and are evaluated on one or several of the following crite-
implantation. ria that are known to affect recipient outcomes: donor
age, degree of steatosis, history or presence of trauma,
viral or bacterial infection, and donor malignancy.
EXTENDED CRITERIA DONORS
As noted earlier, the concept of DRI has forced the trans-
Older Donors
plant community to attempt to quantify characteristics of Early in the LT experience, potential donors above age
less-than-ideal but usable donor grafts. These liver grafts 50 years were routinely rejected. It is well documented
are generally classified as extended criteria donor grafts that associated with the use of “older” donors for LT is an
 40 Donor Selection and Management 541

increased incidence of generalized chronic vascular dis- 100

ease and parenchymal abnormalities such as steatosis.
The pathological conditions of atherosclerotic arterial
80
vessels in older donors, including the presence of calcified

Patient survival, %
hepatic artery plaque, may be the source of complications
such as hepatic artery thrombosis. In addition, older 60
donors have a higher prevalence of hypertension and dia-
betes mellitus. The combination of older donor age, sys- Control group
temic illness, and moderate to severe steatosis may have 40
HBcAb+ group
an adverse impact on early graft survival. Lastly, donors
of advanced age are associated with a higher incidence of 20
undiagnosed malignancies such as renal cell and prostate
cancer. Meticulous intraoperative examination of all
abdominal organs by the procuring surgeon, particularly 0
in donors of advanced age, may safeguard against unin- 0 1 2 3 4 5 6
tended transmission of donor malignancy. Years since transplant, n
Through careful liberalization of this practice, we have FIGURE 40-2 n No difference in patient survival after liver trans-
learned that donor age alone does not determine graft out- plantation in hepatitis B core antibody–positive (HBVcAb+)
come. At present, advanced age is not a barrier to organ recipients transplanted with grafts from HBVcAb+ donors ver-
sus HBVcAb+ recipients receiving grafts from HBVcAb-negative
donation. The key concept is the donor’s physiological donors. (From Joya-Vazquez PP, Dodson FS, Dvorchik I, et al.
age. Controversy regarding an upper age limit for liver Impact of antihepatitis Bc–positive grafts on the outcome of liver
donation has been overcome by reports demonstrating transplantation for HBV-related cirrhosis. Transplantation. 2002;73:
that the course and outcome of LT are not influenced by 1598-1602.)
donor age.21,22 Minimizing other donor risk features, such
as limiting cold ischemia time to less than 8 hours, has been
shown to produce outcomes in older grafts equivalent to
those of grafts from donors less than 50 years of age.23 affects the respiratory and urinary tracts.27 In addition,
15% of donors have pneumonia and 10% have positive
blood cultures.28 Donor-derived transmission of bacte-
Hepatic Steatosis ria and fungi with recipient mortality has been exten-
Fatty infiltration of the liver is characterized as macrove- sively documented; however, adequate antibiotic
sicular (large fat vacuoles that displace hepatocyte nuclei) treatment of both donor and recipient can prevent
or microvesicular (multiple small fatty cytoplasmic hepa- transmission of infection. If properly treated, recipi-
tocyte inclusions). The quantitative evaluation of steatosis ents of organs from infected donors have the same inci-
is based upon the percentage of hepatocytes containing dence of complications and similar rates of patient and
cytoplasmic fat inclusions. Severely steatotic grafts (>60% graft survival as do recipients of liver grafts from unin-
hepatocytes with macrovesicular fat) have been associated fected donors,27 hence the significance of thorough
with the development of primary nonfunction and should follow-up and postprocurement communication
not be utilized.24 Though primary nonfunction is still a between the OPO and procuring team with regard to
concern when compared with nonsteatotic grafts, the final culture results.
chance of success with use of grafts with moderate steato-
sis (30% to 60%) is more variable. Given the pressing
problem of waiting list mortality, it is reasonable to care- Viral Infections
fully consider use of these grafts, particularly in the absence Hepatitis B
of other significant risk factors. It is now understood that
use of livers with mild steatosis (<30%) is not associated Grafts from hepatitis B (HBV) core antibody (cAb)–
with a worse outcome versus nonsteatotic grafts.25,26 positive donors are acceptable for use in recipients with
HBV-related cirrhosis. Their use does not affect graft
or patient survival (Fig. 40-2); however, HBV disease is
Hepatic Trauma or Other Lesions 2.5 times more likely to recur.29 This risk is mitigated
Acquired localized benign parenchymal liver lesions such by use of hepatitis B immune globulin (HBIg) and anti-
as simple cysts, hematoma, and simple trauma do not viral therapy. The risk for transmission to HBV-naive
exclude potential donors from recovery for LT. In a recipients is unacceptably high and is not reduced by
donor with ischemic parenchymal injuries to hilar struc- administration of HBIg and therefore should not be
tures or vena cava, transplantation is likely not feasible used. Recipients who have preexisting antibodies to
unless the lesion can be repaired or resected and suffi- HBV (IgG HBcAb-positive) because of exposure (with-
cient undamaged parenchyma remains. out HBV cirrhosis) can also safely receive grafts from
IgG HBcAb-positive donors, provided prophylaxis is
given. Thus the most ideal use of HBcAb-positive donor
Bacterial or Fungal Infections grafts are in HBV-infected recipients undergoing LT
Bacterial or fungal infection or colonization is present who are already committed to posttransplant antiviral
in as many as 60% of deceased donors and mainly therapy.
542 PART V Operation

Hepatitis C When evaluating donors with a remote history of

solid organ neoplasm, the biological behavior of the
Approximately 5% of all potential organ donors in the tumor, as well as the stage and grade at diagnosis and the
United States have serological evidence of hepatitis C duration of the disease-free interval, should be consid-
virus (HCV) exposure; half of these donors are RNA ered. Caution must be exercised when considering
HCV positive by polymerase chain reaction.30 Trans- donors with a history of lung or breast carcinoma, which
plantation of livers from HCV antibody–positive donors have been shown to display unpredictable metastatic
into HCV antibody–positive recipients does not seem to potential and late recurrence. Generally, potential
accelerate short- or intermediate-term morbidity or mor- donors can be considered cured when a 5-year disease-
tality from recurrent HCV in the LT recipient when free survival can be demonstrated34; however, meticu-
compared with transplantation of grafts from HCV anti- lous assessment for solitary masses or lymphadenopathy
body–negative donors. Moreover there has been no dif- during recovery is essential. The 2002 United Network
ference in either patient or graft survival or the incidence, for Organ Sharing (UNOS) report on 488 recoveries
timing, or severity of recurrent HCV disease (Fig. from donors with a remote history of malignancy result-
40-3).30,31 ing in 1276 transplants and a 0 rate of disease transmis-
Analysis of graft histological study results before sion corroborates these recommendations.35
transplantation is advised because laboratory data are
often unreliable; only organs with little or no fibrosis
and minimal inflammation should be considered for
transplantation.
SPECIAL CONSIDERATIONS:
INCREASING THE DECEASED
Human Immunodeficiency Virus DONOR POOL
Currently a ban on the use of organs from donors infected Over the last 3 decades, novel techniques have been
with human immunodeficiency virus (HIV) is in effect. introduced in an attempt to reduce the persistent gap
Over the last year, two bills have been introduced in between available deceased donor grafts and the number
Congress, which, if passed, would result in lifting the ban of patients awaiting LT. Those with proven or promising
on these organs—specifically for use in HIV-positive success are discussed in the following sections.
recipients. It is estimated that approximately 1000 addi-
tional transplants would be performed annually should
the bills pass.32
Split-Liver Transplantation
Split-liver transplantation (SLT) has evolved into a surgi-
Malignancy cal procurement technique that allows creation of two
functional allografts from one deceased donor liver. Ini-
Potential donors with untreated low-grade basal or squa- tially conceived as reduced LT by Bismuth and Houssin36
mous cell malignancies, as well as carcinomas in situ (e.g., in 1984, use of SLT accomplishes two goals: potential
cervical), and primary brain tumors with no evidence of elimination of the need for use of a living donor in both
extracranial metastases can be considered for recovery.33 adults and pediatric recipients, and a further step toward

1.0 HCV donor 1.0 HCV donor

HCV donor HCV donor

0.75 0.75
Cumulative survival

Cumulative survival

0.50 0.50

0.25 0.25

0.0 0.0
0 5 0 5
A Time (years) B Time (years)
FIGURE 40-3 n A and B, No significant difference in Kaplan-Meier patient survival (A) or hepatitis C recurrence–free survival (B) in hepa-
titis C antibody–positive recipients receiving liver grafts from hepatitis C antibody–positive donors versus hepatitis C antibody–posi-
tive recipients with grafts from hepatitis C antibody–negative donors. (From Saab S, Ghobrial RM, Ibrahim AB, et al. Hepatitis C positive
grafts may be used in orthotopic liver transplantation: a matched analysis. Am J Transplant. 2003;3:1167-1172.)
 40 Donor Selection and Management 543

more efficient use of deceased donor organs; however, (domino liver transplant) into non-MSUD recipients
proper donor and recipient selection are critical for opti- with acceptable outcomes and no reported dietary
mal outcomes. In 1999 Busuttil and Goss37 enumerated restriction or insufficiency of branched-chain amino
criteria for SLT donor consideration (Table 40-4) that acid metabolism.41
remain relevant in contemporary LT. Adherence to these
principles has resulted in a collective experience with
SLT outcomes that rival those of deceased donor whole Hepatocyte Transplantation
organs.38 General Overview and Indications
Hepatocyte transplantation is a novel, less invasive, alter-
Domino Transplantation native therapy to solid organ liver transplant that pro-
Explanted liver grafts from LT recipients have been vides synthetic and hepatocyte function for patients with
successfully reused for transplantation.39 These recipi- acute liver failure and congenital hepatic-dominant meta-
ents can serve as living donors in very specific circum- bolic disturbances. Indications for hepatocyte transplant
stances (domino, or sequential, liver transplantation). are listed in Table 40-5. Auxiliary or “bridge” liver trans-
In addition to standard donor requirements, condi- plant, to decrease the mortality of acute liver failure, has
tions for domino transplantation include (1) a fully set the precedent for progress in hepatocyte transplant.
functional donor liver and (2) an extrahepatic genetic Due to the redundancy in much of the hepatic mecha-
defect. One such disease is familial amyloid polyneu- nisms, it is estimated that an infusion of 10% to 20% of
ropathy, an autosomal dominant disease involving a functional liver tissue is sufficient to reverse a variety of
genetic defect in transthyretin that is predominantly hepatic enzyme–deficient conditions.42 Over the course
produced by the liver and deposited in renal, gastroin- of the patient’s life span, immunosuppression and associ-
testinal tract, myocardial, and nervous tissues. LT is a ated complications are decreased when compared with
widely accepted treatment, and liver grafts from these solid organ liver transplant. Long-term hepatocyte func-
patients can be used in recipients who are 55 years and tion is limited, however, by chronic rejection and atrophy
older because the latency period for the development of hepatocellular rests. In most cases, patients benefit
of symptoms related to amyloid deposition is approxi- from repeated hepatocyte transplant to provide an ongo-
mately 20 years.40 Another indication for domino ing minimal threshold of metabolic function.
transplant is maple syrup urine disease (MSUD).
MSUD is an autosomal recessive disorder resulting Donor Selection
from a deficiency in branched-chain keto-acid dehy-
drogenase. The unrecognized or untreated condition As with solid organ transplant, donor livers who are
results in branched chain keto-acid accumulation and older than 60 years and have high-grade macrosteatosis
correlative risk of life-threatening cerebral edema, (>60%), extensive cold ischemia (>10hrs), intrahepatic
dysmyelination, and life-long cognitive impairment. or extrahepatic malignancy, hepatocellular dysfunction
Branched-chain keto-acid dehydrogenase is a multi- by biochemical lab testing, transmissible infections, or
subunit enzyme complex of the inner mitochondrial in general, unacceptably high donor risk indices are not
membrane located in the liver (~30%), kidney (~2%)
and skeletal muscle (~60%). Due to this anatomic dis-
tribution, it has been established that patients with TABLE 40-5 D
 isease Indications for Hepatocyte
MSUD benefited from liver transplantation as a Transplant That Have
branched-chain keto-acid dehydrogenase replacement Demonstrated Potential Benefit in
therapy. In turn, the normal non-MSUD patient Human and Animal Studies
retains more than 70% of their extrahepatic branch-
chain amino acid metabolism, and thus the explanted Acute liver failure
liver from patients with MSUD have been transplanted Crigler-Najjar syndrome
Phenylketonuria
Hemophilia
TABLE 40-4 C
 riteria for Selection of In Situ Urea cycle defects
Split-Liver Donors Wilson’s disease
Infantile Refsum’s disease
Hemodynamically stable, heart-beating, cadaveric ­multiorgan Maple syrup urine disease
donor Familial hypercholesterolemia
Minimal to moderate vasopressors (e.g., dopamine <15 Tyrosinemia
mcg/kg/min, norepinephrine 8 mcg/kg/min) Hyperuricemia
Hospitalization <5 days Progressive familial intrahepatic cholestasis
Liver function tests (excluding prothrombin time) abnormality Hyperoxaluria type 1
no greater than 3 × normal
Serum Na <160 mg/dL Data from Jorns C, Ellis EC, Nowak G, et al. Hepatocyte transplan-
Age 10-35? tation for inherited metabolic diseases of the liver. J Intern Med.
2012;272(3):201-223 and Dhawan A, Puppi J, Hughes RD, et al.
From Busuttil RW, Goss JA. Split liver transplantation. Ann Surg. Human hepatocyte transplantation: current experience and future
1999;229:313-321. challenges. Nature Rev Gastroenterol Hepatol 2010;7:288-298.
544 PART V Operation

suitable for optimal hepatocyte transplantation. Rem- the risk of PV thrombus formation and portal hyperten-
nant portions of liver following anatomic split or reduc- sion secondary to decreased terminal radicle PV flow.43-46
tion procedures for solid organ transplant are ideal for No anticoagulation is required unless thrombotic com-
hepatocyte transplant and typically yield the highest plications occur. Repeated transplants are performed to
percentage of viable hepatocytes per gram of donated achieve the necessary “engraftment” and metabolic func-
liver tissue.43 tion. Following hepatocyte infusion, the portal pressure
All of the same donor management principles previ- transiently decreases but then should normalize. Postin-
ously identified, as well as the standard practices of organ fusion hepatic Doppler studies should be performed to
preservation with University of Wisconsin (UW) solu- ensure patency and normalization of portal flow.44-46
tion and cooling to approximately 4° C, optimize the Protocol MRI and technetium scintigram studies can be
potential for successful hepatocyte isolation, cryopreser- performed in followup to demonstrate viable vascularized
vation, and post-reperfusion hepatocellular function. hepatocyte cell populations in either the spleen or liver.
Special research consent from the donor’s next-of-kin Unlike islet cell transplant, there is no biochemical
and a contractual agreement with a hepatocyte isolation marker of hepatocyte function that can be measured in
lab are prerequisites to allocation of any portion of a the recipient.45-48
donor liver for clinical hepatocyte transplant. A whole
donor liver or segment may provide adequate hepatocyte Early Outcomes
function to several recipients.
The number of patients who have undergone hepatocyte
transplant to date is relatively small when compared with
Hepatocyte Isolation, Yield, and
the vast experience in solid organ liver transplantation,
Cryopreservation
and thus the there is no comparable long-term follow-up.
Hepatocyte isolation following standard organ preserva- Hepatocyte function tends to deteriorate after 9 months
tion and recovery occurs via established protocols under precipitating either solid organ or repeat hepatocyte
sterile conditions. Critical steps in hepatocyte isolation transplant. Although many of the enzymatic processes
and preparation for transplant include: and sequelae of acute or metabolic hepatocellular dys-
1. Normothermic (at 37° C) collagenase digestion of function are temporarily reversed, hepatocyte transplant
liver matrix scaffolding via intact hepatic as of yet is not a definitive therapeutic modality. In the
vasculature future, genetically modified hepatocytes or pluripotent
2. Low-speed centrifugation and decanting of hepato- stem cells may serve as the therapy for many liver-based
cyte pellet diseases.49
3. Cell washing and purification with ice-cold buffer
solution
4. Cell counting, viability testing (Percent of yield =
Machine Perfusion
Viable cells/Total cells) via trypan blue exclusion Unfavorable characteristics in extended criteria donor
test, and plating efficiency (cell adhesion and sur- LT are often multiplicative rather than additive. For
rogate measure of engraftment capability) instance, the reduced ischemic tolerance of extended cri-
5. Cryopreservation and cell banking (for up to 3 days teria grafts jeopardizes organ viability during cold storage
without significant loss of viability or plating and can compound the negative effect of other risk fac-
efficiency) tors. Organ machine perfusion, similar to that used for
The average yield from a whole liver is 3-20 × 106 renal grafts, has been developed to limit ischemic dam-
hepatocytes per gram of liver tissue, but this average is age, likely by limiting upregulation of adhesion molecules
negatively impacted by the aforementioned unsuitable and major histocompatibility molecules50,51; both are
conditions.44,45 known to mediate ischemic graft injury. Experimental
models have demonstrated that preservation by oxygen-
ated machine perfusion improves parenchyma viability
Hepatocyte Transplant Procedure
and mitigates the vascular immunogenicity seen with
For clinical transplant, hepatocytes are ABO-compatible, cold storage lesions. Future research in warm machine
have demonstrated plating efficiency and cytochrome perfusion may in fact provide the ideal form of liver pres-
P450 enzyme function with ammonia metabolism, and ervation. Initial studies have demonstrated a 20% reduc-
the percent of yield is greater than 50%.44 Following tion in delayed graft function.52
resuspension of the hepatocytes into perfusate solution
(consistency of fresh frozen plasma), the recipient portal
system is accessed intraoperatively via the inferior mesen- ABSOLUTE CONTRAINDICATIONS
teric vein (IMV), splenic vein, or superior mesenteric
vein (SMV). Alternatively, the portal system can be
TO ORGAN DONATION
accessed percutaneously through the liver into the portal Infectious Diseases
system, or via the splenic vein. Hepatocyte admixture
infusion has been described into the liver, spleen, and Despite the aforementioned advances in expansion of the
even the peritoneum. During any single administration, donor pool for LT recipients, absolute contraindications
the patient receives approximately 5% (up to 108/kg to donation remain. They involve the presence of trans-
bodyweight) of the hepatocellular volume to minimize missible agents with an attendant high risk for mortality
 40 Donor Selection and Management 545

or severely debilitating disease in the profoundly immu- 3. Choi E-K, Fredland C, Zachodni C, et al. Brain death revisited: the
nosuppressed recipient and include donor fungemia, case for a national standard. J Law Med Ethics. 2008;36(4):
824-836.
mycobacterial infection, and disseminated multisite bac- 4. Merrill JP, Murray JE, Tackacs FJ, et al. Successful transplantation
terial infections with resistant strains. Less common, but of kidney from a human cadaver. JAMA. 1963;185:347-353.
potentially highly fatal prion-related infections such as 5. A definition of irreversible coma Report of the Ad Hoc Committee
Creutzfeldt-Jakob disease are also included. of the Harvard Medical School to Examine the Definition of Brain
Death. JAMA. 1968;2015:337-340.
As noted earlier, use of organs from HIV-infected 6. Guidelines for the determination of death Report of the medical
donors is prohibited, as is use of organs from HBVcAb- consultants on the diagnosis of death to the President’s Commis-
positive or HCV antibody–positive donors in HBV-­ sion for the Study of Ethical Problems in Medicine and Biomedical
negative or HCV-negative recipients, respectively.29,31 and Behavioral Research. JAMA. 1981;246:2184-2186.
Viral testing has become more accurate since the intro- 7. Brierley JB, Prior PF, Calverly J, et al. The pathogenesis of isch-
aemic neuronal damage along the cerebral artery boundary zones
duction of nucleic acid testing in 2002 because the test in Papio anubis. Brain. 1980;103:929-965.
effectively reduces the “window period” during which a 8. Guideline three: Minimum technical standards for EEG recording
donor may be recently infected, but traditional antibody in suspected cerebral death. American Electroencephalographic Society
testing remains negative. In fact through 2009 the donor J Clin Neurophysiol. 1994;11:10-13.
9. Meinitzer A, Kalcher K, Gartner G, et al. Drugs and brain death
HIV transmission rate in the United States has been cal- diagnostics: determination of drugs capable of inducing EEG zero
culated as 0.00002.53,54 Specificity, however, remains line. Clin Chem Lab Med. 2008;46:1732-1738.
problematic. It is estimated that 141 organs are declined 10. Roper AH, Kehne SM, Weschler L. Transcranial Doppler in brain
annually because of nucleic acid testing results that are death. Neurology. 1987;37:1733-1735.
false-positive for HIV.53 11. De la Riva A, Gonzalez FM, Llamas-Elvira JM, et al. Diagnosis of
brain death: superiority of perfusion studies with 99mTc-HMPAO
over conventional radionuclide cerebral angiography. Br J Radiol.
Malignancy 1992;65:289-294.
12. Monsein LH. The imaging of brain death. Anaesth Intensive Care.
The presence of an active hematological malignancy, 1995;23:44-50.
13. Neades BL. Presumed consent to organ donation in three Euro-
extracranial malignancy, or primary brain tumor with pean nations. Nurs Ethics. 2009;16:267-282.
extracranial metastases is an absolute contraindication to 14. Jenkins DH, Reilly PM, Schwab CW. Improving the approach to
organ donation. organ donation: A review. World J Surg. 1999;23:644-649.
Because the criteria for donation are continuing to 15. Oakes DD, Sherck JP, Haddow GR, et al. The Anesthesiologist
selectively expand, LT has become an option for a greater and the brain-dead patient. Optimal strategies for multiple organ
procurement. Rev EEUU Anest. 1997;7:55-58.
number of patients with end-stage liver disease, thereby 16. Demling R, Riessen R. Pulmonary dysfunction after cerebral
helping transplant professionals meet the increased need injury. Crit Care Med. 1990;18:768-774.
for transplantable organs. 17. Saner FH, Kavuk I. Radtke: Organ protective management of the
brain-dead donor. Eur J Med Res. 2004;9:485-490.
18. Masson F, Thicoipe M, Latapie MJ, et al. Thyroid function in
Pearls and Pitfalls brain-dead donors. Transpl Intl. 1990;3:226-233.
19. Salim A, Vassiliu P, Velmahos GC. The role of thyroid hormone
• Optimization of liver graft function requires early iden- administration in potential organ donors. Arch Surg. 2001;136:
1377-1380.
tification and meticulous management of all potential
20. Kotsch K, Ulrich F, Reutzel-Selke, et al. Methylprednisolone ther-
donors—all livers are usable until proven otherwise. apy in deceased donors reduces inflammation in the donor liver
• Expanded criteria for liver graft use have been successfully and improves outcome after liver transplantation: a prospective
applied to increase the number of patients receiving liver randomized controlled trial. Ann Surg. 2008;248:1042-1050.
transplants annually. 21. Feng S, Goodrich NP, Bragg-Gresham JL, et al. Characteristics
• The use of select grafts from donors with traumatic inju- associated with liver graft failure: the concept of a donor risk index.
ries, viral exposures, and history of neoplasms, as well as Am J Transplant. 2006;6:783-790.
the use of partial liver grafts and reuse of domino grafts, 22. Wall WJ, Mimeault R, Grant DR, et al. The use of older donor liv-
are all proven effective methods for expanding the LT do- ers for hepatic transplantation. Transplantation. 1990;49:377-381.
23. Cescon M, Grazi GL, Cucchetti A. Improving the outcome of liver
nor pool.
transplantation with very old donors with updated selection and
• Failure to provide adequate physiological support to po- management criteria. Liver Transpl. 2000;14:672-679.
tential donors accounts for loss of at least 25% of donor 24. Veretemati M, Sabatella G, Minola E. Morphometric analysis of
organs. primary graft non-function in liver transplantation. Histopathology.
• Full understanding of protocols for brain death deter- 2005;46:451-459.
mination and brain death physiological characteristics is 25. Crowley H, Lewis HD, Gordon F, et al. Steatosis in donor and
necessary for successful recovery of liver grafts. liver biopsies. Hum Pathol. 2000;31:1209-1213.
• Donor characteristics negatively influencing graft func- 26. Imber CJ, St Peter SD, Handa A, et al. Hepatic steatosis and its
tion include advanced age, prolonged ischemia, and relationship to transplantation. Liver Transpl. 2002;8:415-423.
27. Lopez-Navidad A, Caballero F. Extended criteria for organ accep-
steatosis. These characteristics are multiplicative rather
tance. Strategies for achieving organ safety and for increasing
   than additive. organ pool. Clin Transplant. 2003;17:308-324.
28. Freeman RB, Glatras I, Falagas ME, et al. Outcome of transplanta-
tion of organs procured from bacteremic donors. Transplantation.
1999;68:1107-1111.
REFERENCES 29. Joya-Vazquez PP, Dodson FS, Dvorchik I, et al. Impact of anti-
1. Jenkins DH, Reilly PM, McMahon DJ, et al. Minimizing charges hepatitis Bc –positive grafts on the outcome of liver transplantation
associated with the determination of brain death. Crit Care. for HBV-related cirrhosis. Transplantation. 2002;73:1598-1602.
1997;1:65-70. 30. Saab S, Ghobrial RM, Ibrahim AB, et al. Hepatitis C positive grafts
2. UNOS: United Network for Organ Sharing http://www.unos.org. may be used in orthotopic liver transplantation: A matched analy-
accessed December 15, 2012. sis. Am J Transplant. 2003;3:1167-1172.
546 PART V Operation

31. Northrup PG, Argo CK, Nguyen DT. Liver allografts from hepa- 43. Puppi J, Strom SC, Hughes RD, et al. Improving the techniques
titis C donors can offer good outcomes in hepatitis C positive recip- for human hepatocyte transplantation: a report from a consensus
ients: a US national transplant registry experience. Transpl Intl. meeting in London. Cell Transplant. 2012;21(1):1-10.
2010;23:1038-1044. 44. Jorns C, Ellis EC, Nowak G, et al. Hepatocyte transplantation for
32. Boyarsky BJ, Hall EC, Singer AL, et al. Estimating the potential inherited metabolic diseases of the liver. J Inter Med.
pool of HIV-infected deceased organ donors in the United States. 2012;272(3):201-223.
Am J Transplant. 2011;11:1209-1217. 45. Jorns C, Gramignoli R, Saliem M, et al. Strategies for short-term
33. Nalesnik MA, Woodle ES, Dimiao JM, et al. Donor-transmitted storage of hepatocytes for repeated clinical infusions. Cell Trans-
malignancies in organ transplantation: assessment of clinical risk. plant. 2014;4:1009–1018.
Am J Transplant. 2011;11:1140-1147. 46. Dhawan A, Puppi J, Hughes RD, et al. Human hepatocyte trans-
34. Kauffman HM, McBride MA, Delmonico FL. First report of the plantation: current experience and future challenges. Nature Rev
United Network for Organ Sharing Transplant Tumor Registry: Gastroenterol Hepatol. 2010;7:288-298.
donors with a history of cancer. Transplantation. 2000;70: 47. Ito M, Nagata H, Miyakawa S, et al. Review of hepatocyte trans-
1747-1751. plantation. J Hepatobiliary Pancreat Surg. 2009;16(2):97-100.
35. Myron KH, McBride MA, Cherikh WS, et al. Transplant tumor 48. Wang F, Zhou L, Ma X, et al. Monitoring of intrasplenic hepatocyte
registry: Donor related malignancies. Transplantation. transplantation for acute-on-chronic liver failure: a prospective five-
2002;74:358-362. year follow-up study. Transplant Proc. 2014;46(1):192-198.
36. Bismuth H, Houssin D. Reduced-size orthotopic liver graft for 49. Hughes RD, Mitry RR, Dhawan A. Current status of hepatocyte
liver transplantation in children. Surgery. 1984;95:367-370. transplantation.Transplantation. 2012;93(4):342-347.
37. Busuttil RW, Goss JA. Split liver transplantation. Ann Surg. 50. Schlegel A, Rougement O, Graf R, et al. Protective mechanisms
1999;229:313-321. of end-ischemic cold machine perfusion in DCD liver grafts.
38. Merion RM, Rush SH, Dykstra DM, et al. Predicted lifetimes for J Hepatol. 2013;58:278-286.
adult and pediatric split liver versus adult whole liver transplant 51. Henry SD, Nachber E, Tulipan J, et al. Hypothermic machine pres-
recipients. Am J Transplant. 2004;4:1792-1798. ervation reduces molecular markers of ischemia/reperfusion injury in
39. Carrera MT, Eh Bogue, Schiano TD. Domino liver transplanta- human liver transplantation. Am J Transplant. 2012;12:
tion: a practical option in the face of the organ shortage. Prog 2477-2486.
Transplant. 2003;13:151-153. 52. Wight JP, Chilcott JB, Holmes MW, et al. Pulsatile machine per-
40. Yamamoto S, Wilczek HE, Nowak G, et al. Liver transplantation fusion vs. cold storage of kidneys for transplantation: a rapid and
for familial amyloidotic polyneuropathy (FAP): a single center systematic review. Clin Transplant. 2003;17:293-307.
experience over 16 years. Am J Transplant. 2007;7(11):2597-2604. 53. Shafer TJ, Schkade D, Schkade L. Zero risk tolerance costs lives:
41. Mazariegos GV, Morton DH, Sindhi R, et al. Liver transplantation loss of transplantable organs due to human immunodeficiency
for classical maple syrup urine disease: long-term follow-up in 37 virus nucleic acid testing of potential donors. Prog Transplant.
patients and comparative UNOS experience. J Pediatr. 2011;21:236-247.
2012;160(1):116-121. 54. Ison MG, Llata E, Friedewald JJ, et al. Transmission of human
42. Gramignoli R, Tahan V, Dorko K, et al. Hypothermic storage of immunodeficiency virus and hepatitis C virus from an organ donor
human hepatocytes for transplantation. Cell Transplant. 2013. June to four transplant recipients. Am J Transplant. 2011;11:
13 [Epub ahead of print]. 1218-1225.
 CHAPTER 41

Extended Criteria Donors

Ronald W. Busuttil • Joseph DiNorcia • Fady M. Kaldas

CHAPTER OUTLINE

ADVANCED AGE DAMAGED LIVERS

HEPATIC STEATOSIS REUSE OF LIVER ALLOGRAFTS
POSITIVE VIRAL SEROLOGIC STUDY RESULTS DOMINO LIVER TRANSPLANTATION
CENTERS FOR DISEASE CONTROL AND PROLONGED COLD ISCHEMIA TIME
PREVENTION HIGH-RISK DONORS
INFORMED CONSENT
INFECTION
FUTURE DIRECTIONS
PRIOR MALIGNANCY
CONCLUSION
DONATION AFTER CARDIAC DEATH

The disparity between supply and demand of organs for the largest expanding component of the donor organ
transplantation continues to grow, and the organ short- pool, and their use has had a significant impact on the rate
age has made it necessary to liberalize acceptance criteria of liver transplantation.8 Several studies in the literature
to include donors beyond traditional criteria. These have demonstrated that outcomes after liver transplanta-
donors collectively are known as extended criteria donors. tion from elderly donors are comparable to outcomes
(ECDs) In the past, an “ideal” donor was defined as age from younger donors. These studies demonstrate good
less than 40 years, trauma as the cause of death, donation outcomes with livers from donors older than 60, 70, and
after brain death (DBD), hemodynamic stability, and even 80 years.9-15 Although there is no absolute age limit,
absence of steatosis, chronic liver disease, or transmissible several points about older liver allografts deserve
disease.1,2 Use of an allograft from an ECD versus from emphasis.
an ideal donor puts the recipient at higher risk for postop- Elderly donors have decreased physiological reserve
erative complications such as impaired allograft function and frequent comorbidities that may affect organ pro-
(delayed graft function or primary graft nonfunction) or curement.8 The recovery surgeon should work in concert
transmission of a donor-derived disease (infection, malig- with the organ procurement, anesthesia, and hospital
nancy, or other disease). Although organs from ECDs teams to optimize donor physiological condition and
may not be ideal, they are viable alternatives while await- operating room conditions. The presence of atheroscle-
ing liver transplantation. Centers across the world are rotic disease, aneurysmal disease, and prior cardiotho-
using grafts from ECDs with outcomes comparable to racic or abdominal surgery may require modification of
grafts from normal donors.3-7 Although there is no pre- the methods normally used to procure the liver safely.
cise definition of an ECD in liver transplantation, refer- Characteristic features of older liver allografts include
enced donor factors that have been associated with poorer smaller size, steatosis, capsular fibrosis, and arterial ath-
outcomes or disease transmission include advanced age, erosclerosis.16 Careful inspection of the liver before and
hepatic steatosis, positive viral serological study results, after cold perfusion is necessary to evaluate the degree of
donation after cardiac death (DCD), and history of infec- these features and how they might affect the intended
tion, malignancy, or metabolic disease. This chapter recipient. In addition, the higher incidence of undiag-
examines how each of these factors defines an ECD and nosed malignancy in elderly donors requires meticulous
affects the use of liver allografts. examination of the entire operative field to safeguard
against the transmission of a previously unknown cancer.
Allografts from elderly donors are more susceptible to
ADVANCED AGE cold ischemia time and can have increased delayed graft
function and prolonged cholestasis consistent with sig-
As the population ages and the availability of suitable nificant ischemia-reperfusion injury.16,17 Thus minimiz-
organs decreases, the acceptable age of potential donors ing cold ischemia time is of paramount importance. In
has increased. Organs from elderly donors now represent addition, selected recipients of older allografts should be

547
548 PART V Operation

able to endure a degree of delayed graft function. Older minimal effect on graft function, macrovesicular steatosis
liver allografts also have an increased risk for hepatitis C has been associated with poor graft function. Macrove-
virus recurrence and should be used with caution in sicular steatosis can be subcategorized as mild (<30%),
patients with hepatitis C–related liver disease. Data in the moderate (30% to 60%), and severe (>60%). Substantial
literature consistently demonstrate earlier hepatitis C data have correlated the extent of macrovesicular steato-
recurrence, increased graft failure, and decreased survival sis with the incidence of graft dysfunction.31-34 Mild mac-
in hepatitis C–positive recipients of allografts from rosteatosis has minimal impact on graft function, provided
donors older than 60 years.18-25 that the cold ischemia time is short. Allografts with mild
In summary, liver transplantation outcomes with macrosteatosis can be used safely in select recipients.35,36
allografts from elderly donors can be excellent provided Moderate macrosteatosis has variable effect on outcomes,
there are no additional risk factors. Age alone therefore and use of these grafts remains challenging. The inci-
should not exclude potential liver donors, especially for dence of delayed function approaches 35%, and primary
recipients who might otherwise have a prolonged wait on nonfunction is reported as high as 15% in grafts with
the list. Use of allografts from elderly donors should be moderate macrosteatosis.1 Careful donor evaluation to
limited to those with minimal steatosis. Attention to exclude additional risk factors, careful selection of recipi-
other donor risk factors, recipient factors, and especially ents who can tolerate potential delayed graft function,
cold ischemia time is necessary to ensure optimal out- and minimization of cold ischemia time are paramount to
comes after transplantation of older liver allografts. the successful use of moderately steatotic allografts.
Allografts with severe macrosteatosis have a high rate of
primary nonfunction and should not be used.37 Any
HEPATIC STEATOSIS degree of fibrosis associated with steatosis also should
preclude the use of the graft.
Hepatic steatosis is one of the most important factors
affecting allograft function. Early functional recovery and
regenerative capacity of liver allografts are significantly POSITIVE VIRAL SEROLOGIC
impaired when steatosis is present, likely because of more STUDY RESULTS
severe ischemia-reperfusion injury.26,27 With the grow-
ing obesity epidemic, transplant surgeons are encounter- Liver allografts from donors with positive viral serologic
ing more hepatic steatosis in donors. The prevalence of study results should be used only if the recipient is already
steatosis within developed countries ranges between 10% infected with the same agent or has a critical need for
and 30% of the population.28,29 Steatosis is most common liver transplantation. Use of serologically positive
in donors with a history of obesity, diabetes, and alcohol allografts requires a frank discussion with the recipient
consumption, and the presence of these factors should and informed consent before transplantation.38 Several
prompt careful evaluation for steatosis at the time of pro- studies in the literature report favorable outcomes with
curement. Inspection at procurement helps detect steato- the use of liver allografts from patients with positive sero-
sis (Fig. 41-1), but biopsy is the gold standard to grade logical study results for hepatitis C virus (HCV), hepatitis
the degree of steatosis.30 B virus (HBV), and human T-cell lymphotropic virus 1/2
Steatosis can be subdivided into microvesicular or (HTLV-1/2).
macrovesicular steatosis. In microvesicular steatosis, mul- Approximately 5% of all potential organ donors in the
tiple small fat vacuoles occupy the cytoplasm of the hepa- United States and Europe are positive for antibody to
tocyte. In macrovesicular steatosis, one large fat vacuole HCV, and half of these donors are positive for HCV
replaces most of the cytoplasm and displaces the nucleus RNA by polymerase chain reaction.7 HCV-positive
of the hepatocyte.27 Whereas microvesicular steatosis has allografts without severe inflammation or fibrosis are best
used for recipients with HCV-related liver disease. Data
in the literature clearly indicate that there is no difference
in HCV recurrence, graft survival, or patient survival
with the use of HCV-positive allografts in HCV-positive
recipients compared to recipients receiving an HCV-
negative allograft.39-45 Studies also have examined the
dynamic interaction of donor and recipient HCV strains
after liver transplantation and found no consistent pat-
tern of viral repopulation.46 Liver recipients in whom the
donor HCV strain becomes predominant can have sig-
nificantly longer disease-free survival than recipients who
retain their own HCV strain.44 Because genotype is pre-
dictive only of response to interferon-based therapy and
not disease severity, genotype is not an important consid-
eration in the decision to transplant a liver from an HCV-
positive donor.47 In summary, the literature shows that
transplanting an HCV-positive allograft into an HCV-
positive recipient is safe with long-term outcomes com-
FIGURE 41-1 n Steatotic donor liver. parable to HCV-negative allografts. The procurement
 41 Extended Criteria Donors 549

team should consider donor liver biopsy to evaluate for strategies with anti-HBV medications and hepatitis B
severe inflammation or fibrosis, the presence of which immune globulin are ultimately successful in HBV DNA
should preclude use of the allograft.29,48 The use of HCV- negative seroconversion.50
positive liver allografts for HCV-negative recipients or Transplantation of liver allografts from donors with
for HCV-positive recipients with an undetectable viral HTLV-1/2 infection risks transmission to the recipient
load should be reserved for cases of extreme necessity.8 and subsequent development of either adult T-cell leuke-
The risk for transmission of HBV via liver transplanta- mia or myelopathy (tropical spastic paraparesis).57 The
tion is high. However, allografts from hepatitis B surface majority of HTLV-1 infections do not cause disease in
antigen (HBsAg)-negative/hepatitis B core antibody immunocompetent hosts, and HTLV-2 has not been
(HBcAb)-positive donors are being used to expand the linked to human disease. However, the immunocompro-
donor pool with comparable graft and patient surviv- mised status of liver transplant recipients may increase
als.49,50 HBcAb-positive donors represent 3% to 6% of their risk for developing HTLV-associated disease. In
the donor pool in the United States, 8% to 15% of the the United States the prevalence of HTLV-1/2 infection
donor pool in Europe, and 50% to 55% of the donor pool is estimated to be 0.05% to 0.1%, and therefore most
in Asia, and the need to use HBcAb-positive allografts donors are not routinely tested for HTLV-1/2.29 The
varies with the regional incidence of HBV.51 Persistent prevalence can be as high as 30% in endemic areas such
intrahepatic HBV DNA in HBsAg-negative/HBcAb- as the Caribbean, South America, Africa, and Asia.29
positive patients is a reservoir for potential viral reactiva- Studies from across the world thus demonstrate varying
tion, particularly in the setting of posttransplant rates of transmission of infection and development of dis-
immunosuppression.52,53 Thus, in the absence of postop- ease.5,58-63 Despite the small but real risk for developing
erative antiviral prophylaxis, the rate of de novo HBV HTLV-associated disease after liver transplantation,
infection is reported as high as 75% to 80% in HBsAg- HTLV-positive allografts can be used for select recipi-
negative/HBcAb-negative recipients, 15% to 20% in ents, including those who have urgent need, older recipi-
HBsAg-positive or HBcAb-positive recipients, and 5% to ents, and patients who are HTLV-positive before
10% in hepatitis B surface antibody (HBsAb)-positive/ transplantation. Recipients of HTLV-positive liver
HBcAb-positive recipients.54 The presence of antibodies allografts should undergo heightened screening after
to hepatitis B surface antigen and hepatitis B core antigen transplantation.
in the recipient reduces the rate of HBV infection after
transplantation with an HBcAb-positive liver allograft.55,56
Liver allografts from HBcAb-positive donors thus should CENTERS FOR DISEASE CONTROL AND
be used preferentially in recipients who are undergoing PREVENTION HIGH-RISK DONORS
transplantation for HBV-related liver disease. Because of
the effectiveness of anti-HBV medications, HBcAb-posi- Unexpected transmission of human immunodeficiency
tive liver allografts also can be used safely in HBsAg-neg- virus (HIV), HCV, and HBV through organ transplanta-
ative/HBcAb-negative recipients but should be reserved tion remains a patient safety and public health concern.
for cases of urgent need and in areas with high HBV The Centers for Disease Control and Prevention (CDC)
prevalence when possible.51 Lifelong compliance with has identified certain criteria that confer increased risk
anti-HBV prophylaxis and permanent surveillance post for recent HIV, HCV, and HBV infection in the donor
transplantation are imperative (Fig. 41-2). Should de (Table 41-1).64 Donors who meet these criteria are desig-
novo infection occur in the recipient, various treatment nated as CDC high-risk. Despite advances in screening for

ANTI-HEPATITIS B CORE POSITIVE LIVER GRAFTS

HBsAg-positive Anti-HBc–positive and/or Anti-HBc–negative and

recipients anti-HBs–positive anti-HBs–negative
recipients recipients

anti-HBc+ anti-HBc+ anti-HBc–

anti-HBs+ anti-HBs– anti-HBs+
HBIg
Post-LT prophylaxis + none LAM LAM LAM
LAM
FIGURE 41-2 n Proposed algorithm for allocation and management of anti–hepatitis B core (HBc)–positive liver grafts. Such grafts
should be offered first to hepatitis B surface antigen (HBsAg)-positive, then to anti-HBc– and/or anti-HBs–positive, and lastly to hepa-
titis B virus (HBV)-naive (both anti-HBc– and anti-HBs–negative) recipients. HBIg, Hepatitis B immune globulin; LAM, lamivudine; LT,
liver transplantation. (From Cholongitas E, Papatheodoridis GV, Burroughs AK. Liver grafts from anti-hepatitis B core positive donors: a
systematic review. J Hepatol. 2010;52(2):272-279.)
550 PART V Operation

infection is particularly concerning because of immuno-

TABLE 41-1 CDC High-Risk Criteria
suppression in the recipient. Although the overall risk is
• People who have had sex with a person known or very low, transmissions of bacterial, fungal, viral, and
suspected of having HIV, HBV, or HCV infection in the parasitic infections via liver transplantation have been
preceding 12 months reported in the literature. Rare cases of aspergillosis, his-
• Men who have had sex with men (MSM) in the preceding toplasmosis, strongyloidiasis, and West Nile virus trans-
12 months mission have also been reported.67-72 Thus in areas where
• Women who have had sex with a man with a history of certain infections are endemic, increased screening of
MSM behavior in the preceding 12 months
donors is necessary.
• People who have had sex in exchange for money or
drugs in the preceding 12 months Systemic bacterial or fungal infection in the donor
• People who have had sex with a person who had sex in used to preclude organ use;, however, large series have
exchange for money or drugs in the preceding 12 months documented that, with appropriate antibiotic treat-
• People who have had sex with a person who injected ment, graft and patient survivals are comparable to
drugs by intravenous, intramuscular, or subcutaneous those of recipients of grafts from donors without infec-
route for nonmedical reasons in the preceding 12 months tion.57,73,74 After transplantation, recipients of liver
• A child who is 18 months of age and born to a mother allografts from bacteremic donors should receive a
known to be infected with, or at increased risk for, HIV,
HBV, or HCV infection
course of antibiotics directed against the donor iso-
• A child who has been breast-fed within the preceding 12
late.74-76 Liver allografts from donors with bacterial
months and the mother is known to be infected with, or meningitis also can be used safely provided that both
at increased risk for, HIV infection the donor and recipient are treated appropriately.73,77
• People who have injected drugs by intravenous, intra- Liver allografts should not be used if the donor has sus-
muscular, or subcutaneous route for nonmedical reasons tained bacteremia despite treatment, disseminated
in the preceding 12 months infection, or infection with an unidentified agent. An
• People who have been in lockup, jail, prison, or a juvenile unknown cause of death in the donor should raise con-
correctional facility for more than 72 consecutive hours in
the preceding 12 months cern and preclude use of the liver without further inves-
• People who have been newly diagnosed with, or have tigation to exclude occult infection.
been treated for, syphilis, gonorrhea, Chlamydia, or
genital ulcers in the preceding 12 months
Donors who meet the following criterion should be PRIOR MALIGNANCY
identified as being at increased risk for recent HCV infection
only:
• People who have been on hemodialysis in the preceding
Allografts from donors with a documented history of
12 months malignancy should be used with extreme caution. There
are several reports in the literature of transmission of
CDC, Centers for Disease Control and Prevention; HBV, hepatitis B malignancy from the donor to the recipient with poor
virus; HCV, hepatitis C virus; HIV, human immunodeficiency outcomes.78-82 The most frequently transmitted malig-
virus.
nancies in solid organ transplantation include central
nervous system tumors, melanoma, and renal cell, lung,
these pathogens, the risk for transmission through liver and breast carcinomas.83,84 When considering an organ
transplantation persists. Infection in the donor may go from a donor with malignancy, the risk for transmission
undetected because multiple blood transfusions confound must be weighed carefully against the recipient’s risk for
testing by serum dilution or because the testing happened death on the waiting list. Liver allografts from donors
during the window period for the infection.65,66 When with low-grade central nervous system tumors or a dis-
considering an allograft from a CDC high-risk donor, the tant history (>5 years) of treated low-grade malignancies
transplant team must weigh the risk for transmission of a (e.g., nonmelanoma skin cancers) may be considered for
potentially fatal disease against the risk for recipient death transplantation.47,85,86 High-grade malignancy and meta-
on the waiting list. These risks can be difficult to quantify static malignancy are associated with an increased risk for
and must be individualized to the specific donor and transmission and therefore should preclude organ dona-
recipient. Frank disclosure about the risks and voluntary tion. Recipients of allografts from donors with malig-
consent from the recipient are mandatory before trans- nancy should have their immunosuppression modulated
plantation.38 After transplantation, recipients of allografts to avoid oversuppressing the immune system’s innate
from CDC high-risk donors should undergo appropri- tumor surveillance. There is a potential benefit to using
ately timed screening for HIV, HCV, and HBV. mammalian target of rapamycin inhibitors in these
patients because of the combined antiproliferative and
immunosuppressive effects.87
INFECTION
The presence of infection in the donor is common, with DONATION AFTER CARDIAC DEATH
bacterial and fungal infection or colonization present in
up to 60% of donors.7 Donor infection alone is not a risk Formerly referred to as non–heart-beating donors, DCD
factor for subsequent graft failure but requires compre- donors can be classified according to the Maastricht cri-
hensive donor and recipient assessment and treatment teria (Table 41-2).88 In Maastricht category 1, death is
at the time of liver transplantation. Transmission of declared at a site outside the hospital, and the potential
 41 Extended Criteria Donors 551

include age less than 50 years, absence of steatosis, and

TABLE 41-2 T
 he Modified Maastricht
warm ischemia time less than 30 minutes. The incidence
Classification of Donation After
of biliary complications increases significantly with warm
Cardiac Death Donors
ischemia times beyond 30 minutes.98,99 Optimal recipi-
Category 1 Dead on arrival ent-related characteristics include age less than 50 years,
Category 2 Unsuccessful resuscitation body mass index less than 30, negative hepatitis C virus
Category 3 Anticipated cardiac arrest status, and low Model for End-Stage Liver Disease
Category 4 Cardiac arrest in a brain-dead donor (MELD) score. In addition, every effort should be made
Category 5 Unexpected cardiac arrest in an to limit the cold ischemia time of DCD allografts to less
intensive care unit patient than 8 hours.100-102 The literature reports large differ-
ences in graft and patient survivals between recipients of
DCD versus DBD livers.29 However, the consensus is
donor is brought to the hospital without resuscitation. that through careful consideration and optimization of
In Maastricht category 2, arrest occurs unexpectedly, donor- and recipient-related characteristics, outcomes
and resuscitation is unsuccessful. Maastricht category 3 after liver transplantation with DCD allografts can be
is anticipated cardiac arrest after removal of ventilator similar to those with DBD allografts.103
support, and Maastricht category 4 is unanticipated car-
diac arrest in a brain-dead donor.89,90 A modified clas-
sification includes Maastricht category 5, unanticipated DAMAGED LIVERS
cardiac arrest in an intensive care unit patient.91 Cate-
gories 1, 2, and 5 are considered uncontrolled donation, Hepatic trauma in the donor should not automatically
which require maintenance of organ perfusion and exclude the graft from transplantation. It should prompt
rapid cooling by either postmortem cardiopulmonary the transplant team to investigate the donor’s cause of
resuscitation or cardiopulmonary bypass with external death and hospital course to exclude significant events
oxygenation.92 Categories 3 and 4 are considered con- such as hemodynamic instability, oxygen desaturation, or
trolled donation. Whereas use of controlled DCD uncontrolled hemorrhage that suggest prolonged graft
allografts has increased steadily, now accounting for compromise. Hematomas and lacerations must be evalu-
5% of liver transplantation,93 use of uncontrolled DCD ated on a case-by-case basis to determine the degree of
allografts is rare in the United States, with the majority damage. Although superficial or localized traumatic
of DCD cases being Maastricht category 3. DCD there- lesions most often do not preclude transplantation, injury
fore refers to Maastricht category 3 in the following to the hilar structures, hepatic veins, or vena cava must be
discussion. amenable to repair without graft compromise.104,105 A
DCD is a fundamentally different organ procure- donor liver with ischemic parenchyma requires particu-
ment technique based on cardiopulmonary criteria larly close scrutiny to assess the cause and degree of
rather than neurological criteria for death. Patients who injury. A graft with localized ischemia may be salvage-
do not meet neurological criteria for death, but who able, whereas one with diffuse ischemia should not be
have no hope for a meaningful recovery can become used. In all cases of hepatic trauma, there must be suffi-
organ donors. After the family independently decides to cient uncompromised hepatic parenchyma to recover and
withdraw life support, the organ procurement organiza- function after reperfusion.
tion can discuss donation and obtain consent. Unlike
allografts from DBD donors, which experience normal
organ perfusion until the point of induced circulatory REUSE OF LIVER ALLOGRAFTS
arrest and cold preservation, allografts from DCD
donors experience significantly longer warm ischemia Transplanted liver allografts have been reused success-
time that begins with withdrawal of life support, pro- fully. The opportunity for reuse arises when a former
ceeds through progressive hypoxia, hypoperfusion, and liver transplant recipient experiences brain death with a
cardiopulmonary arrest, and ends with no organ perfu- functioning graft and thus becomes an organ donor him-
sion at body temperature for an observation period to self or herself. Reuse of liver allografts can be divided
ensure no spontaneous resuscitation. The procurement temporally into immediate reuse (within hours or days)
and cold preservation thus begins after a variable period and late reuse (within months or years). Immediate reuse
of warm ischemia (i.e., from terminal extubation to ini- can occur when a liver transplant recipient suffers brain
tiation of cold preservation). This warm ischemia time death during or shortly after liver transplantation. There
increases the risk for delayed graft function, primary are several reports of immediate reuse in the litera-
graft nonfunction, and long-term biliary complications ture.106-109 Late reuse is rare but has been reported as dis-
from ischemic cholangiopathy.94 tant as 5 and 13 years after the initial liver transplant.110,111
In early reports DCD livers had unacceptably worse Repeat transplantation of a single liver allograft in two
outcomes compared to DBD livers. However, judicious different recipients is technically challenging and requires
donor and recipient selection and advances in procure- meticulous dissection of the anastomoses to ensure ade-
ment techniques have improved DCD graft and patient quate length and mobility and, in the case of the bile
survivals.95 Incidence of primary graft nonfunction is duct, sufficient blood supply. Most often choledochojeju-
now less than 15%.96,97 Although recommendations in nostomy is required for safe biliary reconstruction of the
the literature vary, optimal donor-related characteristics reused liver allograft.
552 PART V Operation

DOMINO LIVER TRANSPLANTATION mechanism is unknown, cold ischemia time is believed to

affect graft function by contributing to ischemia-reperfu-
Domino liver transplantation involves select liver trans- sion injury.29 Surveys from both the United States and
plant candidates with hereditary metabolic diseases who Europe have shown that liver transplant recipient survival
donate their explanted livers for use as allografts in other is adversely affected by cold ischemia time over 10 and 12
patients. The domino liver transplant donor undergoes hours, respectively.4,125 Although minimizing cold isch-
transplant with a third party graft from a deceased or liv- emia time is essential for the success of every allograft, it
ing donor, while the domino liver transplant recipient is paramount for grafts from ECDs. In particular,
receives the domino donor’s explanted liver. The recipi- allografts from elderly or steatotic donors are more sus-
ents of domino liver transplants include those whose con- ceptible to injury from prolonged cold ischemia time, and
ditions ensure a long time on the waiting list or whose optimal allograft recovery and function occur when cold
malignancies might not meet criteria for transplantation. ischemia time is less than 8 hours.17 These data empha-
The ideal patient to receive a domino liver transplant is size the need to minimize the cold ischemia time of all
age 55 to 60 years with a life expectancy shorter than the liver allografts from ECDs.
time required to develop the symptoms of the domino
donor’s metabolic disease.112
Domino liver transplantation has been used for a vari- INFORMED CONSENT
ety of metabolic diseases, including familial amyloid poly-
neuropathy, maple syrup urine disease, and homozygous Participation in ECD allocation should be voluntary for
familial hypercholesterolemia. Patients with primary hyp- all patients listed for liver transplantation.38,126,127
eroxaluria and acute intermittent porphyria have also Patients should be informed about extended criteria
undergone domino liver transplantation, though out- donation during the evaluation and listing process.
comes are less encouraging because of early-onset renal Aspects of liver transplantation that should be disclosed
failure in the former and neurotoxicity in the latter.112 during the consent process are outlined in Table 41-3.
These hereditary metabolic diseases are caused by aber- The discussion should be documented in the form of
rant or deficient protein production in the liver and can be consent that reflects that patient’s understanding of the
cured with liver transplantation. Although they cause risks and benefits of participation in ECD allocation. In
severe systemic disease in the donor, these livers are oth- this way, when an ECD organ becomes available, the
erwise structurally and functionally normal and should patient will understand the implications and be able to
not produce symptoms in the recipients for many years. engage in an informed discussion with the transplant
Domino liver transplantation is technically challenging team about the organ offer. The patient again should sign
because of the difficulty reconstructing the venous out- consent for the use of the ECD organ at the time of con-
flow of the domino liver graft. Cava-sparing techniques sent for the operation. In addition to reviewing the gen-
have emerged, as well as techniques using venous patches eral risks, benefits, and expectations of liver
or interposition grafts.113 Given the risk for developing de transplantation, the discussion should reiterate those
novo metabolic disease, recipients of a domino transplant risks specific to the ECD graft. These risks may include
should undergo lifetime surveillance after transplant. higher rates of biliary complications and graft failure or
Familial amyloid polyneuropathy is the most common possible transmission of infection, depending on the spe-
indication for domino liver transplant. It is a neurodegen- cific graft.
erative disease caused by an autosomal dominant genetic
mutation that causes the transthyretin protein to form amy-
loid fibrils in the heart, kidneys, and peripheral and central TABLE 41-3 A
 spects of Liver Transplantation
nervous systems.114,115 Clinically the disease manifests as That Should Be Disclosed During
cardiomyopathy, renal failure, and peripheral and auto- the Consent Process
nomic neuropathy. More than 95% of transthyretin is pro-
duced in the liver, and liver transplantation is curative.116 • Known risks of transplantation include the rare risk for
Outcomes of domino liver transplant for familial amyloid transmission of HIV, HBV, HCV, and other infectious
agents.
polyneuropathy are comparable to the outcomes of deceased
• Because of the scarcity of organs, organs from ECDs,
donor liver transplantation.117-119 However, transmission of DCD, and donors with a slight risk for certain infections
the metabolic defect is constant, and domino recipients do are sometimes used.
have detectable levels of variant transthyretin. Several • Patients may decline ECD organs, but doing so may delay
reports of amyloid polyneuropathy developing in domino their receipt of an organ and possibly even result in death
recipients have emerged in the literature recently.120-123 while on the waiting list.
Although relatively uncommon, the development of amy- • Physicians’ understanding of donor characteristics that
loid disease in the recipient is a real risk that must be dis- confer risk is incomplete and continually evolving.
cussed with potential domino liver transplantation patients. • New risks may arise in the future (e.g., as new transmit-
table infections are identified), and all efforts to minimize
these risks will be made.

PROLONGED COLD ISCHEMIA TIME Modified from Halpern SD, Shaked A, Hasz RD, et al. Informing
candidates for solid-organ transplantation about donor risk
factors. N Engl J Med. 2008;358(26):2832-2837.
Prolonged cold ischemia time is an independent risk fac- DCD, Donation after cardiac death; ECD, extended criteria donor;
tor for the development of delayed function and primary HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human
nonfunction of the allograft.124 Although the exact immunodeficiency virus.
 41 Extended Criteria Donors 553

FUTURE DIRECTIONS implications of ex vivo reconditioning of ECD livers are

far-reaching.
ECD livers are more likely to have early graft dysfunction In summary, machine perfusion holds promise to
or primary graft nonfunction because of increased sensi- reduce preservation injury and help optimize liver
tivity to preservation-associated ischemia-reperfusion allografts from ECDs. Whether hypothermic or normo-
injury.128 Machine perfusion is a promising tool to limit thermic, machine perfusion may improve ECD allograft
ischemic damage and optimize liver allografts before function and quality, further expanding the number of
transplantation. Several studies using various models of livers available for transplantation.
hypothermic and normothermic machine perfusion have
emerged recently in the literature (Fig. 41-3).129
Hypothermic machine perfusion has been correlated CONCLUSION
with improved graft and patient survival in renal trans-
plantation.130 In clinical liver transplantation, however, Liver allografts from ECDs are a viable means to expand
hypothermic machine perfusion is still experimental.131 the donor pool and provide select recipients with liver
Initial results from the first clinical trial of hypothermic transplantation. Recipients must participate voluntarily
machine perfusion of ECD livers suggest that it reduces in ECD allograft allocation and give informed consent
the incidence of preservation injury and facilitates the before transplantation of an ECD liver. Careful donor
safe use of livers deemed unfit for transplant.132 Normo- and recipient selection and matching can result in favor-
thermic machine perfusion avoids cold ischemic preser- able outcomes after transplantation of livers that other-
vation altogether and may also improve the use of ECD wise might not be used. Short cold ischemia time is
livers. An important theoretical advantage of normother- extremely important. In the future, machine perfusion
mic machine perfusion over both static cold preservation and newer technology may help optimize these marginal
and hypothermic machine perfusion is that it provides grafts to further augment the number of livers suitable
full metabolic support to the allograft. Thus while reduc- for transplantation.
ing preservation injury, normothermic machine perfu-
sion also may allow ex vivo assessment of graft viability
before transplantation, potentially opening new avenues Pearls and Pitfalls
for selection of ECD livers.133
Another novel concept involves using machine perfu- • Identification and meticulous assessment of all poten-
tial donors is the first step in increasing the donor pool.
sion to rescue cold-stored ECD livers by gentle, oxygen- • The use of liver grafts from extended criteria donors
ated rewarming ex vivo before reperfusion in vivo. Several is widely accepted. With careful donor assessment and
animal models suggest that thermally graduated oxygen- experienced donor-recipient matching, donation after
ation before reperfusion may ameliorate ischemia-reper- cardiac death patient and graft survivals are similar to
fusion injury and improve subsequent organ donation after brain death outcomes.
recovery.134,135 In the future, normothermic machine • Skilled management and optimization of extended cri-
perfusion may help recondition livers that otherwise teria donors before procurement and minimization of
would be discarded.27 For example, in experimental mod- cold ischemia time after procurement are essential to
els, ex vivo normothermic machine perfusion of severely reducing the risk for graft dysfunction or nonfunction
steatotic porcine and rat livers using specialized perfusate after liver transplantation.
• Given the profound organ shortage and prolonged
can facilitate a reduction in hepatic steatosis.136,137 The waiting list times, all livers should be considered usable
until proven otherwise.
• Full informed consent of potential recipients is critical
IVC effluent cannula when considering liver grafts from extended criteria
Temperature probe donors.
• Early studies using machine perfusion show promise to
   further increase the number of usable liver grafts.

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71. Rodriguez-Hernandez MJ, Ruiz-Perez-Pipaon M, Canas E, et al. 94. Foley DP, Fernandez LA, Leverson G, et al. Biliary complications
Strongyloides stercoralis hyperinfection transmitted by liver after liver transplantation from donation after cardiac death
allograft in a transplant recipient. Am J Transplant. Nov donors: an analysis of risk factors and long-term outcomes from a
2009;9(11):2637–2640. single center. Ann Surg. Apr 2011;253(4):817–825.
72. Centers for Disease Control and Prevention. West Nile virus 95. Hong JC, Yersiz H, Kositamongkol P, et al. Liver transplantation
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Oct 14 2005;54(40):1021–1023. 1017–1023.
73. Satoi S, Bramhall SR, Solomon M, et al. The use of liver grafts 96. Muiesan P, Girlanda R, Jassem W, et al. Single-center experience
from donors with bacterial meningitis. Transplantation. Sep 27 with liver transplantation from controlled non-heartbeating donors:
2001;72(6):1108–1113. a viable source of grafts. Ann Surg. Nov 2005;242(5):732–738.
74. Freeman RB, Giatras I, Falagas ME, et al. Outcome of transplan- 97. Abt PL, Desai NM, Crawford MD, et al. Survival following liver
tation of organs procured from bacteremic donors. Transplanta- transplantation from non-heart-beating donors. Ann Surg. Jan
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556 PART V Operation

98. Bernat JL, D'Alessandro AM, Port FK, et al. Report of a National 119. Herlenius G, Wilczek HE, Larsson M, et al. Familial Amyloidotic
Conference on Donation after cardiac death. Am J Transplant. Polyneuropathy World Transplant R. Ten years of international
Feb 2006;6(2):281–291. experience with liver transplantation for familial amyloidotic
99. D'Alessandro AM, Fernandez LA, Chin LT, et al. Donation after polyneuropathy: results from the Familial Amyloidotic Polyneu-
cardiac death: the University of Wisconsin experience. Ann ropathy World Transplant Registry. Transplantation. Jan 15
Transplant. 2004;9(1):68–71. 2004;77(1):64–71.
100. Harring TR, Nguyen NT, Cotton RT, et al. Liver transplanta- 120. Llado L, Baliellas C, Casasnovas C, et al. Risk of transmission of
tion with donation after cardiac death donors: a comprehensive systemic transthyretin amyloidosis after domino liver transplanta-
update. J Surg Res. Nov 2012;178(1):502–511. tion. Liver Transpl. Dec 2010;16(12):1386–1392.
101. Mathur AK, Heimbach J, Steffick DE, et al. Donation after car- 121. Stangou AJ, Heaton ND, Hawkins PN. Transmission of systemic
diac death liver transplantation: predictors of outcome. Am J transthyretin amyloidosis by means of domino liver transplanta-
Transplant. Nov 2010;10(11):2512–2519. tion. N Engl J Med. Jun 2 2005;352(22):2356.
102. de Vera ME, Lopez-Solis R, Dvorchik I, et al. Liver transplanta- 122. Conceicao I, Evangelista T, Castro J, et al. Acquired amyloid neu-
tion using donation after cardiac death donors: long-term follow- ropathy in a Portuguese patient after domino liver transplanta-
up from a single center. Am J Transplant. Apr 2009;9(4): tion. Muscle Nerve. Nov 2010;42(5):836–839.
773–781. 123. Pradotto L, Franchello A, Milesi A, et al. Amyloid polyneuropa-
103. Grewal HP, Willingham DL, Nguyen J, et al. Liver transplanta- thy following domino liver transplantation. Muscle Nerve. Jun
tion using controlled donation after cardiac death donors: an 2012;45(6):918–919.
analysis of a large single-center experience. Liver Transpl. Sep 124. Piratvisuth T, Tredger JM, Hayllar KA, et al. Contribution of
2009;15(9):1028–1035. true cold and rewarming ischemia times to factors determining
104. Avolio AW, Agnes S, Chirico AS, et al. Successful transplantation outcome after orthotopic liver transplantation. Liver Transpl Surg.
of an injured liver. Transplant Proc. Feb 2000;32(1):131–133. Sep 1995;1(5):296–301.
105. Jimenez Romero C, Moreno Gonzalez E, Garcia Garcia I, et al. 125. Adam R, Cailliez V, Majno P, et al. Normalised intrinsic mortal-
Successful transplantation of a liver graft with a calcified hydatid ity risk in liver transplantation: European Liver Transplant Reg-
cyst after back-table resection. Transplantation. Oct 27 istry study. Lancet. Aug 19 2000;356(9230):621–627.
1995;60(8):883–884. 126. Bruzzone PA. preliminary European study on extended-criteria
106. Nafidi O, Letourneau R, Willems BE, et al. Reuse of liver graft liver donation and transplant recipient consent. Transplant Proc.
from a brain dead recipient. Clin Transplant. Nov-Dec 2007; Sep 2012;44(7):1857–1858.
21(6):773–776. 127. Bruzzone P, Giannarelli D, Nunziale A, et al. Extended criteria
107. Ortiz J, Reich DJ, Manzarbeitia C, et al. Successful re-use of liver liver donation and transplant recipient consent: the European
allografts: three case reports and a review of the UNOS database. experience. Transplant Proc. May 2011;43(4):971–973.
Am J Transplant. Jan 2005;5(1):189–192. 128. Henry SD, Nachber E, Tulipan J, et al. Hypothermic machine
108. Moreno Gonzalez E, Gomez R, Gonzalez Pinto I, et al. Reuse of preservation reduces molecular markers of ischemia/reperfusion
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Mar-Apr 1996;20(3):309–312. discussion 312–313. 2012;12(9):2477–2486.
109. Tantawi B, Cherqui D, Duvoux C, et al. Reuse of a liver graft five 129. Dutkowski P, de Rougemont O, Clavien PA. Machine perfusion
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110. Rentsch M, Meyer J, Andrassy J, et al. Late reuse of liver allografts 130. Moers C, Smits JM, Maathuis MH, et al. Machine perfusion or
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111. Tayar C, Karoui M, Laurent A, et al. Successful reuse of liver 131. Guarrera JV, Henry SD, Samstein B, et al. Hypothermic machine
graft 13 years after initial transplantation. Transplantation. Dec 15 preservation in human liver transplantation: the first clinical
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112. Popescu I, Dima SO. Domino liver transplantation: how far can 132. Guarrera JV. Assist devices: machine preservation of extended cri-
we push the paradigm? Liver Transpl. Jan 2012;18(1):22–28. teria donors. Liver Transpl. Nov 2012;18(Suppl 2):S31–33.
113. Kitchens WH. Domino liver transplantation: indications, tech- 133. op den Dries S, Karimian N, Sutton ME, et al. Ex vivo normo-
niques, and outcomes. Transpl Rev. Oct 2011;25(4):167–177. thermic machine perfusion and viability testing of discarded
114. Hou X, Aguilar MI, Small DH. Transthyretin and familial amy- human donor livers. Am J Transplant. May 2013;13(5):
loidotic polyneuropathy. Recent progress in understanding the 1327–1335.
molecular mechanism of neurodegeneration. FEBS J. Apr 134. Minor T, Efferz P, Fox M, et al. Controlled oxygenated rewarm-
2007;274(7):1637–1650. ing of cold stored liver grafts by thermally graduated machine
115. Ando Y, Nakamura M, Araki S. Transthyretin-related familial perfusion prior to reperfusion. Am J Transplant. Jun 2013;13(6):
amyloidotic polyneuropathy. Arch Neurol. Jul 2005;62(7): 1450–1460.
1057–1062. 135. Schlegel A, Rougemont O, Graf R, et al. Protective mechanisms
116. Tincani G, Hoti E, Andreani P, et al. Operative risks of domino of end-ischemic cold machine perfusion in DCD liver grafts.
liver transplantation for the familial amyloid polyneuropathy liver J Hepatol. Feb 2013;58(2):278–286.
donor and recipient: a double analysis. Am J Transplant. Apr 136. Jamieson RW, Zilvetti M, Roy D, et al. Hepatic steatosis and nor-
2011;11(4):759–766. mothermic perfusion-preliminary experiments in a porcine
117. Bispo M, Marcelino P, Marques HP, et al. Domino versus model. Transplantation. Aug 15 2011;92(3):289–295.
deceased donor liver transplantation: association with early graft 137. Nagrath D, Xu H, Tanimura Y, et al. Metabolic preconditioning
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17(3):270–278. ex vivo. Metab Eng. Jul-Sep 2009;11(4-5):274–283.
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 CHAPTER 42

Donation After Cardiac Death

David J. Reich

CHAPTER OUTLINE

DEFINING DONATION AFTER CARDIAC DEATH Ischemia Times

Uncontrolled Donation After Cardiac Death Biliary Protection
Controlled Donation After Cardiac Death DONATION AFTER CARDIAC DEATH PRACTICE
The Maastricht Categories GUIDELINES
HISTORICAL PERSPECTIVE ETHICO-LEGAL ISSUES AND PROFESSIONALISM
The Impact of Brain Death Recognition Basic Principles
Controlled Donation After Cardiac Death Liver Controversial Ethics Topics
Transplantation—Early Efforts
Controlled Donation After Cardiac Death Liver IDENTIFYING APPROPRIATE CANDIDATES FOR
Transplantation—Challenges POTENTIAL DONATION AFTER CARDIAC DEATH
Donation After Brain Death Is Preferable to
CURRENT RESULTS OF DONATION AFTER Donation After Cardiac Death
CARDIAC DEATH ORGAN TRANSPLANTATION Organ Procurement Organization Efforts
Kidney, Pancreas, and Lung Transplantation
Following Donation After Cardiac Death PREOPERATIVE MANEUVERS AND OPERATIVE
Uncontrolled Donation After Cardiac Death STRATEGY FOR DONATION AFTER CARDIAC
Liver Transplantation and the Spanish DEATH ORGAN PROCUREMENT
Model Preparation
Liver Transplantation Results After Controlled Superrapid Surgical Technique
Donation After Cardiac Death—Mixed Premortem Cannulation Technique, With
Experiences or Without Extracorporeal Membrane
IMPROVING THE OUTCOMES OF CONTROLLED Oxygenation
DONATION AFTER CARDIAC DEATH LIVER DONATION AFTER CARDIAC DEATH LIVER
TRANSPLANTATION TRANSPLANTATION RESEARCH
Reducing the Risk
CONCLUSIONS

Donation after cardiac death (DCD), formerly referred one method of increasing the donor pool is to use living
to as non–heart-beating donation, has become the fastest- donor livers, a high-stakes endeavor, and to use expanded
growing source of transplant organs in the United States criteria organs, including older, hepatitis C virus–posi-
over the past decade, bringing full circle the history of tive, hepatitis B core antibody–positive, steatotic, injured,
organ donation.1 This chapter reviews the history, ethics, and reduced in size (split) livers. DCD is an additional
practice guidelines, surgical techniques, clinical out- type of expanded criteria donor, used in the United
comes, and challenges of DCD liver transplantation, States, Europe, and Asia to boost the number of deceased
focusing on the controlled subgroup of DCDs. Profound donors and decrease the dire shortage of transplantable
disparity in supply and demand for transplantable livers organs. The percent of deceased donors in the United
causes tragic numbers of end-stage organ failure patients States that are DCD has grown from 1% in 1996 to 13%
to succumb before receiving a transplant. Current mor- in 2011; 5% of deceased donor liver transplants per-
tality rates for patients on the United Network for Organ formed in 2011 were from DCD as were 16% of deceased
Sharing (UNOS) and Eurotransplant waiting lists are donor kidney transplants,1 and DCDs have also provided
approximately 16% and 27%, respectively.1,2 In response, for transplantation of pancreata and lungs.

557
558 PART V Operation

Deceased donor
circulatory support), most often in the operating room,
with a donor surgical team readily available. Except in
rare circumstances, the potential controlled DCD does
not meet brain death criteria, but the donor has sustained
a catastrophic brain injury or other illness such as end-
DBD donor DCD donor stage musculoskeletal disease, pulmonary disease, or high
Donation after brain Donation after cardiac
spinal cord injury and has no expectation of meaningful
death death
No brainstem function No circulation survival as determined by the treating physician(s). The
Ischemia minimized Ischemia prone patient’s legal decision maker(s) request withdrawal of
support, whether or not organ donation is to be pursued.
Subsequently, informed consent for organ donation is
obtained from them if the patient is otherwise medically
suitable for donation. Controlled DCD offers the family
Controlled DCD Uncontrolled DCD and patient with a hopeless prognosis the opportunity to
Planned withdrawal Unplanned circulatory donate when criteria for brain death will not be met
of life support arrest
before cardiac death.
Terminal illness Failed CPR or DOA
Intermediate ischemia Protracted ischemia
The Maastricht Categories
FIGURE 42-1 n Definitions of controlled and uncontrolled dona-
tion after cardiac death (DCD) and donation after brain death In the early 1990s, investigators from Maastricht in the
(DBD). CPR, Cardiopulmonary resuscitation; DOA, dead on Netherlands described four categories of DCD donors:
arrival.
(1) dead on arrival, (2) unsuccessful resuscitation,
(3) awaiting cardiac arrest, and (4) cardiac arrest while
brain dead.3 A DCD donor who is dead on arrival is
DEFINING DONATION AFTER brought to the emergency department after being
CARDIAC DEATH declared dead in the field. A DCD donor who is unsuc-
cessfully resuscitated undergoes a determination that
DCD is characterized by irreversible unresponsiveness, lifesaving efforts are useless. A DCD donor who is await-
apnea, and absence of circulation, in contrast to donation ing cardiac arrest has extensive brain damage but does
after brain death (DBD), defined by irreversible cessa- not meet the criteria for brain death, and controlled
tion of all brain functions. Organ ischemia is minimized withdrawal of support is then arranged. Finally, the
in DBD because circulatory arrest typically occurs con- fourth category includes DCD donors in whom brain
currently with perfusion of preservation solution and death has been diagnosed and who sustain premature and
rapid core cooling. Thus the procurement procedure unexpected cardiac arrest before the beginning of the
does not implicitly involve circulatory dysfunction. donor operation. All but the third category are consid-
DCDs are less than ideal because the organs suffer isch- ered uncontrolled DCD situations.
emia during the prolonged periods between circulatory
dysfunction, circulatory arrest, and subsequent perfusion
and cooling. Furthermore, the surgical procedure for HISTORICAL PERSPECTIVE
DCD organ recovery is demanding and rushed. It is
important to differentiate controlled from uncontrolled The Impact of Brain Death Recognition
DCDs (Fig. 42-1).
During the earliest years of kidney transplantation,
organ donation amounted to removal of kidneys from
Uncontrolled Donation After Cardiac Death patients whose hearts had stopped beating. The first
Uncontrolled DCDs sustain circulatory arrest and either human kidney, liver, and heart transplants, in 1958,
fail to respond to cardiopulmonary resuscitation or are 1963, and 1967, respectively, were performed using
declared dead on arrival at the hospital. Uncontrolled organs recovered from uncontrolled DCDs. Through
DCD is unplanned, so the organs suffer protracted isch- the 1960s, determination of death required heartbeat
emia before recovery. Although kidneys tolerate a short cessation. However, World War II led to the birth of
period of the resultant warm ischemia, transplantation of modern critical care, including the use of respirators
extrarenal organs from uncontrolled DCDs carries a and cardiopulmonary resuscitation. It became possible
much greater risk. to reestablish or maintain cardiopulmonary function in
severely ill patients, which led neurophysiologists of the
1950s to study irreversible coma. Subsequently, in 1968
Controlled Donation After Cardiac Death the multidisciplinary Ad Hoc Committee of the Har-
Controlled DCDs provide organs that are exposed to sig- vard Medical School to Examine the Definition of Brain
nificantly less ischemic damage than those of uncontrolled Death issued a landmark report that included criteria
DCDs and in general offer superior posttransplantation for the determination of brain death (Harvard Neuro-
function when compared with uncontrolled DCDs. Con- logic Definition and Criteria for Death).4 In 1980 the
trolled DCDs undergo circulatory arrest following Uniform Law Commissioners adopted the Uniform
planned withdrawal of life support (ventilatory and Determination of Death Act (UDDA). According to the
 42 Donation After Cardiac Death 559

UDDA, “an individual who has sustained either (1)

irreversible cessation of circulatory and respiratory
functions, or (2) irreversible cessation of all functions of
the entire brain, including the brainstem, is dead.”5
The UDDA has been endorsed by the major American
and European medical and legal professional associa- Bile cast
tions, and all 50 states have enacted brain death
legislation.
During the mid-1970s, the practice of recovering
organs from DCD donors was essentially abandoned.
Organs recovered from DBD donors are considered
more desirable because they are protected from the
effects of warm ischemic injury and are less prone to poor
graft function. For the following 25 years, virtually all
donation was from DBD or live donation. Biliary strictures

Controlled Donation After Cardiac Death

Liver Transplantation—Early Efforts
DCD organ transplantation was reintroduced by the FIGURE 42-2 n Endoscopic retrograde cholangiopancreatogra-
University of Pittsburgh transplantation program in phy depicting ischemic cholangiopathy (bile casts and biliary
1992.6 The Pittsburgh program and the program in strictures) in a donation after cardiac death liver transplant
recipient.
Madison, Wisconsin, were pivotal in initiating con-
trolled DCD organ transplantation and were the first
to describe results of controlled DCD kidney and liver Controlled Donation After Cardiac Death
transplantation, both in 1995.7,8 The experiences were Liver Transplantation—Challenges
small and provided survival rates inferior to those after
DBD liver transplantation, but these pioneering teams’ In 2003, the University of Pennsylvania group was the
reports were encouraging and provided the impetus to first to report a higher risk for major biliary complica-
further develop the field of controlled DCD liver tions in DCD liver recipients and to caution that DCD
transplantation. In 2000 Reich et al published the first biliary epithelium is particularly prone to ischemia-­
successful series of controlled DCD liver transplanta- reperfusion injury.14 Thereafter, enthusiasm for DCD
tion; at a mean follow-up of 18 months, patient and livers has been tempered by widespread experiences of
graft survival rates were 100%, and there were no ischemic cholangiopathy, inferior survival and higher
instances of primary nonfunction, hepatic artery cost after transplant.11-15,28-38,57 Ischemic cholangiopathy
thrombosis, or ischemic cholangiopathy.9 Thereafter manifests as biliary strictures and bile cast syndrome, and
other reports of increasingly larger DCD experiences tends to present within the first few months after trans-
were published.10-16 plantation (Fig. 42-2). It may resolve with biliary drainage
These early experiences with controlled DCD or require repeated long-term endoscopic or percutane-
occurred concurrently with the public’s increasing ous manipulations. Ischemic cholangiopathy often leads
reluctance to prolong futile treatment and artificial life to graft loss and retransplantation or death. Unease about
support of terminally injured and ill patients and with DCD liver transplantation is amplified by regulators’ and
increasing use of advance directives and health care payers’ increasing focus on clinical outcomes and cost-of-
proxies. In 1997 the Institute of Medicine (IOM) of the care.39 The volume of DCD liver transplants performed
National Academy of Sciences published its first report has plateaued since 2005.1 Further concern about DCD
on DCD.17 The IOM, commissioned by the Depart- relates to the decreased yield of transplantable organs
ment of Health and Human Services, considered DCD from DCDs, some of whom might advance to brain death
to be an ethical way to address the organ shortage and if given time.
sought to increase such donations through their follow-
up reports of 2000 and 2006.18,19 Starting in 2003, the
Department of Health and Human Services organized CURRENT RESULTS OF DONATION
the Organ Donation Breakthrough Collaboratives,
mandating increased DCD20 and leading to a surge in AFTER CARDIAC DEATH ORGAN
DCD kidney and liver transplants. DCD has also been TRANSPLANTATION
endorsed by the American Society of Transplant Sur-
geons (ASTS), the Society of Critical Care Medicine, Kidney, Pancreas, and Lung
UNOS, the Joint Commission, and the Centers for Transplantation Following Donation After
Medicare and Medicaid Services.21-27 Early estimates Cardiac Death
were that DCD could increase the deceased donor pool
in the United States by over 1000 donors per year. The DCD kidney recipients are at increased risk for delayed
number of DCD donors steadily increased from only 42 graft function (DGF), and DCD increases the kidney
in 1993 to 846 in 2008.1 donor risk index. However, DCD kidneys provide
560 PART V Operation

survival outcomes similar to those of DBD kidneys.40-43 GRAFT SURVIVAL ADJUSTED FOR COVARIATES
Reviews of the U.S. Renal Data System database and 100
single-center results reveal that DCD kidney recipients 89.2
had nearly twice the incidence of DGF as did standard 83.0
criteria donor kidney recipients, but 1-, 5-, and 10-year 80 75.0
83.0
allograft survival rates were comparable between the

% Graft survival
groups.40-42,44,45 Uncontrolled and controlled DCD kid- 70.1
60
neys provide similar patient and graft survival results.40,44 60.5
Relatively few DCD pancreas transplants are per- 40
formed annually. Initial reports of the University of Wis-
consin single-center experience and the Scientific HR  1.85
Registry of Transplant Recipients (SRTR) results reveal 20 P  .0001 DBD
patient and pancreas survival rates were each similar DCD
between DCD and DBD organs.46,47 Subsequent review 0
of the SRTR data reveals that the DCD source of pan- 0 1 2 3 4
creata had become a marginally significant risk for graft Time (years)
failure, likely a consequence of expansion of organ selec- SRTR
tion criteria as comfort grew with this source of donor
FIGURE 42-3 n Graft survival following donation after cardiac
organs.48 Authors advocate that pancreata from hemody- death (DCD) and donation after brain death (DBD) liver trans-
namically stable, young, and slender DCD donors should plantation (DCD livers carried a hazard ratio for graft failure of
be considered in select circumstances to expand the donor 1.85). HR, Hazard ratio. (Courtesy the Scientific Registry of Trans-
pool. plant Recipients and Robert M. Merion, MD, Ann Arbor, MI.)
There has been growing experience with DCD lung
transplantation, and several groups have recently reported
their outcomes. The results with DCD and DBD lung outcomes inferior to DBD liver transplantation, with
transplants seem comparable, including similar lung patient and graft 1-year survival rates ranging from 74%
function, risk for bronchiolitis obliterans syndrome, and to 92% and 61% to 87%, respectively.9,11-15,30-38,55
patient and graft survival rates. Some DCD lung proto- Review of the SRTR data by Merion et al31 revealed that,
cols use ex vivo perfusion to assess adequacy of grafts for compared with DBD livers, DCD livers carried an
transplantation and to recondition them for increased adjusted odds ratio for graft failure of 1.85 (Fig. 42-3).
availability.49-52 A subsequent SRTR review by Merion et al analyzed
1567 DCD liver transplants from 2001 through 2009;
3 years post transplantation 64.9% of recipients were
Uncontrolled Donation After Cardiac alive with functioning grafts, 13.6% required retrans-
Death Liver Transplantation and the plantation, and 21.6% died.57 Ischemic cholangiopathy
Spanish Model has been reported in 9% to 50% of DCD recipi-
ents.12-14,34-38 Because failing DCD livers can survive for
In contrast to controlled DCD liver transplantation, an extended period of time, nuanced consideration of
uncontrolled DCD liver transplantation provides 1-year intermediate-term graft survival after DCD liver trans-
graft survival rates of only 17% to 70%.53 Various post- plantation, such as 1-year survival, should account for not
mortem measures have been used to increase the yield of only graft losses attributable to death or retransplantation
transplantable organs from uncontrolled DCDs, includ- but also impending losses in patients with damaged grafts
ing cardiopulmonary resuscitation, femoral vessel cannu- still awaiting retransplantation.
lation for hypothermic or normothermic extracorporeal Of note, the pooled registry and single-center experi-
membrane oxygenation (ECMO) and for perfusion with ences do include cohorts of patients that did well after
hypothermic preservation solution, and core cooling via controlled DCD liver transplantation and identify risk
peritoneal catheterization before organ retrieval.53,54 factors for worse outcomes. Some single centers that con-
Some protocols involve nonconsensual measures, such as sistently use standardized DCD protocols and strict
cardiopulmonary resuscitation, femoral vessel cannula- organ selection criteria report excellent results, compa-
tion, and ECMO and are therefore potentially ethically rable to DBD liver transplant.* DCD liver transplanta-
problematic, even though organ procurement is aborted if tion has not resulted in an increased incidence of primary
consent for donation is not obtained. Spain has established nonfunction (0% to 12%) or hepatic artery thrombosis
uncontrolled DCD organ procurement programs that are (0% to 9%).12-15,34-38
based on such nonconsensual initial measures.53,54 In 2011 the group from Mayo Clinic, Jacksonville,
compared 200 DCD liver transplants to 1830 DBD trans-
plants.34 Their patient and graft survivals at 1, 3, and 5
Liver Transplantation Results After years were not significantly different between DCD and
Controlled Donation After Cardiac Death— DBD groups. Ischemic cholangiopathy developed in
Mixed Experiences 12% of DCD recipients, and half required retransplanta-
tion. The Mayo group’s excellent experience is similar to
Numerous single-center and pooled registry analyses of
controlled DCD liver transplantation generally portray *References 9, 13, 15, 16, 34, 56.
 42 Donation After Cardiac Death 561

that reported by Reich et al in their 2006 update; patient

and graft survival rates were both 90% at 1 year post Waiting
Withdrawal MAP  50 until Incision
transplantation and 85% at 2 years; ischemic cholangi- until MAP  50 declaration
period
to flush
opathy developed in 13% of recipients and caused graft (2-5 min)
failure in 10%.56
In contrast, a 2009 report from the Northwestern
group revealed that their recipients of DCD livers had a Total warm ischemia time (withdrawal to flush)
36% higher incidence of ischemic cholangiopathy com-
pared with their recipients of DBD livers and, primarily
True warm ischemia time
for this reason, a 2.1 times greater risk for graft failure (MAP  50 until flush)
and 3.2 times greater risk for retransplant.35 It is possible
that the DCD outcomes of this experienced team are
inferior to those reported by other centers because the Recommended time limits:
Liver: Total WIT  30-45 min, True WIT  20-30 min, CIT  6-10 hr.
others were able to use more consistent DCD protocols Kidney: Total WIT  45-60 min, CIT  24 hr.
and stricter selection criteria. For example, the North- Pancreas: Total WIT  30-60 min, CIT  18 hr.
western group reported variability in the timing of sys-
FIGURE 42-4 n Recommended ischemia time limits for controlled
temic heparinization (before or after withdrawal), location donation after cardiac death liver transplantation. A drop in
of withdrawal (in or out of the operating room), and mean arterial pressure (MAP) below 50 mm Hg is defined by the
source of the donor (local or regional share) for their 32 author as marking the development of significant hypotension
DCD liver donors. Furthermore, their cohort had a mean and the start of the true warm ischemia time (WIT; this point in
time is variably defined by others). CIT, Cold ischemia time.
age greater than 40 years (43 ± 18), and there was a 9.3
increased odds of ischemic cholangiopathy if the DCD
donor was older than 40 years.
surgery.34,35,58 DCD liver biopsies can exclude use of
grafts with centrilobular necrosis, steatosis, or other his-
tological predictors of poor quality.
IMPROVING THE OUTCOMES OF Recipient risk factors for better outcome after DCD
CONTROLLED DONATION AFTER CARDIAC liver transplantation have also been identified. Younger,
hemodynamically stable, and technically less challenging
DEATH LIVER TRANSPLANTATION recipients generally fair better with DCD livers than do
other recipients.9,11,31-33 This is likely related to the
Reducing the Risk importance of keeping cold ischemia time short and plac-
Two 2006 SRTR analyses of DCD liver transplantation ing the liver into a hemodynamically favorable environ-
focused on risk factors for graft failure. Lee et al32 showed ment to protect against additional ischemia. DCD liver
that a low-risk DCD cohort provided similar outcomes to transplantation is not well suited for patients who would
those after DBD; the low-risk criteria were donor age less be ill equipped to deal with the burden of biliary compli-
than 45 years, cold ischemia time of less than 10 hours, cations (increased hospital visits and interventions, per-
and warm ischemia time of less than 15 minutes. Mateo cutaneous tubes), such as patients who live far from the
et al similarly identified donor risk factors for poor out- transplant center or have poor social support. The risk-
come after DCD (warm ischemia time over 30 minutes, benefit ratio of DCD liver transplantation is improved if
cold ischemia time over 10 hours) and also found recipi- donor and recipient risk factors are not compounded.
ent risk factors, including retransplantation, being on life The current Model for End-Stage Liver Disease (MELD)
support before transplantation, and having a serum cre- allocation and distribution system creates regional dis-
atinine level of over 2.0 mg/dL. Low-risk DCD grafts parities in the utilization of DCD livers in that transplant
transplanted into low-risk recipients provided favorable centers in less competitive organ procurement organiza-
outcomes, similar to those after DBD.33 A 2008 SRTR tions (OPOs) can select ideal recipients for DCD livers,
analysis by Selck et al30 demonstrated higher graft failure whereas centers in more competitive OPOs must typi-
within the first 180 days with convergence thereafter; the cally accept DCD liver offers for candidates high on the
DCD allografts were more frequently imported from match runs or lose access to the offers. Additional under-
another allocation region. standing of the various risk factors and of risk interactions
Some categorically advise against using livers from is needed.35,58
DCD donors more than 40 to 60 years old because they
are particularly vulnerable to biliary ischemia and graft Ischemia Times
loss,12,14,35,36 but others have shown that, selectively, they
can provide good outcomes.15,34,56 Other factors that may When deciding on whether to transplant a procured
be relevant to the better outcomes with DCD liver trans- DCD organ, there needs to be great emphasis on assess-
plantation at some centers include donor surgeon experi- ing the various ischemia time intervals (Fig. 42-4). Con-
ence, local or regional share status of the donor, and trolled DCD liver transplantation may carry increased
specifics of the individual DCD protocols such as use and risk in the face of true warm ischemia time—the interval
timing of anticoagulant or vasodilator, withdrawal of sup- between significant (variably defined) hypotension or
port in or out of the operating room, and duration of the hypoxemia and initiation of perfusion—up to and perhaps
waiting time between declaration of death and start of somewhat beyond 20 to 30 minutes.13,15,56 Total warm
562 PART V Operation

ischemia time—the interval between discontinuation of biliary issues. In 2009, Reich et al23 published evidence-
mechanical ventilation and initiation of perfusion—may based recommendations on controlled DCD on behalf of
extend up to and perhaps somewhat beyond 30 to 45 min- the ASTS. The ASTS recommendations attempt to
utes.23,58,59 In the Mayo Clinic experience, each minute address the unique challenges posed by DCD organ pro-
increase in the asystole-to-cross-clamp duration was asso- curement and transplantation and to facilitate improve-
ciated with a 16.1% increased odds of ischemic cholangi- ment in outcomes. They complement guidelines
opathy.34 The risk from DCD livers is lowest when cold published earlier by UNOS,24-26 the IOM,17-19 the Soci-
ischemia time is kept below 6 hours9 and is minimized ety of Critical Care Medicine,27 and in a multiorganiza-
when it is kept below 6 to 10 hours.23,58,59 In the 2010 tion national conference report.59
SRTR analysis by Mathura et al of DCD liver transplan-
tation, each hour increase in cold ischemia time was asso-
ciated with a 6% higher graft failure rate, and cold ETHICO-LEGAL ISSUES
ischemia time between 6 and 10 hours was associated with
a 64% higher graft failure risk compared to cold ischemia
AND PROFESSIONALISM
time of less than 6 hours.57 Basic Principles
Controlled DCD kidney transplantation may be asso-
ciated with increased DGF if total warm ischemia time is DCD organ procurement honors the donor’s wishes,
longer than 45 to 60 minutes or cold ischemia time is brings some comfort to the family, and benefits the recip-
longer than 24 hours.23,46,59 Controlled DCD pancreas ients. However, as DCD develops, relevant ethical and
transplantation has been generally limited to cases of logistical issues have stimulated scrutiny, discussion, and
total warm ischemia time of less than 30 to 60 minutes debate among lay and medical communities. The original
and cold ischemia time of less than 18 hours.23,46,48,59 study of DCD by the IOM was organized partly in
response to a well-publicized, controversial 1997 60 Min-
utes CBS television report that negatively portrayed DCD
Biliary Protection initiatives and led to public skepticism about organ dona-
The following additional tactics may be considered in an tion in general.17 Some ethico-legal principles pertinent
effort to reduce biliary problems after DCD liver trans- to DCD include the following: individuals may not be
plantation: performance of an expeditious in situ biliary killed for their organs or killed as a result of the removal
flush to minimize bile-induced epithelial damage,23,56 of their organs (the “dead donor” rule), patients must not
arterial revascularization before or simultaneously with be jeopardized to facilitate organ procurement, euthana-
portal revascularization,14,23 use of a T tube to facilitate sia is prohibited, informed consent and respect for family
frequent interrogation of the ducts and early intervention wishes must not be violated, and the autonomous right of
to dredge sludge and dilate strictures before casting patients to refuse treatment must be upheld.† It is imper-
occurs,23 and liberal use of prophylactic bile acid (ursode- ative to ensure that there is no conflict of interest between
oxycholate) after transplantation. Fung et al recommend the duty to provide optimal patient care and the desire to
using a thrombolytic in addition to an anticoagulant to recover organs for transplant.23,65-67 Specifically, the
decrease periductular microvascular thrombosis and isch- rationale for withdrawal of life support and the determi-
emic cholangiopathy after DCD.60,61 They attribute their nation of death must be extricable from the decision to
low incidence of ischemic biliary disease after DCD liver recover organs. Therefore the patient care and organ
transplantation to injection of tissue plasminogen activa- donor teams need to be completely separate.
tor into the donor hepatic artery on the back-table. They Even though DCD procurement is often hectic, the
also use histidine-tryptophan-ketoglutarate preservation donor surgical team should behave courteously and
solution rather than the more viscous and particulate respectfully at the donor facility. The risks and benefits of
University of Wisconsin (UW) solution, to further DCD organ transplantation, including the possibility and
decrease periductular microvascular thrombosis.60,61 implications of biliary complications (or DGF in the case
However, in a UNOS database analysis by Stewart et al,62 of kidney transplantation) should be discussed with trans-
published in 2009, HTK compared to UW preservation plant candidates during the transplant evaluation
was associated with an increased risk for graft loss, espe- process.23
cially for DCD allografts. Several authors have called for
a change in allocation policy for recipients of failing DCD
grafts so as to expedite access to retransplant.30,35,63
Controversial Ethics Topics
Several issues related to the ethics and laws of DCD organ
procurement remain sources of debate. Interventions that
DONATION AFTER CARDIAC DEATH improve the chance of successful donation rather than
PRACTICE GUIDELINES directly benefit the donor are permitted, as long as they
are consensual, do not hasten death or harm the donor,
DCD protocols and techniques vary among OPOs and and are not prohibited by the local procurement protocol.
transplant centers. Best practice guidelines for DCD That said, there are differing views regarding use of anti-
organ procurement and transplantation are available and coagulants, vasodilators, and premortem placement of
cover many aspects of the endeavor, including donor cri-
teria, consent, withdrawal of support, operative tech-
nique, ischemia times, recipient considerations, and †References 6, 7, 23, 27, 59, 64-67.
 42 Donation After Cardiac Death 563

intravascular cannulas .‡ Medications routinely provided injury and either brain death is not imminent or a brain
for patient comfort are permitted even if they might has- death protocol is precluded because of hemodynamic
ten death; these are given at the discretion of the patient’s instability or a family's absolute refusal to wait. Strong
treating care team, and procurement team members shall OPO initiatives are crucial for increasing DCD, and cer-
not participate in decisions regarding the use of such tain OPOs have developed highly successful DCD pro-
agents.23,27,59 A highly publicized lawsuit involved the grams69,70; in 2011, 17% of the deceased donors that
professional behavior of a surgeon who became involved yielded transplants from the Gift of Life Donor Program
in administration of a narcotic and anxiolytic during an OPO of the Delaware Valley donor service area involved
attempted DCD.68 DCD (69 of 399) (Fig. 42-5).10 There have been attempts
Another issue that is debated is whether determina- to develop a system that predicts the time to cardiac death
tion of death for a DCD requires loss of cardiac electrical after withdrawal of support from a particular potential
activity or if absence of heart sounds, pulse, and blood DCD, to help identify when it is worth pursuing organ
pressure is a sufficient criterion, just as it is for patients donation, but no model has performed reliably.71
who are not organ donors.6,18 Ultimately, the donor hos-
pital and care team have the responsibility for defining
and declaring patient death. Another important ethical
question that affects the warm ischemic time endured by PREOPERATIVE MANEUVERS AND
DCD organs relates to the duration of the waiting period OPERATIVE STRATEGY FOR DONATION
used to ensure irreversible death. Autoresuscitation after AFTER CARDIAC DEATH ORGAN
1 minute of pulselessness has not been reported in the
literature.65 However, different waiting times from cir-
PROCUREMENT
culatory arrest to initiation of organ procurement sur- Preparation
gery have been prescribed by various groups, ranging
from 2 to 10 minutes.§ The ASTS recommends 2 min- The DCD protocol I and those at other programs in our
utes,23 the Society of Critical Care Medicine recom- OPO use is summarized in Table 42-1. The donor surgery
mends 2 to 5 minutes,27 and the IOM recommends should be performed by a surgeon who is familiar with the
5 minutes.17-19 ethics and laws of DCD and is experienced in rapid pro-
curement techniques. Communication between the DCD
surgeon and the donor coordinator(s) and operating room
personnel about conduct of the operation, before with-
IDENTIFYING APPROPRIATE CANDIDATES drawal of support, facilitates cooperation and speediness of
FOR POTENTIAL DONATION AFTER the recovery. Upon withdrawal of support, a preprinted
CARDIAC DEATH flow sheet should be filled out by a coordinator in the oper-
ating room, documenting hemodynamic measurements
Donation After Brain Death Is Preferable to every minute and the times of discontinuation of mechani-
Donation After Cardiac Death cal ventilation, cessation of cardiorespiratory function,
waiting period, declaration of death, incision, and perfusion
Enthusiasm about the option of DCD ought to be tem-
pered by the realization that both the yield of transplant-
able organs from DCDs and the outcomes of DCD organ
transplants are not generally as favorable as with DBDs. GIFT OF LIFE DONOR PROGRAM
Therefore, when it seems that DBD will be possible, DONORS AFTER CARDIAC DEATH 1995–2011
DCD should not be viewed as an equally acceptable alter- n  635
native. A potential organ donor’s family and health care
providers should be encouraged to wait for completion of 80 75
a brain death protocol when brain death seems present or 69
70 63
imminent. This approach is important even if brain death
60 57
protocols might be viewed as cumbersome at a time when
50 50
hospitals are increasingly pressed to empty critical care 50
42 43
beds and transplant professionals strive to expedite organ 39
donation. 40 33
30 27
23 22
20
Organ Procurement Organization Efforts 20
Potential DCDs are identified by mandatory referral of 9 11
10
dying patients to the OPO, pursuant to local state laws.69 2
DCD can provide genuine expansion of the donor pool if 0
DBD is not feasible. Such situations include a request for
19 5
19 6
19 7
19 8
20 9
20 0
20 1
20 2
20 3
20 4
20 5
20 6
20 7
20 8
20 9
20 0
11
9
9
9
9
9
0
0
0
0
0
0
0
0
0
0
1
19

withdrawal of life support when there is catastrophic

FIGURE 42-5 n Gift of Life Donor Program donors after cardiac
death that contributed at least one transplant, 1995 through
‡References 19, 23, 25-27, 59, 66. 2011. (Courtesy Howard M. Nathan and Richard D. Hasz, Gift of Life
§References 17-19, 23, 27, 59, 64-66. Donor Program, Philadelphia, PA.)
564 PART V Operation

ice bucket to prevent warming. During this prepping and

TABLE 42-1 C
 ontrolled Donation After Cardiac
draping it is critical to recognize that the potential DCD
Death Protocol Used by the
donor is a patient who is still alive.
Author and Other Groups Served
Following these preparatory maneuvers, the surgical
by the Gift of Life Donor Program
team should exit the operating room and wait until potential
Donor Eligibility
procurement, to avoid conflict of interest during withdrawal
Medically suitable for donation
of support and declaration of death. The family can be given
Brain death criteria not met
the opportunity to be present after the surgical team leaves,
Catastrophic brain injury or end-stage musculoskeletal
until cessation of cardiorespiratory function. If the patient is
disease, pulmonary disease, or high spinal cord injury not declared dead within the time frame stipulated by the
No expectation of meaningful survival according to local procurement protocol, then donation is aborted and
patient’s physicians the patient is returned to the ward for comfort care;17,23,25,26
Withdrawal of support requested by patient’s legal decision in the rare instances in which this occurred in our OPO, the
maker(s) patient always died within the next few hours.
Consent for donation obtained After death a midline laparotomy is performed. Upward
Withdrawal of Support traction on two Kocher clamps placed on each side of the
To OR with full life support (withdrawal outside OR not umbilicus expedites rapid entry without injury to the vis-
optimal) cera. A large scalpel is used to incise all layers of the abdom-
Preparation and draping by transplant surgeon inal wall. A moist towel is used to retract the small intestine
Heparin (some OPOs omit heparin; some OPOs give to the right while the sigmoid colon is retracted to the left.
phentolamine) Although not pulsatile, the aorta is easily palpated just
Comfort care provided at discretion of patient’s care team above its bifurcation on the left side of the vertebral col-
Transplant team leaves OR umn. Metzenbaum scissors are used to clear the retroperi-
Patient’s care team stops ventilation toneum over a small segment of distal aorta in preparation
Patient’s care team declares death (if patient alive after 60 for cannulation. There is no need to dissect out the inferior
minutes, procurement aborted and patient returned to
ward for comfort care)
mesenteric artery. A right-angle clamp is used to pass a
Five-minute waiting period (ASTS endorses 2-minute
moist umbilical tape around the distal aorta, which will be
waiting period) used to secure the cannula. Distally, the aorta is clamped
Transplant team reenters for superrapid recovery with a Kelly clamp. Next, the cannula is passed cephalad
through an aortotomy and secured with the umbilical tape.
Operative Technique
The flush should be started immediately at this point, with-
Modified Pittsburgh “superrapid technique” (some groups
in other OPOs prefer the premortem cannulation out waiting to cross-clamp the proximal aorta or vent the
technique) vena cava (Fig. 42-8). Using this approach, flush is typically
Rapid laparotomy and distal aortic cannulation initiated within 2 to 3 minutes of incision.
Preservation fluid flush and ice cooling The surgeon should not be disturbed to see a dark,
Sternal split, IVC vent, and thoracic aortic clamping purple, and somewhat engorged liver at initial inspection,
Hepatectomy and nephrectomies (with or without because this is the typical appearance of a DCD liver.
pancreatectomy) Assessment of liver quality is best left until after perfusion,
Portal flush on back-table at which point the liver should appear normal. Next, the
round and falciform ligaments are divided sharply. The
ASTS, American Society of Transplant Surgeons; IVC, inferior vena
cava; OPO, organ procurement organization; OR, operating room.
knife is used to open from the suprasternal notch to the
abdomen. Median sternotomy is performed with a pneu-
matic saw and a Finochietto sternal retractor is placed.
It is my preference to clamp the thoracic rather than
of each organ (Fig. 42-6). After procurement, this informa- supraceliac aorta during superrapid procurement. The
tion is critical for assessing ischemic injury.23,26,59 descending thoracic aorta can be easily accessed through
the left thoracic cavity just above the diaphragm. The vena
Superrapid Surgical Technique cava is vented above the diaphragm. A Balfour retractor is
placed across the upper abdomen. Ice slush should be
Most surgeons who procure DCD organs use some mod- placed on the abdominal organs simultaneously with the
ification of the superrapid technique described by the sternotomy. Approximately 5 L of cold UW solution, con-
Pittsburgh group.7,9,23,56,72 Ideally, patients undergo taining dexamethasone 16 mg/L and insulin 40 units/L, is
withdrawal of support in the operating room. Otherwise, infused through the adult DCD aorta. To provide a clear
transporting the DCD donor to the operating room after effluent, 1 L is used before sternotomy, cross-clamping,
declaration of death may exclude subsequent liver trans- and venting, and then 4 L afterward. Approximately twice
plantation because of excessive hepatic ischemia. To min- this volume is necessary when using HTK solution.
imize operating and ischemic times, the potential donor Because all the visceral dissection is performed in the
should be prepared and draped before withdrawal of sup- cold, without blood flow and without having had oppor-
port. Instruments for rapid entry and aortic cannulation tunity to assess pulses, particular care must be taken not
should be chosen, as depicted (Fig. 42-7). The cannula to damage vital structures. The hepatoduodenal ligament
and tubing should be flushed and placed on the field, is divided from right to left as close to the duodenum as
maintaining the containers of preservation solution in an possible, taking care to preserve the hepatic artery.
 42 Donation After Cardiac Death 565

GIFT OF LIFE DONOR PROGRAM

TITLE: Operating Room Donation After Cardiac Death Flow Sheet

Patient Name UNOS #

INTRAOPERATIVE MANAGEMENT
Blood drawn Date / / Time : (EST)
Heparin administered Date / / Time : (EST)
Entered OR Date / / Time : (EST)
Withdrawal of support Date / / Time : (EST)
Pronouncement Date / / Time : (EST)
Incision Date / / Time : (EST)
Cross-clamp Date / / Time : (EST)
Time from withdrawal to pronouncement minutes
Time from pronouncement to cross-clamp minutes
Total warm ischemic time (withdrawal to cross-clamp) minutes
Flush solution 1st liter in @ : Total flush cc
Family present for withdrawal Yes No Location of withdrawal OR ICU PACU Other
Care and comfort administered Yes No Was patient extubated Yes No
START TIME : HEMODYNAMIC MEASUREMENTS
@ Min Min Min Min Min Min Min Min Min Min Min Min Min Min Min Min Min Min Min
Start 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
HR
BP
RR
SPO2
Min Min Min Min Min Min Min Min Min Min Min Min Min Min Min Min Min Min Min Min
20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39
HR
BP
RR
SPO2
Min Min Min Min Min Min Min Min Min Min Min Min Min Min Min Min Min Min Min Min
40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59
HR
BP
RR
SPO2
FIGURE 42-6 n Gift of Life Donor Program donation after cardiac death operating room flow sheet. BP, Blood pressure; EST, Eastern S­ tandard
Time; HR, heart rate; ICU, intensive care unit; OR, operating room; PACU, postanesthesia care unit; RR, respiratory rate; SPO2, oxygen
saturation as measured by pulse oximetry. (Courtesy Howard M. Nathan and Richard D. Hasz, Gift of Life Donor Program, Philadelphia, PA.)

First, the common bile duct is divided and the biliary tree artery and to expedite organ extraction time. After a
flushed with chilled preservation solution through an Kocher maneuver, the duodenum and pancreatic head are
opening in the gallbladder and through the common duct elevated and retracted caudally to expose the superior mes-
directly. Expeditious performance of this maneuver may enteric artery, which is then dissected down to the aorta.
reduce bile-induced epithelial damage and ischemic chol- Care is taken not to transect an accessory or replaced right
angiopathy following DCD liver transplantation. The hepatic artery by avoiding dissection on the right side of
portal vein is divided at the confluence of the superior the superior mesenteric artery. Rather than taking extra
mesenteric and splenic veins. The gastroduodenal and time to search for a right branch, it is safest to assume that
right gastric arteries need not be clearly delineated. one exists and to take a common patch of superior mesen-
The left lateral segment of the liver is elevated by teric and celiac arteries with the liver. An aortotomy is per-
dividing the left triangular ligament. It is safest to assume formed between the superior mesenteric and right renal
that there is a replaced or accessory left hepatic artery arteries and extended to provide the arterial patch.
arising from the left gastric artery. Therefore the lesser The left diaphragm is then divided down toward the
omentum and left gastric artery should be separated from Carrel patch. The suprahepatic inferior vena cava is
the lesser curvature at the level of the stomach. The divided. The right diaphragm is then divided down to the
splenic artery is divided to the left of the midline, far from upper pole of the right kidney. The infrahepatic inferior
the celiac axis, and then dissected toward the aorta, so vena cava is then transected just above the renal veins.
that it can be rotated to the right for exposure of the The liver is extricated, and immediate back-table portal
superior mesenteric artery, which lies deep to it. flush with 1 L of chilled UW solution is performed; some
Unless the plan is to procure the DCD pancreas, dis- cannulate and flush the portal system in situ via the infe-
cussed later, the head of the pancreas should be taken with rior mesenteric vein. It is particularly important to per-
the liver to avoid transecting an aberrant right hepatic form back-table inspection and trimming of the DCD
566 PART V Operation

FIGURE 42-8 n The distal aorta is clamped and the cannula passed
cephalad through an aortotomy and secured with umbilical
tape; flush is started immediately without waiting to cross-
clamp the proximal aorta.

FIGURE 42-7 n Example of instruments for rapid entry and aortic inherent with the superrapid recovery technique and may
cannulation; to minimize operating time the potential donor decrease warm ischemia time, particularly if withdrawal
should be prepared and draped before withdrawal of support of support is performed outside the operating room. The
(instruments include a scalpel, a pair of Kocher clamps, a moist
towel, Metzenbaum scissors, a right-angle clamp, a moist technique requires consensual, preextubation (premor-
umbilical tape, two Kelly clamps, a sternal saw, abdominal and tem) femoral vessel cannulation.ǁ Femoral artery and
sternal retractors, and a flushed cannula and tubing connected femoral vein cannulas are inserted under local anesthesia.
to preservation solution in an ice bucket). After declaration of death, cold preservation solution is
immediately infused via the femoral artery cannula, and
the femoral vein cannula is opened to gravity to decom-
liver well in advance of the recipient surgery, to ensure press the venous system. Thereafter, median sternotomy
that it is safe to transplant the organ. and midline abdominal incisions are made, and the intra-
Adding whole-organ pancreatectomy to hepatectomy abdominal organs are topically ice cooled and then
during a superrapid recovery carries risk for transecting removed en bloc or separately.
an aberrant right hepatic artery because there is no The University of Michigan group and others use pre-
opportunity to palpate arterial pulsations in the DCD. mortem cannulation in conjunction with postmortem,
Meticulous in situ dissection in search of a right branch normothermic ECMO to restore the flow of warm oxy-
can significantly increase extraction time. Therefore the genated blood to the intra-abdominal organs during the
DCD liver is typically removed with the pancreatic head interval between death and organ procurement.45,75 This
to avoid injuring an aberrant right hepatic artery. We do not only facilitates unhurried procurement, it may also
not routinely procure DCD whole pancreata when pro- improve graft function. To prevent resumption of circu-
curing DCD livers, unless there is favorable donor body lation to the heart and brain, an occlusion balloon cathe-
habitus, short warm ischemia time, and other aspects of ter is introduced in the contralateral femoral artery and
the individual case are optimal.73 Alternatively, the liver inflated in the descending aorta.
and pancreas may be removed en bloc.
Bilateral nephrectomies may be performed after hepa-
tectomy. The kidneys can be kept en bloc for machine DONATION AFTER CARDIAC DEATH
perfusion or separated and sent directly to the recipient LIVER TRANSPLANTATION RESEARCH
centers. Even though DCD organ procurement is a
rushed procedure, it is still crucial to perform careful A major focus of DCD liver transplantation research
donor exploration in an effort to discern the possibility of involves preservation methods to decrease the ischemic
unrecognized malignancy or infection. insult of DCD.58,76-79 In renal transplantation, pulsatile
ex vivo machine perfusion of kidneys is used to reduce DGF
and improve outcomes.42,45,80 In liver transplantation the
Premortem Cannulation Technique, current paradigm of static hypothermic preservation may
With or Without Extracorporeal Membrane eventually change to dynamic, ex vivo machine perfusion.
Oxygenation In 2010 Guarrera et al78 reported the first prospective study
of human liver transplantation using organs preserved with
The premortem cannulation technique, described by ex vivo hypothermic machine perfusion, demonstrating its
Groth and colleagues in Stockholm, Sweden74 and later
by the group in Madison, Wisconsin,8 decreases the rush ǁReferences 17-19, 23,25, 26, 59.
 42 Donation After Cardiac Death 567

safety and raising interest in this approach to improve pres-

ervation and reconditioning of DCD livers and to predict • Start the aortic flush immediately after cannulation—
which ones are likely to perform well. Numerous investiga- do not wait until cross-clamping or venting. Flush the
portal system on the back-table, not in situ.
tors are attempting to assess whether hypothermic or nor- • Maintain a low threshold for performing a donor liver
mothermic preservation is better for reducing the biopsy to exclude centrilobular necrosis and other predic-
ischemia-reperfusion injury associated with DCD liver tors of poor graft quality.
transplantation. In 2012 Boehnert et al79 showed that nor- • Use T tubes liberally to facilitate (1) evaluation of possible
mothermic ex vivo perfusion reduces liver and bile duct early post–liver transplantation cholestasis and (2) surveil-
injury of pig livers retrieved after cardiac death. Another lance for ischemic cholangiopathy.
area of research on improving DCD liver transplantation • Beware of confusing uncontrolled DCDs with controlled
outcomes focuses on cytoprotection to preserve cellular DCDs; in general, livers from the former pose a much
energy stores and viability. These and other innovative higher risk than those from the latter.
strategies potentially applicable to DCD are in early devel- • Be familiar with the ethico-legal principles of DCD.
• Pitfalls include inadequate planning and poor communi-
opment and not yet ready for widespread use. Other topics cation with the donor coordinator and operating room
of study relate to the risks, benefits, utility, and costs of nurses.
DCD liver transplantation and to organ allocation policy • Conflicts of interest include involvement in decisions
for retransplantation of recipients with failed DCD livers. about patient prognosis, withdrawal of support, or deter-
mination of death.
• Avoid adding whole-organ pancreatectomy to hepatec-
CONCLUSIONS tomy during DCD recovery, unless there is a favorable
donor body habitus and a short warm ischemia time. The
DCD has been embraced by various professional societ- DCD liver is typically removed with the pancreatic head
ies and federal governmental agencies of the United to avoid transecting an aberrant right hepatic artery and
to minimize extraction time; alternatively, the liver and
States as an effective way to deal with the shortage of pancreas may be removed en bloc.
transplantable organs.19-27 Ideally, patients who are brain • Avoid DCD liver transplantation after excessive ischemia
dead, or will likely soon become so, should donate organs times:
according to brain death protocols because the yield of • A true warm ischemia time (interval between a signifi-
transplantable organs from DCDs and outcomes of DCD cant ischemic insult, such as a drop in mean arterial
liver transplantation are generally not as favorable as with pressure below 50 mm Hg, and initiation of perfusion)
heart-beating donors. The increased risk for ischemic up to and perhaps somewhat beyond 20 to 30 minutes
cholangiopathy after DCD liver transplantation can be seems safe.
mitigated by adherence to recommended best practice • A total warm ischemia time (interval between with-
DCD protocols, careful selection of DCD organs, and drawal of support and initiation of perfusion) up to and
perhaps somewhat beyond 30 to 45 minutes seems safe.
rapid procurement by surgeons familiar with DCD oper- • Keep the cold ischemia time as short as possible.
ative techniques. The current agenda of those working to • Avoid transplanting livers from DCDs with too many ad-
advance the field of DCD liver transplantation involves ditional extended donor or graft criteria.
further identification of risk factors for graft failure after • Do not send an inexperienced surgical team for DCD liv-
transplantation and research into organ preservation er procurement or import a DCD liver from an unfamiliar
methods to decrease the ischemic insult of DCD.58,76,77    team.

Pearls and Pitfalls

• Discuss the possibility of donation after cardiac death REFERENCES
(DCD) liver transplantation with patients during the liver 1. Organ Procurement and Transplantation Network (OPTN) and
transplantation evaluation so that they are not surprised if Scientific Registry of Transplant Recipients (SRTR): OPTN/
asked to provide informed consent later on. SRTR 2011 Annual Data Report. Department of Health and
Human Services, Health Resources and Services Administration,
• Make sure to be familiar with the organ procurement or- Healthcare Systems Bureau, Division of Transplantation, 2012.
ganization's DCD protocol. Available at: http://srtr.org/annual_Reports/2011. Accessed June
• Have the coordinator fill out a preprinted DCD flow 13, 2013.
sheet to document hemodynamic measurements every 2. Annual report. Eurotransplant International Foundation, 2012.
minute and the times of discontinuation of mechanical Available at: http://www.eurotransplant.org/cms/mediaobject.php?
ventilation, cessation of cardiorespiratory function, wait- file=AR2012.pdf. Accessed June 13, 2013.
ing period, declaration of death, incision, and perfusion 3. Daemen J-WHC, Koostra G, Wijnen RMH, et al. Nonheart-­
of each organ. After procurement, careful assessment of beating donors: The Maastricht experience. In: Terasaki PI, Cecka
information on the flow sheet is critical for appraising the M: Clinical Transplants 1994. Los Angeles: UCLA Tissue Typing
Laboratory; 1994:303-316.
ischemic injury. 4. A definition of irreversible coma. report of the Ad Hoc Committee
• Decrease operating/ischemic time: of the Harvard Medical School to Examine the Definition of Brain
• Before withdrawal of support, communicate with the Death. JAMA. 1968;205:337-340.
nursing staff about conduct of the operation, prepare 5. UDODA—Guidelines for the determination of death. Report of the
and drape, and set up instruments. Then, exit the oper- medical consultants on the diagnosis of death to the President’s
ating room but remain gowned and gloved. Commission for the Study of Ethical Problems in Medical and
Biomedical and Behavioral Research. JAMA. 1981;246:2184-2186.
568 PART V Operation

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11. Abt PL, Desai NM, Crawford MD, et al. Survival following liver liver transplantation from donation after cardiac death donors: an
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12. Foley DP, Fernandez LA, Leverson G, et al. Donation after car- 34. Taner CB, Bulatao IG, Willingham DL, et al. Events in procure-
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2003;75:1171-1174. donation after cardiac death: a single center experience. Transplan-
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17. Institute of Medicine, National Academy of Sciences. Non-Heart- Liver Transpl. 2007;13:1645-1653.
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Accessed June 13, 2013. 45. Farney AC, Hines MH, al-Geizawi S, et al. Lessons learned from a
22. Centers for Medicare and Medicaid Services (CMS), Department single center's experience with 134 donation [sic] after cardiac death
of Health and Human Services. Medicare and Medicaid Programs: donor kidney transplants. J Am Coll Surg. 2011;212:440-451.
conditions for coverage for organ procurement organizations 46. Fernandez LA, Di Carlo A, Odorico JS, et al. Simultaneous pan-
(OPOs). Final rule. Fed Regist. 2006;71:30981-31054. creas-kidney transplantation from donation after cardiac death:
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guidelines for controlled donation after cardiac death organ pro- 47. Salvalaggio PR, Davies DB, Fernandez LA, et al. Outcomes of pan-
curement and transplantation. Am J Transplant. 2009;9:2004-2011. creas transplantation in the United States using cardiac-death
24. United Network for Organ Sharing. Donation after cardiac death: A donors. Am J Transplant. 2006;6:1059-1065.
reference guide. Richmond, VA: UNOS; 2004. 48. Axelrod DA, Sung RS, Meyer KH, et al. Systematic evaluation of
25. Attachment III to Appendix B of the OPTN [Organ Procurement pancreas allograft quality, outcomes and geographic variation in
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Controlled DCD Recovery Protocols. [Updated March 23, 2007] 49. Mason DP, Brown CR, Murthy SC, et al. Growing single-center
Available at: http://optn.transplant.hrsa.gov/policiesandBylaws2/by experience with lung transplantation using donation after cardiac
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26. United Network for Organ Sharing: Critical Pathway for Dona- 50. Zych B, Popov AF, Amrani M, et al. Lungs from donation after
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Critical_Pathway_DCD_Donor.pdf. Accessed June 13, 2013. donors? Midterm results at a single institution. Eur J Cardiothorac
27. Recommendations for nonheartbeating organ donation. A position Surg. 2012;42:542-549.
paper by the Ethics Committee, American College of Critical Care 51. Cypel M, Yeung JC, Keshavjee S. Novel approaches to expanding
Medicine, Society of Critical Care Medicine. Crit Care Med. the lung donor pool: donation after cardiac death and ex vivo con-
2002;29:1826-1831. ditioning. Clin Chest Med. 2011;32:233-244.
28. Tuttle-Newhall JE, Krishnan SM, Levy MF, et al. Organ donation 52. De Oliveira NC, Osaki S, Maloney JD, et al. Lung transplantation
and utilization in the United States: 1998–2007. Am J Transplant. with donation after cardiac death donors: long-term follow-up in a
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 42 Donation After Cardiac Death 569

53. Fondevila C, Hessheimer AJ, Flores E, et al. Applicability and 68. Rubenstein S. California surgeon cleared of hastening organ
results of Maastricht type 2 donation after cardiac death liver trans- donor’s death. Health Blog. Goldstein J, lead writer Wall Street
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54. Sánchez-Fructuoso AI, Marques M, Prats D, et al. Victims of car- lth/2008/12/19/california-surgeon-cleared-of-hastening-organ-do-
diac arrest occurring outside the hospital: a source of transplant- norsdeath. Accessed June 13, 2013.
able kidneys. Ann Intern Med. 2006;145:157-164. 69. Edwards JM, Hasz RD, Robertson VM. Non-heart-beating organ
55. Reich DJ, Manzarbeitia CY. Non-heart-beating donor liver trans- donation: process and review. AACN Clin Issues. 1999;10:293-300.
plantation. In: Busuttil RW, Klintmalm GB: Transplantation of the 70. Reiner M, Cornell D, Howard RJ. Development of a successful
Liver. Philadelphia: WB Saunders; 2005:529-543. non-heart-beating organ donation program. Prog Transplant.
56. Reich DJ. Non-Heartbeating donor organ procurement. In: 2003;13:225-231.
Humar A, Payne WD, Matas AJ: Atlas of Organ Transplantation. 71. Suntharalingam C, Sharples L, Dudley C, et al. Time to cardiac
London, UK: Springer; 2006:23-33. death after withdrawal of life-sustaining treatment in potential
57. Mathura AK, Heimbach J, Steffick DE, et al. Donation after car­ organ donors. Am J Transplant. 2009;9:2157-2165.
diac death liver transplantation: predictors of outcome. Am J 72. Olson L, Davi R, Barnhart J, et al. Non-heart-beating cadaver
Transplant. 2010;10:2512-2519. donor hepatectomy “the operative procedure”. Clin Transplant.
58. Reich DJ, Guy SR. Donation after cardiac death in abdominal 1999;13:98-103.
organ transplantation. Mt Sinai J Med. 2012;79:365-375. 73. Jeon H, Ortiz JA, Manzarbeitia CY, et al. Combined liver and pan-
59. Bernat JL, D’Alessandro AM, Port FK, et al. Report of a National creas procurement from a controlled non-heart-beating donor
Conference on Donation after cardiac death. Am J Transplant. with aberrant hepatic arterial anatomy. Transplantation. 2002;74:
2006;6:281-291. 1636-1639.
60. Fung JJ, Eghtesad B, Patel-Tom K. Using livers from donation 74. Yamamoto S, Wilczek HE, Duraj FF, et al. Liver transplantation
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61. Hashimoto K, Eghtesad B, Gunasekaran G, et al. Use of tissue 75. Magliocca JF, Magee JC, Rowe SA, et al. Extracorporeal support
plasminogen activator in liver transplantation from donation after for organ donation after cardiac death effectively expands the
cardiac death donors. Am J Transplant. 2010;10:2665-2672. donor pool. J Trauma. 2005;58:1095-1102.
62. Stewart ZA, Cameron AM, Singer AL, et al. Histidine-Tryptophan-­ 76. Sass DA, Reich DJ. Liver transplantation in the 21st century:
Ketoglutarate (HTK) is associated with reduced graft survival in expanding the donor options. Gastroenterol Clin North Am. 2011;40:
deceased donor livers, especially those donated after cardiac death. 641-658.
Am J Transplant. 2009;9:286-293. 77. Reich DJ, Hong JC. Current status of donation after cardiac death
63. Renz JF. Is DCD for liver transplantation DNR? Am J Transplant. liver transplantation. Curr Opin Organ Transplant. 2010;15:
2008;8:485-488. 316-321.
64. Kootstra G. The asystolic, or non-heartbeating, donor. Transplan- 78. Guarrera JV, Henry SD, Samstein B, et al. Hypothermic machine
tation. 1997;63:917-921. perfusion in human liver transplantation: the first clinical series.
65. Whetstine L, Bowman K, Hawryluck L. Pro/con ethics debate: is Am J Transplant. 2010;10:372-381.
nonheart-beating organ donation ethically acceptable? Critical 79. Boehnert MU, Yeung JC, Bazerbachi F, et al. Normothermic acel-
Care. 2000;6:192-195. lular ex vivo liver perfusion reduces liver and bile duct injury of pig
66. Bell MD. Non-heart beating organ donation: old procurement livers retrieved after cardiac death. Am J Transplant. 2013;13:
strategy—new ethical problems. J Med Ethics. 2003;29:176-181. 1441-1449.
67. Arnold RM, Younger SJ. Time is of the essence: the pressing need 80. Cantafio AW, Dick AA, Halldorson JB, et al. Risk stratification of
for comprehensive non-heart-beating cadaveric donation policies. kidneys from donation after cardiac death donors and the utility of
Transplant Proc. 1995;27:2913-2921. machine perfusion. Clin Transplant. 2011;25:E530-E540.
 CHAPTER 43

The Donor Operation

John F. Renz • Hasan Yersiz

CHAPTER OUTLINE

EVALUATION OF THE POTENTIAL RECIPIENT Organ Cold Perfusion

Cold Dissection
EVALUATION OF THE POTENTIAL DONOR
Special Circumstances
THE DONOR OPERATION: CONVENTIONAL ADULT Back-Table Preparation of the Liver Allograft
LIVER PROCUREMENT Arterial Variations and Reconstruction
Preoperative Preparation Pediatric Procurement
Preparation for Cold Perfusion

The expeditious assessment and recovery of cadaver serological studies (hepatitis B, hepatitis C, human
organs without surgical injury will always be the central immunodeficiency virus, Epstein-Barr virus, and cyto-
mission of the donor surgeon; however, the current cli- megalovirus), and intra-abdominal procedures that could
mate of organ scarcity1-3 has placed increasing demands affect vascular inflow/outflow.7,8 The physiological con-
upon the donor surgeon that require enhanced skill and dition of the recipient candidate is assessed with respect
experience to routinely perform these procedures so as to to encephalopathy, coagulopathy, hemodynamic stabil-
extract the maximal potential from the existing cadaver ity, pressor requirements, and potential need for addi-
donor pool. Organ procurement organizations (OPOs) tional organ(s). The goal of this survey is to determine
have responded to the relative plateau in cadaver dona- the anticipated needs of the recipient with respect to
tion by expanding potential donor criteria with respect to immediate graft function so that the donor organ can be
age, medical comorbidities, high-risk social behaviors, assessed from this perspective. The potential recipient’s
prolonged hospitalization, known congenital anomalies, abdominal cavity is assessed for capacity; specifically, the
and partial brain-death criteria. Donors outside tradi- potential of previous intra-abdominal operations to
tional donation criteria, termed extended criteria donors,4-6 reduce overall abdominal capacity through adhesions,
currently represent the largest potential expansion of the decreased intra-abdominal organ mobility, or scarring of
existing donor pool. Furthermore, procurement agencies the abdominal wall.
desire maximal utility from each existing donor through
the procurement of all possible organs with clinical or
research potential. These practices increase demands EVALUATION OF THE POTENTIAL DONOR
upon the donor surgeon for skilled assessment, diagnosis,
and management of clinical conditions outside the donor It is imperative that the procurement team demonstrate
organ of interest in addition to the performance of the highest regard for the suffering of donor families and
advanced procurement techniques. These techniques the medical professionals who have valiantly cared for
must be widely applicable to a broad patient population at their patient. They have referred their patient to us, and
a variety of donor facilities and require no specialized the family has consented to a procedure that will inevita-
equipment or staff. bly prolong the grieving process. Procurement teams
must recognize these sacrifices and reciprocate through
friendly, courteous, and professional conduct at the donor
EVALUATION OF THE POTENTIAL facility. Patient confidentiality must be vigorously upheld,
RECIPIENT because inadvertent and unknowing contact with donor
family members during the course of transporting highly
The donor process begins with complete evaluation of recognizable procurement equipment to the operating
the recipient candidate before departure for the donor room or in other areas of the facility is always possible. By
medical facility. The potential recipient is evaluated for the nature of their illness, donors frequently use many
medical/surgical history, physiological condition, and components of the hospital, including emergency ser-
size of the abdominal compartment. Pertinent medical/ vices, intensive care, radiology, and surgical services.
surgical history includes blood group, results of serum Thus the donor team is scrutinized from arrival to

570
 43 The Donor Operation 571

departure. Arrogant, condescending, or unfriendly actions Expediency and accuracy are essential to successful
by a group of individuals who arrive via a high-profile organ recovery. Brief operating room times reduce costs,
vehicle do immeasurable disservice to the transplant com- lower operating staff stress, and increase efficiency. The
munity and belittle the efforts of the donor’s health care technique described herein is a balance between the ini-
professionals and family. tial procurement technique of Starzl9 advocating exten-
Initial donor assessment addresses hemodynamic sta- sive warm dissection and the later “rapid flush technique”
bility, support services, and vascular access. The current advocating en bloc evisceration with back-table cold dis-
condition of the donor with respect to oxygenation, section.10-12 The described technique consistently yields
hemodynamic stability, vasopressor requirements, urine aortic cross-clamp times of less than 1 hour with total
output, and laboratory data, particularly serum electro- procurement times under 2.5 hours and requires no
lyte levels, is evaluated and optimized. Support equip- ­specialized equipment or staff.
ment and personnel for critical care transport to the
operating room are verified. Donor surgeons should par-
ticipate in transport to the operating room to assist in
Preparation for Cold Perfusion
care and be immediately available in the case of a donor Donor position is supine with both arms tucked. The sur-
arrest. Lastly, adequate vascular access at sites that will gical preparation and draping extends from the cricoid
not be affected by the donor operation are verified and cartilage to the midthigh to ensure complete access to the
secured by the donor surgeon as necessary. Our prefer- thoracic and abdominal cavities. A midline incision from
ence is vascular access above the diaphragm with the use the xiphoid process to the pubis is made with electrocau-
of a central line in the setting of vasopressors or hemody- tery, and the abdomen is entered. An extended Balfour
namic instability. Femoral arterial catheters are accept- self-retaining retractor (greater than 400-mm spread)
able with the caveat that information will be lost with with penetrating prongs is used to facilitate exposure, and
interruption of the infrarenal aorta. a complete laparotomy to exclude occult malignancy,
As the donor is prepared for surgery, the donor sur- assess traumatic organ injury or compromise, and diag-
geon has the opportunity to review the medical chart to nose potential sources of sepsis is performed. Bilateral
confirm pertinent details of the past medical history, subcostal incisions may enhance exposure in unique cir-
social history, appropriate documentation of brain death, cumstances such as morbid obesity or delayed entry to
blood type, and results of serum serological studies. Of the thoracic cavity, but we have not found these addi-
particular note is a history of liver disease, diabetes, tional incisions to be routinely necessary.
hypertension, or malignancy in addition to previous The liver is assessed for color, texture, parenchyma
intra-abdominal surgery. Is there a behavioral high-risk quality, evidence of ischemia, and size. Evidence of early
history? ischemia or volume overload may be corrected through
The hospital course of the donor is reviewed, includ- interaction with the anesthesiologist and the administra-
ing date of admission, traumatic injuries, performance of tion of appropriate medical therapy.7 Frequently these
surgical procedures, documented infections, vasopressor measures are rewarded with significant improvement in
requirements, cause of death, and period of cardiac arrest the appearance of the liver before aortic cross-clamping.
with duration of cardiopulmonary resuscitation.7,8 Lastly, The critical decision at this point is, Can this organ, based
a photocopied chart containing all essential clinical and upon the accumulated data, provide the immediate meta-
laboratory data is available for packaging with the bolic needs of the potential recipient it has been offered
allograft. The chart should also contain copies of any to? If so, the recipient team can be notified to prepare the
reports of pathological findings with slides for review. recipient. If not, the OPO coordinator should be notified
to offer the organ to another potential recipient. To place
an organ that has been declined by the donor surgeon
THE DONOR OPERATION: CONVENTIONAL may necessitate discussions with other recipient surgeons
ADULT LIVER PROCUREMENT to address specific issues in the field. The donor surgeon
should readily be available to assist in organ placement.
Preoperative Preparation Intra-operative photography with images sent as text or
email are invaluable.13
Donor procurements are a relatively infrequent proce- If preliminary assessment of the liver is acceptable, the
dure performed at community hospitals. Thus it is skin incision is carried to the suprasternal notch and the
unusual for operating room staff to have experience in chest is entered via a median sternotomy using a pneu-
organ recovery. Before scrubbing for surgery, the donor matic saw or Lebsche knife. A Finochietto self-retaining
surgeon should introduce the procurement team to the sternal retractor is positioned and the pericardium
operating room staff, provide instructions to the nurses entered through the midline at the diaphragm and
and technicians of his or her preferences with respect to extended to above the right atrium. The right chest is
the procedure, verify essential equipment/staff are pres- widely opened through the parietal pleura, and the peri-
ent, and establish a collegial atmosphere. Participation by cardial wall on the right is split to the level of the phrenic
local staff interested in the procedure should be welcome nerve to complete the thoracic dissection (Fig. 43-1).
in an observation role only. If additional procurement The round ligament is divided between heavy silk
teams are in attendance, briefly reviewing your plan and sutures and the falciform ligament dissected to the hepatic
estimated aortic cross-clamp time will help coordinate vein–inferior vena cava confluence. The left coronary and
their efforts. triangular ligaments are released and the left lateral
572 PART V Operation

A B
FIGURE 43-1 n A, The donor incision extends from the suprasternal notch to the pubic symphysis. The cardiac, thoracic, and abdomi-
nal cavities have been entered with the extended Balfour and Finochietto retractors positioned. B, The parietal pleura and pericar-
dium of the right chest have been widely opened to facilitate exsanguination into the right chest following cold perfusion.

A B
FIGURE 43-2 n A, Dissection of the gastrohepatic ligament begins over the caudate lobe. Thin, transparent tissue is divided with elec-
trocautery from the lymph nodes overlying the common hepatic artery to the diaphragm (B).

segment of the liver elevated and retracted medial to artery with preservation of approximately 5 mm of adven-
reveal the gastrohepatic ligament, which is carefully titia on each side of the artery. Only portions of the gas-
inspected for a replaced/accessory left hepatic artery. trohepatic ligament that are translucent should be
This anatomical variant courses transversely from the left divided. The dissection proceeds from the lymph nodes
gastric artery on the lesser curvature of the stomach overlying the common hepatic artery superiorly to the
across the gastrohepatic ligament to the umbilical fissure diaphragm (Fig. 43-2).
in approximately 15% to 23% of cadaver donors and Retroperitoneal dissection is initiated with medial
should not be injured during the dissection.7,14,15 If this rotation of the right colon and duodenum en bloc as
variant is present, the gastrohepatic ligament is dissected described by Cattel and Braasch.16 The right colon,
below and above the replaced/accessory left hepatic duodenum, and remaining small bowel are mobilized
 43 The Donor Operation 573

FIGURE 43-3 n Placement of the surgeon’s index finger below the

FIGURE 43-4 n Complete liberation of the retroperitoneum to the
gallbladder through the foramen of Winslow identifies neural
origin of the superior mesenteric artery (enclosed in vessel
and connective tissue to be divided to facilitate complete expo-
loops). Complete exposure of the abdominal aorta, inferior vena
sure of the retroperitoneum and identification of the superior
cava, renal veins, and inferior mesenteric vein (encircled with
mesenteric artery origin.
silk suture) has been achieved.

cephalad out of the incision to the donor’s left. The ret- The abdominal aorta, below the takeoff of the infe-
roperitoneal dissection is carried cephalad to the left rior mesenteric artery, is exposed for cannulation. The
renal vein. Identification of the left renal vein signals peritoneum and lymphatic tissue overlying the distal
the cephalic limit because extensive dissection above aorta are widely divided at the bifurcation and carried to
the left renal vein risks inadvertent injury of the supe- above the takeoff of the inferior mesenteric artery. The
rior mesenteric artery, left renal artery, left kidney, and plane of dissection should be slightly toward the infe-
pancreas or torsion of the superior mesenteric artery rior vena cava to avoid inadvertent injury of the inferior
with rotation of the bowel. The final maneuver to liber- mesenteric artery origin. The aorta is encircled with
ate the retroperitoneum involves placement of the left two umbilical tapes to complete the dissection: the infe-
index finger through the foramen of Winslow beneath rior tape at the level of the aortic bifurcation is held by
the hilum to expose interstitial and neural tissue medial a Kelly clamp, and the superior tape, located just below
to the origin of the superior mesenteric artery (Fig. the inferior mesenteric artery origin, is snared with a
43-3). Placing the left index finger beneath the gall- Rummel tourniquet. Dissection should remain at or
bladder and proceeding toward the aorta easily identi- below the origin of the inferior mesenteric artery to
fies this space. Division of this connective and neural prevent inadvertent injury to accessory inferior polar
tissue results in full exposure of the entire retroperito- renal arteries. If necessary, the inferior mesenteric
neum, including the infrahepatic vena cava, both renal artery can be divided between silk ligatures to facilitate
veins, the superior mesenteric artery, the abdominal exposure.
aorta, and the inferior mesenteric vein (Fig. 43-4). The The right colon and small bowel are returned to the
inferior mesenteric vein is isolated at the ligament of abdominal cavity and the hilum exposed to visualize the
Treitz close to the root of the transverse mesocolon and common bile duct just above the duodenum (Fig. 43-5).
cannulated to begin a precool perfusion17 (see Fig. Hilar dissection proceeds from lateral to medial, remain-
43-4). The cannula should remain only within the infe- ing close to the duodenum. Careful palpation behind the
rior mesenteric vein to prevent inadvertent injury and hilum aids the dissection and may identify an early takeoff
subsequent thrombosis of the splenic vein. The left right hepatic artery or a replaced/accessory right hepatic
colon is released from its retroperitoneal attachments artery, which is found in approximately 10% to 17% of
by opening the white line of Toldt, exposing the left cadaver donor series.7,14,15 When isolating the common
kidney. bile duct, it is critical that the dissection not extend into
Donor hypernatremia may be an independent predic- the hilum. It is far better to risk damaging the common
tor of graft dysfunction after transplantation.18-20 Our bile duct near the duodenum by remaining superficial
protocol is to use a precool solution of 5% dextrose in than stray into the hilum, risking injury to the portal vein
isotonic saline for donor serum sodium levels less than or a replaced/accessory right hepatic artery. The distal
160 mEq/dL and 5% dextrose in water for donor serum common bile duct is tied with a 2-0 silk ligature at the
sodium levels of 160 mEq/dL or higher. Particular atten- duodenal border, and the bile duct is cut sharply above the
tion is directed toward appropriate resuscitation of the tie (see Fig. 43-5). The gallbladder is opened and flushed
donor during the operative procedure to correct with normal saline until the effluent from the transected
hypernatremia.6 common bile duct is clear. This step is paramount because
 43 The Donor Operation 573.e1

FIGURE e43-4 n Complete liberation of the retroperitoneum to the

origin of the superior mesenteric artery (enclosed in vessel
loops). Complete exposure of the abdominal aorta, inferior vena
cava, renal veins, and inferior mesenteric vein (encircled with
silk suture) has been achieved.
574 PART V Operation

A B
FIGURE 43-5 n Dissection of the hilum. A, The common bile duct is isolated along the superior border of the duodenum to preserve
length and avoid disruption of vascular supply. B, The common bile duct is ligated with a silk ligature before proximal division and
evacuation of bile from the biliary tree.

FIGURE 43-7 n The abdominal operation is complete with the

FIGURE 43-6 n Isolation of the supraceliac aorta. cannulas for portal vein perfusion (above) and aortic perfusion
(below) in position.
removal of bile from the biliary tree prevents stasis and
bile-induced autolysis of biliary epithelium during cold presence of atherosclerosis. The surgical assistant then
preservation. occludes the proximal aorta with his or her finger just
Exposure of the supraceliac aorta is the final maneuver above the cephalad umbilical tape while holding up on
before cannulation. The left lateral segment is elevated the Rummel tourniquet with the nondominant hand.
and retracted lateral to expose the diaphragmatic crura. A The donor surgeon opens the aorta just above the distal
cruciform incision using electrocautery opens the right tape ligature and inserts a 22F reinforced cardiac catheter
crus at the midline while the assistant surgeon retracts the into the aorta. As the catheter is inserted, the aorta is
esophagus laterally to expose the aorta (Fig. 43-6). The grasped with the surgeon’s hand to secure its position and
preaortic fascia is sharply transversed with the dissection prevent blood loss while the assistant tightens the Rum-
carried anterior and lateral into the chest to increase aorta mel tourniquet encircling the aorta. The donor surgeon
mobility. A blunt-tipped large right-angle clamp is used continues to control the cannula while the assistant loops
to encircle the aorta with an umbilical tape to aid identi- an umbilical tape around the cannula and Rummel tour-
fication and facilitate accurate aortic cross-clamp. niquet to secure them to each other. The cannula tip is
At this point, 30,000 units of heparin (300 units/kg) positioned approximately 4 cm above the aortotomy and
are administered, preferably via a central line, and circu- verified by the donor surgeon’s fingertip to be below the
lated for at least 3 minutes.21 Cannulation of the abdomi- takeoff of the superior mesenteric and renal arteries (Fig.
nal aorta is initiated with ligation of the distal umbilical 43-7). The OPO coordinator and any other participating
tape at the bifurcation. Particular attention to gentle han- recovery teams are notified that the intra-abdominal dis-
dling of the aorta in the presence of atherosclerotic plaque section is complete and to prepare for cold perfusion.
must be exercised during isolation and cannulation
because the aorta is easily injured, leading to perforation, Organ Cold Perfusion
dissection, or irreparable injury with potential loss of the
donor. Aortic injuries are potentially catastrophic and must be Successful cold perfusion requires the performance of
avoided by attention to detail and gentle manipulation in the several steps in concert to minimize warm ischemia and
 43 The Donor Operation 575

preserve hepatic function. The objectives are rapid and

homogenous delivery of preservation fluid to the liver
such that cooling occurs quickly with uniform exsangui-
nation. This must be achieved without venous hyperten-
sion or congestion so that the liver remains soft. Because
preservation fluid is delivered principally through arterial
supply,22 it is critical to return the abdominal contents to
their natural position to avoid inadvertent torsion, spasm,
or occlusion. This point is particularly relevant in the set-
ting of replaced/accessory arterial anatomy that is easily
torsed by rotation of the mesenteric root during
evisceration.
Cold perfusion is initiated with aortic cross-clamping.
After coordinating the procedure among all recovery
teams present and verifying that adequate suction, ice,
and preservation fluid are available, the donor surgeon
instructs the surgical assistant to gently lift the umbilical
FIGURE 43-8 n The diaphragm has been divided to the right cos-
tape encircling the aorta to facilitate exposure. The donor todiaphragmatic angle, releasing the liver superiorly into the
surgeon’s left hand retracts the left lateral segment to the chest to expose the hilum. The liver has been covered with ice,
right and places a long straight vascular clamp across the and a pool-tip suction catheter has been positioned through the
supraceliac aorta. Cross clamp time is announced to foramen of Winslow to facilitate hilar dissection.
the room as the surgeon quickly moves to transect the
vena cava at the caval-atrial junction, thereby exsangui-
nating the donor into the right thoracic cavity containing
a pool-tip suction catheter. The aortic and inferior mes-
enteric venous cannulas are opened to begin simultane-
ous cold perfusion while ice is liberally poured into the
abdominal cavity to augment rapid viscera cooling. It is
important to gently pack ice around the entire liver,
including the subdiaphragmatic space, hilum, and beneath
the left lateral segment. This is particularly important
because warm blood exsanguinating into the right chest
can transmit heat through the diaphragm onto the right
lobe of the liver. Preservation solution at 4° C (39.2° F) is
run through the aortic and inferior mesenteric venous
cannulas without pressure. Flow is verified visually, and
the liver is examined for uniform asanguinity, softness,
and temperature to assess cold perfusion. Inadvertent
arterial injuries at dissection will be readily apparent by
poor perfusion of the affected hepatic segments.
Infusion volumes average 30 to 60 mL/kg, or approxi- FIGURE 43-9 n Arterial dissection. The gastroduodenal artery has
been identified at the superior edge of the duodenum and dis-
mately 2000 to 3000 mL via the aortic cannula and 1000 sected back to verify a common hepatic artery from the celiac
mL via the inferior mesenteric venous cannula for trunk before division and suture ligation.
adults.7,8,23,24 During cold perfusion the liver is continu-
ally assessed, the effluent from the inferior vena cava is
examined, and the right diaphragm is felt for cold ice in cephalad into the right chest. The liver is covered with
the subdiaphragmatic space over the right lobe. The liver ice, and a pool-tip suction catheter is placed behind the
can occasionally be “vented” or repositioned by bimanual hilum from right to left and anterior to the aorta to pro-
palpation with one hand in the right thoracic cavity and vide a dry field (Fig. 43-8). The duodenum is retracted
another anteriorly in the abdomen. away from the liver, and the gastroduodenal artery is
identified at the level of the superior edge of the duode-
Cold Dissection num, where it is dissected toward the liver until the com-
mon hepatic artery is identified. It is critical to clearly
Upon completion of cold perfusion, the pericardium and verify the common hepatic artery proceeding toward the
diaphragm are divided by the first assistant retracting the liver and from the celiac trunk before ligating the gastro-
esophagus laterally as the surgeon dissects in an anterior- duodenal artery (Fig. 43-9). Dissection of the proper
to-posterior direction down to the aorta. The pericar- hepatic artery above the origin of the gastroduodenal
dium is further divided posterior to the inferior vena artery should be discouraged to maintain adequate blood
cava. The donor surgeon grasps the diaphragm between supply to the common bile duct and avoid inadvertent
the index and middle fingers and guides the assistant, who hepatic arterial injury. While dissecting the gastroduode-
cuts the diaphragm posteriorly around the right lobe to nal artery toward the common hepatic artery, if the portal
the costodiaphragmatic angle, releasing the liver to fall vein is encountered, this signals a completely replaced
576 PART V Operation

arterial system originating from the superior mesenteric The entire dissection of the common hepatic artery
artery, which is encountered in approximately 1% of should be on the inferior-lateral border of the vessel
cadavers.7,15 Dissection proceeds proximally on the com- (approximately four o’clock position) to avoid inadver-
mon hepatic artery to encounter the splenic artery (Fig. tent injury to the origin of the splenic or left gastric arter-
43-10), which is verified, ligated, divided, and gently ies. Throughout the dissection the left gastric artery
retracted medially. The gastroduodenal and splenic arter- origin is not encountered. If a replaced/accessory left
ies should be ligated as distally as possible from their ori- hepatic artery has been identified, the lesser omentum,
gins to preserve vessel integrity and length in the event containing the left gastric artery, is completely mobilized
that either or both are later required for back-table vascu- off the stomach from the pylorus to the esophagus after
lar anastomosis. Dissection continues toward the celiac transection of the splenic artery. A replaced/accessory left
trunk until the aorta is reached (Fig. 43-11). The fibrous hepatic artery can originate from the left gastric artery,
connective tissue, celiac plexus, and diaphragmatic crura celiac trunk, or directly from the aorta, and the origin
encircling the aorta are divided to the left of the aorta as frequently will not be apparent during the dissection.
the dissection is carried superiorly to the level of the aor- Thus maintaining an inferior-lateral position during dis-
tic clamp, where the aorta is divided. section of the celiac trunk toward the aorta and remain-
ing along the left lateral border of the aorta will preserve
each anatomical variant.
The portal vein is located immediately beneath the
origin of the gastroduodenal artery (Fig. 43-12). If the
pancreas will not be procured, the dissection proceeds
into the head of the pancreas to isolate the junction of the
splenic and superior mesenteric veins. The superior mes-
enteric vein is ligated with the suture preserved long for
retraction. The splenic vein is transected open for later
cannulation on the back table. If the inferior mesenteric
vein joins to form a trifurcated portal vein origin, it too is
ligated and divided. Intended pancreas procurement lim-
its portal vein dissection with division immediately distal
to the origin of the coronary vein to provide adequate
vein length for both organs. Following division, the por-
tal vein is mobilized to the level of the bile duct ligature
with small branches identified and ligated.
A mass of connective and neural tissue containing the
FIGURE 43-10 n Identification of the splenic artery. The splenic has common bile duct remains lateral to the portal vein. This
been isolated distal to its origin from the celiac trunk. The origin must be carefully dissected to exclude a replaced/acces-
is clearly identified before division of the splenic to avoid inad- sory right hepatic artery originating from the superior
vertent injury to the celiac trunk. The splenic artery is divided as mesenteric artery or a low takeoff right hepatic artery
distally as possible from its origin to preserve vessel integrity
should vascular reconstruction be required later at the back-table
from the celiac trunk that meanders lateral to the portal
dissection. The ligated gastroduodenal artery is evident. vein. Inadvertent arterial injury at this level is a significant
complication. Carefully, the dissection proceeds through
the fibrous tissue of the hilum and the dense neural tissue
of the celiac plexus between the celiac trunk and the

FIGURE 43-11 n Completion of the arterial dissection. The origin

of the celiac trunk at the aorta is clearly exposed. The distal
splenic and gastroduodenal arterial origins have been preserved FIGURE 43-12 n Identification of the portal vein immediately
and ligated. beneath the gastroduodenal artery.
 43 The Donor Operation 577

superior mesenteric artery to expose the anterior surface increasingly critical. Upon abdominal exploration, evi-
of the aorta. In the absence of a replaced/accessory right dence of peritonitis or an undiagnosed neoplasm may be
hepatic artery, a small anterior aortotomy is performed encountered. Unanticipated peritonitis does not exclude
between the celiac trunk and the superior mesenteric procurement; rather, intraoperative culture and immedi-
artery. Renal artery orifices are identified from within the ate Gram stain followed by copious irrigation with nor-
aorta lumen. Under direct vision the aortotomy is mal saline containing a first-generation cephalosporin
extended obliquely on the left to completely open the can be considered adequate treatment. Naturally the
aorta. The right luminal wall of the aorta can then be donor hospital should be contacted to obtain definitive
divided to the line of aortic transection under direct vision culture information, and the recipient should receive
to yield an aortic patch containing the celiac trunk. If a broad-spectrum antibiotics until definitive culture infor-
replaced/accessory right hepatic artery is present, the ves- mation is available.
sel is followed to the superior mesenteric artery, and the Discovery of a neoplasm does not necessarily preclude
superior mesenteric artery origin is mobilized to the donation. Although a detailed discussion is beyond the
aorta. A low takeoff right hepatic artery from the celiac aim of this text, adenocarcinoma, sarcoma, and stromal
trunk will also become apparent. The anterior aortotomy tumors of the gastrointestinal tract diagnosed at explora-
is performed immediately distal to the superior mesen- tion exclude donation; however, small renal cell carcino-
teric artery origin with very careful attention to identifica- mas, early prostate cancer, and biliary tumors require
tion of renal artery orifices that are in immediate proximity further consideration. Stage A or B prostate cancer and
and may even be cephalad to the superior mesenteric renal cell carcinoma less than 2 cm in diameter with
artery origin. Under direct vision and with extreme care, favorable results of histologic examination (well differen-
an aortic patch containing both the celiac and superior tiated) have very little metastatic potential and should be
mesenteric trunks is created as described earlier. The dis- used with informed consent. In fact, renal cell cancers of
tal superior mesenteric artery is transected immediately 4 to 5 cm in diameter with favorable histologic examina-
beyond the first jejunal branches to ensure adequate vessel tion results may be usable in select patients such as
length for back-table arterial reconstruction. advanced hepatocellular carcinoma or cholangiocarci-
The infrahepatic inferior vena cava is transected above noma with proper informed consent.
the renal veins. Identification of both left and right renal Benign biliary tumors can easily be misinterpreted as
vein origins is recommended because a common mistake malignancy and do not preclude donation.25 These
involves encroachment upon the right renal vein orifice include biliary hamartoma, biliary cystadenoma, and bile
or injury out of concern for preserving sufficient vena duct adenoma, as well as the pathological phenomena of
cava to the liver. Adequate inferior vena cava length is focal fatty change.25 We advocate frozen section at the
rarely a technical concern, whereas any encroachment or donor facility with procurement and final pathological
injury of the right renal vein can significantly affect vas- confirmation at the recipient facility as the default in
cular reconstruction. cases of diagnostic uncertainty or inability to perform
The liver is then supported by the surgeon’s nondom- experienced pathological evaluation at the donor facility.
inant hand by placing the index finger into the inferior The hemodynamically unstable donor and non–heart-
vena cava lumen with the remaining fingers protecting beating donor require specific procurement techniques.
the hilar bundle as remnant diaphragmatic and perito- In each case the goal is rapid heparin administration, aor-
neal attachments are divided to liberate the organ. The tic cannulation, cross-clamping, and organ cold perfusion
assistant protects the right kidney by retracting caudad to minimize warm ischemia. A donor arrest during trans-
while verifying the plane of dissection through the right port is not an uncommon event and is best managed by
adrenal. The liver is removed and placed in a sterile plas- immediate administration of 30,000 International Units
tic bag containing 1 L of preservation solution at 4° C of heparin, cardiopulmonary resuscitation, and donation
(39.2° F). The bile duct is flushed with 20 mL of cold after cardiac death (DCD) techniques.
preservation solution before packaging and storage in an DCD procurements proceed by sharp dissection. The
ice-filled cooler. skin is opened with a knife from the xiphoid to the pubis
Following kidney procurement, the iliac arteries and with the dissection continued sharply into the peritoneal
veins are excised and stored in cold preservation solution. cavity. The Balfour retractor is positioned, and a Cattel-
These vessels may be required as vascular conduits dur- Braasch maneuver performed with Metzenbaum scissors
ing the recipient procedure. If atherosclerotic disease to expose the infrarenal aorta. The abdominal aorta is
prevents use of the iliac arteries, other medium-sized ves- rapidly cannulated, and cold preservation is initiated.
sels, such as the carotid or superior mesenteric artery, The suprahepatic inferior vena cava is then transected
may be used. Premium vessels not used should be banked below the right atrium, the pericardium is opened, and
at the recipient hospital by blood type for later use as the thoracic aorta is cross-clamped in the left chest. The
necessary. white line of Toldt is opened along the left colon to
expose the left kidney, and ice is liberally applied around
the abdominal organs. The inferior mesenteric vein is
Special Circumstances identified within the mesentery at the ligament of Treitz
The above description is applicable to a routine adult and cannulated for portal perfusion. All further dissection
liver procurement; however, there are frequently varia- is made cold after completion of cold perfusion. It is para-
tions that must be anticipated. As donor criteria continue mount to liberally and gently flush the biliary tree with
to expand, the assessment by the donor team and their cold preservation solution during back-table preparation
ability to technically adapt to the specific donor become of a DCD liver allograft.
578 PART V Operation

The donor with a previous median sternotomy or a and posteriorly (Fig. 43-13). Phrenic vein orifices are
donor facility not equipped for cardiothoracic surgery identified and ligated. The graft is repositioned to expose
represent unique situations in which access to the tho- the entire inferior vena cava that is separated from the
racic cavity is potentially limited. We do not recommend surrounding retroperitoneal connective tissue along its
early median sternotomy in donors who have previously entire length. Dissection is performed by spreading and
had a sternotomy because inadvertent cardiac injury can cutting over the midpoint of the posterior inferior vena
result in potential loss of the donor. In these situations cava wall before proceeding laterally, with particular
the donor procurement can be performed entirely within attention to avoiding dissection between the inferior vena
the abdominal cavity through aortic cross-clamping and cava and the caudate lobe. Phrenic veins originating from
cold perfusion. Exsanguination is performed by cannulat- the inferior vena cava are identified and ligated. The right
ing the inferior vena cava just above the iliac bifurcation adrenal remnant is separated from the liver and the adre-
with a 28F straight chest tube (or similar large, noncol- nal vein ligated (Fig. 43-14). If the graft will be implanted
lapsible tubing). Care in isolating the inferior vena cava by the “piggyback” technique, the inferior vena cava can
must be exercised to avoid inadvertent injury to the vessel be oversewn with a running 4-0 polypropylene suture
or right ureter. All other techniques are unchanged. After secured by an 0 silk ligature.
aortic cross-clamping and during cold perfusion, the dia- Isolation of the portal vein begins with the surgical
phragm can be split, the pericardium opened, and the assistant elevating the portal vein at the three- and nine-
caval-atrial junction divided to facilitate venting of per- o’clock positions while the surgeon spreads and cuts the
fusate. Exsanguination through cannulation of the infe- peritoneal tissue along the posterior vessel wall toward the
rior vena cava may also be necessary in the setting of a parenchyma to expose the bifurcation (Fig. 43-15). This
right lung procurement. tissue is principally loose areolar and lymphatics but may
Undiagnosed abdominal aortic aneurysms or severe contain posterior hepatic arterial branches that must be
atherosclerotic disease are also frequently encountered; identified and avoided. If encountered, the portal vein can
particularly in expanded criteria donors. In this setting we be gently slipped under these branches, en bloc, so the
prefer aortic cannulation via the common iliac (right com-
mon iliac is preferable) with careful dissection to avoid the
ureter and precise positioning of the catheter tip above the
aneurysm or severe atherosclerotic disease at the level of
the renal arteries if at all possible. A severely diseased or
difficult-to-access supraceliac aorta should not be manipu-
lated to avoid potential dissection or disruption; rather,
the thoracic aorta should be accessed through the central
tendon of the left diaphragm or via a left thoracotomy for
aortic cross-clamping. An alternative approach of cannu-
lating via the thoracic aorta or aortic arch distal to the left
subclavian artery origin has been advocated26,27; however,
there are several potential disadvantages to attempted tho-
racic cannulation, which include increased technical diffi-
culty, the need to completely transect the aorta in the
presence of often severe supraceliac atherosclerotic dis-
ease, and the potential to shower plaque emboli or create FIGURE 43-13 n With the anterior surface of the liver facing the
dissection or hematoma toward the celiac, superior mesen- surgeon, diaphragmatic remnants are removed, exposing the
teric, and renal artery origins. Thus we prefer to approach bare area, and a plane anterior to the inferior vena cava is estab-
atherosclerotic disease from the iliac arteries or distal aorta lished, permitting the fibrous diaphragmatic attachments to be
to optimize cold perfusion. “unwrapped” from the vessel.

Back-Table Preparation of the Liver

Allograft
Back-table preparation typically occurs at the recipient
hospital during the recipient hepatectomy and includes
detailed inspection for surgical injury, graft preparation,
verification of vascular anatomy, and potential arterial
reconstruction. The allograft should remain immersed in
cold preservation solution within the plastic transport
bag that is enveloped by ice to avoid inadvertent rewarm-
ing. With the anterior liver surface facing the surgeon,
the liver bare area is exposed by complete removal of
remnant diaphragm, and the suprahepatic vena cava is
freed from its diaphragmatic attachments. A plane imme-
diately anterior to the inferior vena cava is established,
and the fibrous diaphragmatic remnant encircling the FIGURE 43-14 n Dissection of the inferior vena cava with ligation
inferior vena cava is divided and “unwrapped” laterally of the right adrenal vein.
 43 The Donor Operation 579

artery remains anterior during implantation. The dissec- Back-table cholecystectomy is optional. We prefer
tion proceeds laterally (opposite the hilum) and proximally cholecystectomy after arterial reperfusion to avoid inad-
along the portal vein with small branches identified and vertent injury of anomalous or replaced right hepatic
ligated. Clear exposure of the bifurcation simplifies orien- arterial branches. Cholecystectomy after arterial reperfu-
tation during portal vein anastomosis. The portal vein is sion facilitates precise identification of the cystic duct–
cannulated to provide for later allograft flush and infused common hepatic duct junction with complete removal of
with cold preservation solution to verify its integrity. the cystic duct; a dissection that could be hazardous if
Arterial dissection begins at the celiac trunk and pro- performed cold on the back table.
ceeds toward the liver. The surgical assistant holds the
aortic patch with one hand and the splenic silk ligature
with the other while the surgeon removes the loose
Arterial Variations and Reconstruction
adventitia of the celiac trunk, exposing the left gastric and Arterial variations are common and most efficiently
possibly phrenic branches. Each branch must be pre- addressed during the back-table dissection at the recipi-
served and followed from its origin to a point of termina- ent institution. Arterial variations may require only care-
tion to exclude the possibility of an early takeoff vessel ful dissection or reconstruction. Fine vascular instruments
proceeding toward the liver. Branches that terminate and nonabsorbable monofilament suture should be read-
outside the liver are ligated. The assistant then reposi- ily available. Injured vessels require similar reconstruc-
tions to support the splenic and gastroduodenal arteries, tion and will be included in this discussion.
exposing the common hepatic that is similarly prepared. Arterial variations that require only careful dissection
Dissection of the proper hepatic artery above the takeoff include a replaced/accessory left hepatic artery originat-
of the gastroduodenal should be avoided because it may ing from the left gastric artery and a completely replaced
compromise the extrahepatic bile duct circulation (Fig. arterial system originating from the superior mesenteric
43-16). The celiac is gently infused with cold preserva- artery. When a replaced/accessory left hepatic artery has
tion solution to identify small branches in the hilum that been identified, the arterial dissection of the celiac trunk
require ligation, and the aortic remnant is fashioned into remains as described through identification of the splenic
a Carrell patch to complete graft preparation. Arterial origin. Following identification and ligature of the splenic
variations and reconstruction are discussed later. origin, the left gastric origin is identified. The assistant
then holds the left gastric origin and the transected distal
left gastric remnant to suspend the replaced/accessory
left branch within the gastrohepatic ligament. The
replaced/accessory left branch is carefully dissected with
the numerous small branches originating from the left
gastric branch and servicing the stomach ligated with fine
suture. The dissection is carried to within 3 mm of the
liver parenchyma to completely define the course of the
replaced/accessory left branch. At this point the distal left
gastric artery beyond the origin of the replaced/accessory
left branch is transected and ligated to complete arterial
preparation.
The goal of arterial reconstruction is to establish a
single source of inflow to the allograft. Our preference
for arterial inflow is celiac trunk, distal superior mesen-
teric artery, and lastly splenic artery. The most common
FIGURE 43-15 n Isolation of the portal vein. arterial variant requiring reconstruction is a replaced/
accessory right hepatic artery originating from the supe-
rior mesenteric artery. In this situation the proximal
superior mesenteric artery trunk is anastomosed to the
distal celiac trunk (Fig. 43-17) using interrupted 6-0
polypropylene suture, and the distal superior mesenteric
artery is used for aortic inflow. If a large size discrepancy
exists between the superior mesenteric artery trunk and
the celiac trunk, the replaced/accessory right hepatic
artery can be anastomosed to the splenic or the gastro-
duodenal origin (interrupted 7-0 polypropylene) and the
celiac trunk used for aortic inflow. A replaced/accessory
left hepatic artery originating from the aorta will also
require reconstruction. For this variant the replaced/
accessory left hepatic artery is separated from the aorta
with a Carrell patch and anastomosed to the splenic or
the gastroduodenal origin (Fig. 43-18), depending upon
FIGURE 43-16 n Back-table arterial dissection. Normal arterial
vessel diameter.
anatomy is shown with an aortic Carrell patch. The splenic and Inadvertent injury during the procurement or back-
gastroduodenal arterial origins are clearly evident. table dissection typically involves transection of a replaced
 A B

FIGURE 43-17 n Replaced/accessory right hepatic artery. A, The

celiac and superior mesenteric arterial trunks are procured on a
common patch of aorta. Each arterial branch (jejunal, splenic,
left gastric, and gastroduodenal) is procured long before liga-
tion to maintain vessel integrity for potential vascular recon-
struction. B, The celiac and superior mesenteric trunks are
inked before transection to verify orientation. C, Completed
vascular reconstruction with distal superior mesenteric artery C
as the single inflow source.

A B

FIGURE 43-18 n Uncommon arterial variant of replaced/acces-

sory left artery originating from the aorta with a replaced/acces-
sory right branch from the superior mesenteric trunk. A, The
replaced/accessory left branch originating from the aorta is
anastomosed to the splenic origin. B, The celiac and superior
mesenteric trunks are anastomosed as described earlier to cre-
ate a single arterial inflow from the distal superior mesenteric C
artery. C, Arterial reconstruction following reperfusion.
 43 The Donor Operation 581

left or right hepatic artery within the hilum. These inju- 5. Busuttil R, Tanaka K. The utility of marginal donors in liver trans-
ries can be primarily repaired, or the remnant transected plantation. Liver Transpl. 2003;9:651-663.
6. Alkofer B, Samstein B, Guarrera JV, et al. Extended-donor criteria
vessel can be anastomosed to the gastroduodenal or liver allografts. Semin Liver Dis. 2006;26(3):221-233.
splenic origin, depending upon vessel diameter and avail- 7. Kato T, Levi D, Nery J, et al. Operative procedures. In: Maddrey
able length. Arterial conduit is rarely necessary. All anas- W, Schiff E, Sorrell M, eds. Transplantation of the Liver. Philadel-
tomoses are performed with interrupted 8-0 polypropylene phia: Lippincott Williams & Wilkins; 2001:47-64.
8. Renz JF, Yersiz H. The donor operation. In: Busuttil R, Klintmalm G,
suture using surgical telescopes with magnification of 4.5 eds. Transplantation of the Liver. 2nd ed. Philadelphia: W.B. Saun-
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9. Starzl TE, Hakala T, Shaw B, et al. A flexible procedure for mul-
tiple cadaveric organ procurement. Surg Gynecol Obstet. 1984;158:
Pediatric Procurement 223-230.
10. Starzl TE, Miller CM, Bronznick B, Makowka L. An improved
The pediatric donor can be approached exactly as technique for multiple organ harvesting. Surg Gynecol Obstet.
described earlier with several minor modifications. The 1987;165:343-348.
only technical variation is the occurrence of a replaced/ 11. Miller C, Mazzaferro V, Makowka L, et al. Rapid flush technique
accessory left hepatic artery in a small infant or neonatal for donor hepatectomy: safety and efficacy of an improved method
of liver recovery for transplantation. Trans Proc. 1988;20:948-950.
donor. In this setting the aorta should be approached 12. Nakazato P, Concepcion W, Bry W, et al. Total abdominal evis-
through the diaphragm or left chest to prevent inadver- ceration: an en bloc technique for abdominal organ harvesting.
tent traction injury. Heparin (500 units/kg) and aortic Surgery. 1992;111:37-47.
flush (50 mL/kg preservation solution) are also adjusted 13. Guarrera JV, Samstein B, Goldstein MJ, et al. Digital imaging of
by weight in pediatric donors.7 Lastly, vascular conduit is extended criteria donor livers to facilitate placement and utiliza-
tion. Prog Transplant. 2010;20(1):14-17.
frequently required in pediatric recipients; as a result, we 14. Todo S, Makowka L, Tzakis A, et al. Hepatic artery in liver trans-
recommend procurement of iliac and carotid arteries, the plantation. Trans Proc. 1987;19:2406-2411.
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when available, to optimize the availability of suitable artery in 1000 cases. Ann Surg. 1994;220:50-52.
16. Cattell R, Braasch J. A technique for the exposure of the third and
conduit with banking of any unused conduit. fourth portions of the duodenum. Surg Gynecol Obstet. 1960;111:379.
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18. Figueras J, Busquets J, Grande L, et al. The deleterious effect of
• Always assess the recipient immediately before leaving to donor high plasma sodium and extended preservation in liver
transplantation. A multivariate analysis. Transplantation. 1996;61:
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• Minimize trauma, handling, and hemorrhage within the 19. Markmann J, Markmann J, Markmann D, et al. Preoperative fac-
donor. If unexpected hemorrhage is encountered, do not tors associated with outcome and their impact on resource use in
attempt repair if the source is not completely obvious and 1148 consecutive liver transplants. Transplantation. 2001;72:
accessible; rather, use an assistant to maintain direct pres- 1113-1122.
sure while expeditiously proceeding with the donor pro- 20. Mangus RS, Fridell JA, Vianna RM, et al. Severe hypernatremia in
cedure. The majority of injuries do not affect organ use deceased liver donors does not impact early transplant outcome.
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perfusion. 21. Ismail T, Ferraz-Neto B-H, McMaster P. Liver transplantation.
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• Avoid traumatic aortic injuries in donors with atheroscle- Pancreatic Surgery. New York: Chapman & Hall Medical;
rosis. These injuries frequently affect organ use and can 1996:62-75.
quickly result in donor loss. 22. Ascher N, Bolman R, Der S. Multiple organ donation from a
• Address all vascular anomalies, potential vascular injuries, cadaver. In: Simmons R, Finch M, Ascher N, Najarian J, eds. Man-
and vascular reconstructions at the recipient institution, ual of Vascular Access, Organ Donation, and Transplantation. New
where specialized materials and expert assistance are York: Springer-Verlag; 1984:105-143.
readily available. 23. Nydegger U, Carrel T, Laumonier T, Mohacsi P. New concepts in
• Speed is critical in donation after cardiac death procure- organ preservation. Transpl Immunol. 2002;9:215-225.
ments. To facilitate efficient recovery, preparation of the 24. McLaren A, Friend P. Trends in organ preservation. Transpl Int.
2003;7.
roles and responsibilities of each team member before 25. Guarrera JV, Alkofer B, Feirt N, et al. Discovery of diffuse biliary
procurement is essential. microhamartomas during liver procurement. Liver Transpl. 2007;
13(10):1470-1471.
26. Fukuzawa K, Schwartz M, Katz E, et al. An alternative technique
for in situ arterial flushing in elderly liver donors with atheroscle-
REFERENCES rotic occlusive disease. Transplantation. 1993;55:445-447.
27. Molmenti E, Klintmalm G. Procurement of liver, pancreas, and
1. Sheehy E, Conrad S, Brigham L, et al. Estimating the number of kidneys. In: Molmenti E, Klintmalm G, eds. Atlas of Liver Trans-
potential organ donors in the United States. N Engl J Med. plantation. New York: Saunders; 2002:11-33.
2003;349:667-674.
2. Langone A, Helderman J. Disparity between solid-organ supply
and demand. N Engl J Med. 2003;349:704-706.
3. Renz JF. A critical analysis of liver allograft utilization from the US
deceased donor pool. Liver Transpl. 2010;16(5):543-547.
4. Angelis M, Cooper J, Freeman R. Impact of donor infections on
outcomes of orthotopic liver transplantation. Liver Transpl.
2003;9:451-462.
 CHAPTER 44

Principles of Liver Preservation

Henrik Petrowsky • Pierre-Alain Clavien

CHAPTER OUTLINE

MECHANISMS OF PRESERVATION INJURY Injury Mediated by Damage-Associated

Prepreservation Injury Molecular Patterns
Underlying Liver Disease Injury Caused by Sterile Inflammatory Immune
Injury Associated with Cardiopulmonary Arrest Response
or Hypotension Role of Reactive Oxygen and Nitrogen Species
Injury During Organ Procurement ELEMENTS OF PRESERVATION
Warm Ischemia Injury in Donation After Hypothermia
Cardiac Death Preservation Solutions
Cold Preservation Injury Collins Solution
Hypothermia-Induced Suppression of Enzyme University of Wisconsin Solution
Activity
Histidine-Tryptophan-Ketoglutarate Solution
Hypothermia-Induced Cell Swelling
Celsior Solution
Pathophysiology of Ischemic Cascade
Which Preservation Solution Should Be Used
Sinusoidal Endothelial Cell Injury for Static Cold Preservation?
Rewarming Injury
Reperfusion Injury NOVEL LIVER PRESERVATION STRATEGIES
Cascade of Events During Reperfusion Ischemic Preconditioning of the Liver
Mitochondrial Injury and Cell Death Pharmacological Conditioning of the Liver
Endothelial Cell Injury Associated with Platelet Machine Perfusion
and Leukocyte Adhesion Normothermic Oxygenated Perfusion
Hypothermic Oxygenated Perfusion

Liver preservation is one of the most important components after liver preservation. In brain-dead donors the four
of liver transplantation because the efficacy of preservation sources of this injury are (1) prepreservation injury, (2)
has an enormous impact on the posttransplant outcome. cold preservation injury, (3) rewarming injury, and (4)
Especially in wide geographical regions with national organ reperfusion injury (Fig. 44-1, A). Allografts from donation
sharing, liver preservation allows organs to travel great dis- after cardiac death (DCD) experience an additional warm
tances. The evolution of organ transplantation was mainly ischemia injury between cardiac death and cold flushing
related to the introduction of new immunosuppressive at procurement (Fig. 44-1, B).
drugs such as cyclosporine, but the development of effective
preservation solutions also contributed to a significant
extent. The University of Wisconsin (UW) solution is Prepreservation Injury
probably the most commonly used static preservation solu- Underlying Liver Disease
tion; it was developed by Belzer and Southard1 before it was
introduced in 1987. The current standard technique of liver The prepreservation injury can be related to preexisting
preservation is static cold preservation using hypothermia liver disease, injury associated with brain death or events
and special preservation solutions. However, the concept of leading to brain death, and injury during organ harvest.
machine perfusion has challenged the standard technique The most common type of preexisting liver injury is
during the past years, and there is growing evidence that related to steatosis,2,3 which is often related to obesity or
continuous machine perfusion might be superior to the sim- alcohol and drug consumption. Steatosis aggravates the
pler cold storage technique. cold preservation injury in hepatocytes4 and sinusoidal
lining cells5 and increases the magnitude of the reperfu-
sion injury,6-8 which is associated with a higher risk for
MECHANISMS OF PRESERVATION primary graft failure or severe primary dysfunction.
INJURY Experimental studies have shown that hepatic arterial
flow and microcirculation are significantly impaired in
The preservation injury is composed of different steatotic livers.9 Especially macrosteatosis is an estab-
components that sequentially occur before, during, and lished clinical risk factor for primary nonfunction or

582
 44 Principles of Liver Preservation 583

Prepreservation Cold preservation Rewarming Reperfusion

injury injury injury injury

- Underlying liver disease Cold ischemia Warm ischemia Reperfusion

(steatosis, fibrosis)
- Cardiopulmonary arrest
with resuscitation
- Donor hypotension
- DCD: warm ischemia

Start of cold End of cold Graft

preservation preservation reperfusion
A

Prepreservation warm ischemia injury

Low-flow warm ischemia Asystolic warm ischemia

Low-flow hypoxia No-flow anoxia

5-min wait time

Withdrawal of Cardiopulmonary Start of Start of cold

life support arrest procurement preservation
B
FIGURE 44-1 n A, Components of preservation injury. B, Livers from donation after cardiac death (DCD) donors experience warm isch-
emia injury as part of prepreservation injury.

dysfunction10 and posttransplant biliary complications.11 deleterious effects on initial graft function in extended
Although organs with mild macrosteatosis (<30%) are criteria donor organs. In addition, the management of
acceptable for transplantation, moderate (30% to 60%) brain-dead patients is in some instances suboptimal (e.g.,
and severe (>60%) macrosteatosis remain a challenging hypotension) before organ donation is considered and
problem in transplantation.10,12 Furthermore, the epi- the procurement organization is involved.
demics of obesity and diabetes in the United States in the
past 2 decades led to an increased incidence of steatotic
Injury During Organ Procurement
donor organs.13,14 Because of the significant gap between
the supply and demand for donor organs, the use of stea- Injury during organ harvesting may occur because of
totic donor livers can significantly contribute to reducing intraoperative hypotension. This type of injury is mainly
this gap.15 The diagnosis of preexisting liver disease is an attributed to hemodynamic instability of the donor dur-
integral part of donor organ evaluation. Screening of ing the procurement procedure rather than to technical
potential donors by history, physical examination, drug misadventure. A donor liver biopsy study demonstrated
toxicity and liver function test results, imaging with ultra- that one third of donors accepted for transplantation have
sound or computed tomography scan, and liver biopsy evidence of prepreservation injury in terms of platelet
results rules out most cases of preexisting liver disease. adhesion to sinusoidal lining cells in biopsies taken at the
time of organ procurement.16 The study found a relation-
ship between the severity of this injury and organ dys-
Injury Associated with Cardiopulmonary
function after graft reperfusion.
Arrest or Hypotension
Another important component of prepreservation injury Warm Ischemia Injury in Donation After
is related to the potential injury that is associated with Cardiac Death
brain death or events leading to brain death. Trauma
leading to brain death is often associated with hypoten- In contrast to organs from donation after brain death
sion or hypoxia, which can lead to warm ischemia of the donors, livers from DCD donors experience a significant
liver. A significant proportion of donors have cardiopul- prepreservation injury after withdrawal of life support
monary arrest secondary to trauma, drug intoxication, (see Fig. 44-1, B). This injury is related to warm ischemia
cardiovascular or cerebrovascular event, or any form of secondary to cardiopulmonary arrest before procure-
asphyxia that leads to brain death. Donors with an ment. There are two types of warm ischemia after with-
unknown or long down time before cardiopulmonary drawal of life support. Warm ischemia starts at the time
resuscitation especially experience a significant warm of extubation and is characterized by hypoperfusion and
ischemia-reperfusion (IR) injury, which may have tissue hypoxemia. This type of ischemia is followed by
584 PART V Operation

100 Van’t Hoff’s rule: Q10 = (k2 /k1 )10/(T2 − T1 )

LDH
90
80
NA, K -ATPase However, the effects of temperature on enzymatic activity
Enzymatic activity (%)

are variable. Some complex enzymatic energy-dependent

70 reactions have a Q10 between 4 and 6 and are completely
10
60
k T2  T1 inhibited at low temperatures. For instance, Na+,K+-
50 Q10  2 adenosine triphosphatase (ATPase) is completely inhibited
k1
40 at 5° C (0.35% activity), but others such as lactate dehydro-
genase, as the key enzyme of anaerobic glycolysis, remain
30
active at approximately 10% at 5° C compared to 37° C (see
20 Fig. 44-2).24,25 The differences in susceptibility of enzymes
10 at low temperatures account for many of the changes that
0 occur in cold-preserved livers and also have harmful conse-
0 45 10 15 20 25 30 3537 quences for cellular and subcelluar structures.
Temperature (°C)
FIGURE 44-2 n Temperature-dependent mammalian enzyme Hypothermia-Induced Cell Swelling
activity according to van’t Hoff’s rule; k1 and k2 represent the
reaction rates at temperatures T1 and T2; Q10 is the van’t Hoff’s Hypothermia-induced cell swelling is the consequence of
coefficient for a temperature change of 10° C and has been impaired function of the membrane-bound Na+,K+-
determined to be 2 for lactate dehydrogenase (LDH). The per- ATPase pump, which maintains the osmotic homeostasis
centage of enzymatic activity was calculated for LDH according between the extracellular and intracellular space.26 Under
to van’t Hoff’s equation and plotted over a temperature range of
0° to 37° C. The activity at 37° C was set at 100%. Data for Na+,K+-
normothermic conditions the pump excretes intracellular
adenosine triphosphatase (ATPase) were extracted from refer- sodium and accumulates potassium in the cell in the ratio
ence 24 and plotted for 0°, 5°, 10°, 22°, and 37° C. 3:2, which generates the cell membrane potential because
of the electrochemical gradient (Fig. 44-3). This process
is energy consuming and requires adenosine triphosphate
asystolic warm ischemia after cardiac arrest. There is (ATP) for normal function. During cold storage the func-
documented evidence that the risk for graft nonfunction tion of the Na+,K+-ATPase is nearly shut off because of
and failure is related to the time interval from donor the temperature-dependent suppression of enzyme activ-
extubation to cardiac arrest, the duration of postextubation ity (see Fig. 44-2) and the insufficient supply of ATP dur-
hypotension and hypoxemia.17-19 Many centers do not ing cold ischemia. Nonfunction of the pump causes an
proceed with procurement of DCD livers if the total osmotic equilibrium of sodium and potassium between
warm ischemia time is more than 30 minutes. the intracellular and extracellular space, resulting in pas-
sive sodium influx into the cell. The influx of sodium ions
is further enforced by intracellular negatively charged
Cold Preservation Injury proteins (anions). The intracellular hyperosmolarity
Although cold preservation injury caused by deleterious finally results in water uptake, which leads to cell swell-
effects of hypothermia and ischemia affects all types of ing, formation of protruding pockets, and lysis.
liver cells (hepatocytes, biliary cells, sinusoidal lining
cells), there is established evidence that sinusoidal lining Pathophysiology of Ischemic Cascade
cells are particularly vulnerable to cold preservation,
which is considered to be the main mechanism of this Although cooling of organs reduces the metabolic
injury. There is established evidence that increased length demand, some metabolic reactions are not stopped at low
of cold ischemia translates into inferior outcome after temperatures. During cold ischemia, liver cells shift from
liver transplantation.20-22 aerobic to anaerobic metabolism (Pasteur effect), which is
self-limiting in terms of insufficient generation of ATP.
The only source of ATP generation is anaerobic glycoly-
Hypothermia-Induced Suppression of Enzyme
sis. The generation of ATP is nineteenfold higher under
Activity
aerobic compared to anaerobic conditions. Despite the
Static cold preservation is the standard method of organ continuous generation of ATP by anaerobic glycolysis,
preservation today. The hepatic core temperature reaches use of ATP rapidly exceeds production, and ATP is
equilibrium near 0° C during static cold storage in the ice therefore depleted. Normally ATP is regenerated from
box.23 The beneficial effects of cold preservation of organs other phosphorylated nucleotides adenosine diphosphate
rely on the principle of suppressing the metabolic rate and adenosine monophosphate, but the energy demand
during the period in which they are not being perfused during ischemia results in the dephosphorylation of ade-
with oxygen and nutrients. The rationale behind this nosine diphosphate and adenosine monophosphate with
principle is that most enzymatic reaction rates (Q10 = 2) further sequential degradation to adenosine, inosine, and
slow down by 50% for every 10° C of temperature reduc- hypoxanthine (Fig. 44-4). Ischemia also promotes the
tion (Fig. 44-2). According to this principle, which is also conversion of xanthine hydrogenase to xanthine oxidase,
known as van’t Hoff’s rule, cooling at 4° C results in a met- which further catalyzes the degradation of hypoxanthine
abolic rate approximately 10% of that at normal body in the presence of oxygen.27 A product of this reaction is
temperature (37° C). the superoxide radical, which belongs to the family of
 44 Principles of Liver Preservation 585

NORMOTHERMIA (37 C) HYPOTHERMIA (0-4 C) HYPOTHERMIA (0-4 C)

Osmotic homeostasis Osmotic swelling

P 3 Na P P
ADP + P ADP + P
ATPase ATPase ATPase

ATP AMP+P ATP

2 K
Intracellular Extracellular Na
Na Na
Na = 5-15 mM Na = 145 mM
K = 140 mM K = 5 mM K K K K
Na
Na

H2O
HYPOTHERMIA (0-4 C)
+
Preservation solution
Impermeable
macromolecules
P
ADP + P S (raffinose)
UW solution
ATPase

Na = 30 mM AMP+P ATP
K = 125 mM
A (lactobionic acid)
Na Na (30 mM)
K K (125 mM)

FIGURE 44-3 n Pathophysiology and prevention of hypothermia-induced cell swelling. Under normothermia the osmotic hemostasis is
maintained by the Na+,K+-adenosine triphosphatase (ATPase) pump, which creates the Na+ and K+ gradient between the extracellular
and intracellular compartment. During hypothermia the Na+,K+-ATPase pump is completely inhibited by hypothermia and adenosine
triphosphate (ATP) depletion, resulting in sodium influx into the cell, which is further enforced by intracellular negatively charged
proteins (P−). The intracellular hyperosmolarity results in water uptake and cell swelling. University of Wisconsin (UW) preservation
solution mimics the intracellular electrolyte composition and therefore prevents the sodium influx and potassium efflux. In addition,
the large impermeable macromolecules S (raffinose) and A− (lactobionic acid) are the extracellular opponent to intracellular P−-. Both
electrolyte and macromolecules of UW solution prevent hypothermia-induced cell swelling. ADP, Adenosine diphosphate; AMP,
adenosine monophosphate.

Ischemia
ISCHEMIC (O2 deprivation) CASCADE

Aerobic ATP Energy loss

Transmitter
ATP CP Cell depolarization release
Glycolysis
ADP
Lipolysis
NADH, Lactate, H (free fatty acids )
AMP

Adenosine H Na Ca

K i Membrane
Inosine injury
Lipase/hydrolase
Hypoxanthine Protein
phosphorylation Proteolysis
XD XO

Protease Receptor/channel
O2* Altered permeability impairment

Cell death (necrosis or apoptosis)

FIGURE 44-4 n Cascade of principal metabolic and ionic changes that proceed after the initiation of ischemia. ADP, Adenosine diphosphate;
AMP, adenosine monophosphate; ATP, adenosine triphosphate; CP, creatine phosphatase; NADH, reduced form of nicotinamide
adenine dinucleotide; XD, xanthine dehdrogenase; XO, xanthine oxidase. (From Taylor M. Biology of cell survival in the cold: the basis for
biopreservation of tissue and organs. In: Baust JC, Baust JM. Advances in Biopreservation. Boca Raton, Fla: CRC/Taylor & Francis; 2007:15-62.)
586 PART V Operation

highly reactive oxygen species (ROS). During cold pres-

ervation this reaction is very slow because of the short
supply of molecular oxygen. However, when oxygen is COLD
supplied at the time of organ reperfusion, an increased
amount of ROS are generated by this mechanism. ROS are
highly toxic because they can oxidize any organic molecule [≠Cai++]
and cause cell membrane damage by lipid peroxidation.
Further deleterious effects during cold ischemia are Increased calpain activity
the development of intracellular acidosis and the rise of
intracellular calcium concentration (see Fig. 44-4). Actin disassembly
Intracellular acidosis is mainly attributed to anaerobic
glycolysis because lactic acid is the end product of this
metabolic pathway. The intracellular accumulation of Expression of:
protons inhibits glycolytic key enzymes (e.g., phospho- platelet receptor
MMP release ACTIVATION WBC receptors
fructokinase) and blocks the residual anaerobic energy
production, which results in further ATP depletion. In
addition, the activation of lipoprotein lipases and lyso- FIGURE 44-5 n Cascade of calpain activation and matrix metallo-
proteinase (MMP) release during cold ischemia in sinusoidal
somal hydrolases by intracellular acidosis causes mem- endothelial cells (SECs). Hypothermia-induced intracellular
brane damage leading to increased permeability.26 The hypercalcemia activates the cascade that finally results in acti-
rise of intracellular calcium concentration is a signal for vation of SEC surface, which traps and activates platelets and
many ischemic mechanisms leading to cell death. Under leukocytes. WBC, White blood cell. (From Upadhya GA, Topp SA,
physiological conditions the extracellular calcium con- Hotchkiss RS, et al. Effect of cold preservation on intracellular cal-
cium concentration and calpain activity in rat sinusoidal endothelial
centration (1 to 2 mM) is approximately 104-fold higher cells. Hepatology. 2003;37:313-323.)
than the intracellular concentration (0.0001 mM). This
gradient is maintained by membrane-bound Ca2+ trans-
locase and Na+-Ca2+ exchange mechanisms, both of 44-4). This was shown first in animal models34,35 and
which are energy dependent. Similar to Na+,K+-ATPase, then confirmed in human allografts.36 One of these
both mechanisms are inhibited during hypothermic important proteases is calpain, a calcium-dependent,
ischemia because of ATP depletion, which results in nonlysosomal cysteine protease. Other important
massive calcium influx and a rise in intracellular calcium proteases are matrix metalloproteinases (MMPs), which
concentration. Other contributing mechanisms are the can degrade all components of the extracellular matrix
leakage of intracellular calcium stores. The enormous and play an important role in IR injury (IRI). MMP-2 and
increase in cytosolic calcium activates Ca2+-dependent MMP-9 were implicated when identified in the effluent
phospholipases and proteases, which have damaging of rat and human allografts and by the finding that less
effects on cellular structures and membranes.28,29 These MMP release was observed when an efficient preservation
enzymes do not require energy, and therefore their solution was used.37 The Ca2+-induced activation of
activity is not influenced by ATP depletion. These calpain leads to a disassembly of actin stress fibers (Fig.
changes result in impairment of cellular integrity and 44-5). This induces the release of MMPs from SECs that
progress to cell death. are able to degrade the protective endothelial layer of
glycoproteins (glycocalyx).38 Damage to the endothelial
Sinusoidal Endothelial Cell Injury glycocalyx is probably the most important mechanism,
resulting in a highly exposed and activated SEC surface,
The classical effects of cold ischemia do not completely as evidenced by increased platelet and leukocyte
explain why some organs tolerate cold ischemia better adhesiveness to the SEC surface.39,40 The activation of
than others do or why UW solution is a more effective the SEC surface, as well as the direct damage to SECs
preservative for the liver than for other organs. There is during cold preservation, is the prerequisite for platelet
convincing evidence that damage to sinusoidal endothelial and leukocyte adhesion, which may lead to microcirculatory
cells (SECs) is the main mechanism of cold preservation disturbances and cause sterile inflammatory immune
injury in the liver. An experimental study demonstrated response after reperfusion.
that SEC injury was the prominent feature of cold
ischemia, whereas warm ischemia affected predominantly
hepatocytes.30 Further evidence comes from a study in
Rewarming Injury
which allograft apoptosis was 42 times greater in SECs After the recipient’s liver is removed and the allograft is
after 12 hours of cold ischemia than that in hepatocytes.31 brought into the operative field, there is a period during
It appears that the described pathophysiological which the vascular anastomoses are created, usually 30 to
mechanisms of hypothermia and ischemia have more 60 minutes. During this time the organ progressively
deleterious effects for SECs than for other types of liver rewarms but is not yet reperfused. This increase in tissue
cells. Mitochondrial dysfunction, ATP depletion, and temperature under anoxic conditions results in a higher
ATP-dependent cytoskeletal disruption were features of energy demand but aggravates the depletion of ATP. After
ischemia injury in hepatic SEC.32,33 ATP depletion 30, 40, and 50 minutes the liver core temperature increases
during cold ischemia results in a rise of intracellular from near zero to 12°, 17°, and 20° C (Fig. 44-6). As
calcium concentration, which activates proteases (see Fig. discussed earlier, warm ischemia is more deleterious to
 44 Principles of Liver Preservation 587

before reperfusion will not develop an injury after reper-

20 fusion. The reperfusion injury has two phases: (1) the
immediate tissue damage upon reperfusion and (2) the
injury that is caused by sterile inflammation as immuno-
Temperature (°C)

logical response to the immediate insult. The immediate

tissue damage occurs after reperfusion within seconds to
10 minutes. This damage is associated with mitochondrial
injury and cell death, as well as platelet and leukocyte
adhesion, which can further lead to microcirculatory dis-
turbances or intravascular thrombosis (no-reflow phe-
nomenon). All the early pathophysiological events initiate
0 a sterile inflammatory immune response that amplifies
local tissue destruction and triggers the activation of cell
−10 0 10 20 30 40 50 60 death programs. Now we will consider the most impor-
Time (Minutes) tant mechanisms of the injury that occurs during and
FIGURE 44-6 n Relation of liver core temperature to length of
after reperfusion of the allograft.
rewarming time before reperfusion in six recipients. (From Hertl M,
Howard TK, Lowell JA, et al. Changes in liver core temperature during
preservation and rewarming in human and porcine liver allografts. Liver
Mitochondrial Injury and Cell Death
Transpl Surg. 1996;2:111-117.) Immediately after reperfusion, parenchymal cells injured
by cold and warm ischemia are stressed by reoxygenation.
hepatocytes than to SECs30 because the former begin to The restoration of energy (ATP) production is probably
have high energy demands at 20° C. It has been shown that the most critical metabolic process that determines cell
there is a time-dependent increase in protease (calpain) survival during the earliest stages of reperfusion. However,
activity during the period of rewarming.41 Furthermore, a the mitochondrial damage established during cold isch-
few minutes at temperatures above 20° C is much more emia and early reperfusion explains why cells might fail to
injurious than the same duration at lower temperatures. It produce sufficient ATP after reoxygenation. The massive
is important for the transplant surgeon to recognize that oxygen consumption during reoxygenation leads to a
the injury caused by rewarming progresses geometrically mitochondrial burst of ROS and reactive nitrogen species
minute by minute. Very long periods of rewarming isch- (RNS), which are generated by excessive electron leakage
emia (>90 minutes) alone can probably result in organ fail- from the mitochondrial electron transport chain
ure. A clinical study on donor grafts with extended criteria (ETC).43,44 ROS and RNS have multiple deleterious
revealed warm ischemia time as the strongest independent effects on mitochondria. They can cause irreversible oxi-
predictor of posttransplant patient survival.20 To remove dation of mitochondrial proteins including the ETC, per-
preservation solution and vasoactive substances before oxidation of mitochondrial membranes, and oxidation of
blood reperfusion, many centers continuously perfuse the mitochondrial and cellular DNA.45 These processes lead
allograft with chilled Ringer’s with albumin solution (4° C) to mitochondrial membrane permeabilization, mitochon-
through the portal vein via an inserted cannula during the drial swelling, and membrane rupture. Similar features
creation of the suprahepatic and infrahepatic anastomosis. were also observed for ROS/RNS-independent mecha-
The advantage of this technique is that it counteracts tem- nisms of mitochondrial injury during early reperfusion.46
perature increase and reduces rewarming injury. Regardless of the specific mechanism, mitochondrial fail-
The extent to which a donor organ sustains the three ure during early reperfusion leads to ATP depletion–
types of injury (prepreservation injury, cold injury, dependent cell death. Experimental studies of IRI in rats
rewarming injury) discussed thus far largely determines showed that oncotic necrosis is the main mechanism of cell
how well the allograft will function on reperfusion. death for hepatocytes and SECs during the early reperfu-
Whereas a 30-minute rewarming time might have no sion phase.47 Others have suggested that apoptosis is the
injurious impact on organs with short cold ischemia time principal cell death mechanism in SECs.31
and no preexisting liver injury, the rewarming injury for
allografts with preexisting liver injury (steatosis) or long Endothelial Cell Injury Associated with
cold ischemia time might be ominous for the same period Platelet and Leukocyte Adhesion
of rewarming. This statement is supported by an outcome
study in human liver transplantation suggesting Activation of the SEC surface is the principal mechanisms
synergistic effects of cold and warm ischemia time on of SEC injury that is associated with platelet and leuko-
postoperative graft function and survival.42 cyte adhesion during early reperfusion. It generates a pro-
inflammatory environment and triggers the inflammatory
response. As described earlier, cold injury results in
Reperfusion Injury release of MMPs and other proteases from SECs that are
activated by ROS/RNS48,49 or proteolytic cleavage.50,51
Cascade of Events During Reperfusion
These enzymes are capable of degrading the protecting
The cascade of damaging events during reperfusion is a endothelial surface layer that is composed of proteogly-
response to the aggravated pre-reperfusion injury of the cans, also known as glycocalyx.52,53 In addition, ROS/RNS,
allograft. In other words, allografts that have no injury generated during graft reperfusion, have the ability to
588 PART V Operation

fragmentize proteoglycans and are therefore a threat to

the glycocalyx.53,54 The destruction of the glycocalyx
results in a hyperexposed and activated endothelial cell

Hepatocytes
surface, which is highly vulnerable to platelet and leuco-
cyte adhesion. Furthermore, platelet adhesion after reper- Necrosis Necrosis
fusion is triggered by increased surface expression of von
Willebrand factor (vWF) and cell adhesion molecule
P-selectin.55-58 Both are stored in Weibel-Palade bodies
in SEC and α-granules of platelets and are rapidly trans-

SEC
Necrosis
located to the endothelial and platelet surface upon reper-
fusion when Weibel-Palade bodies fuse with the cell
membrane.59 Nonactivated platelets adhere to vWF when Proteases +
hydrolases ROS/RNS
it is expressed on SECs and induce activation of platelets Glycocalyx
when they adhere.57 Experiments in P-selectin–deficient DAMPe DAMPi
mice revealed the critical role of P-selection in platelet–

Tissue destruction
Tissue destruction
endothelial cell interaction during reperfusion.56
Similar to platelet adhesion, leucocytes rapidly PRR (TLR4, 9)
adhere to SECs and contribute significantly to the
injury during the reperfusion phase.60-63 Leukocyte KC/
DC
adhesion to SECs during reperfusion is mediated by
intercellular adhesion molecule 1 (ICAM-1)62,64 and
cell adhesion molecule P-selectin in various reperfusion
models of warm and cold ischemia. Under nonstress Innate immune Adaptive immune
response response
conditions, ICAM-1 is expressed at low concentrations
on the endothelial cell surface, but expression becomes Cross talk
significantly induced during the first 30 to 60 minutes PMN CD4
amplification
after reperfusion.62 Cytokines are secreted during
reperfusion and are the primary mediators for ICAM-1 Cytokines,
ROS/RNS
induction.65 The adhesion of activated platelets and leu- SEC attachment
kocytes to SECs contributes significantly to endothelial FIGURE 44-7 n Cell death–induced sterile inflammatory immune
cell and tissue injury. In addition, it generates a proin- response in hepatic ischemia-reperfusion (IR) injury. IR-induced
flammatory environment and causes parenchymal necrosis of parenchymal cells results in leakage of intracellular
microcirculatory disturbances.62,66 When leukocytes damage-associated molecular patterns (DAMPi); extracellular
that bind to ICAM-1 become activated, they migrate damage-associated molecular patterns (DAMPe) are also gener-
ated by degradation of extracellular matrix molecules via prote-
into the parenchymal tissue ases, hydrolases, or ROS/RNS. Both DAMPi and DAMPe, also
known as alarmins, are recognized by pattern recognition recep-
tors (PRRs) on Kupffer cells (KCs) and dendritic cells (DCs). The
Injury Mediated by Damage-Associated most important hepatic PRRs are Toll-like receptors (TLRs)
Molecular Patterns 4 and 9. The activation of PRRs results in induction of an innate
and adaptive immune response that leads to further tissue
The mitochondrial damage of parenchymal cells and destruction in the chronic phase of reperfusion. PMN, Polymor-
the specific SEC damage during preservation and reper- phonuclear; RNS, reactive nitrogen species; ROS, reactive oxy-
fusion results in cell death. Oncotic necrosis is probably gen species; SEC, sinusoidal endothelial cell.
the predominating type of cell death during early reper-
fusion.47 The loss of the cell membrane integrity of
necrotic cells leads to leakage of intracellular material recognized by pattern recognition receptors (PRRs),
that is normally sequestered intracellularly (Fig. 44-7). which activate the innate immune response to IRI.
This material becomes exposed to the immune system
and has the ability to induce a sterile inflammatory Injury Caused by Sterile Inflammatory
immune response similar to that induced by microbial Immune Response
compounds.67 These intracellular molecules have been
named damage-associated molecular patterns (DAMPs) or IRI of parenchymal liver cells causes a DAMP-mediated
alarmins and include high-mobility group box 1, heat immune response that results in further tissue destruction
shock proteins, histones, DNA, ATP, and uric acid.67,68 (see Fig. 44-7). This mechanism involves two distinct but
Furthermore, the release and activation of proteolytic/ complementary immune system pathways66,72: a broadly
hydrolytic enzymes during cold preservation and upon directed innate host defense (evolutionary directed against
reperfusion, as well as the effect of ROS/RNS, result in microbial pathogens) activating a second, adaptive immune
degradation of the extracellular matrix. One of the struc- host defense that leads to specific graft injury. Resident
tures most targeted by this mechanism is the glycocalyx Kupffer cells, dendritic cells, and granulocytes scavenge
on SECs. Fragmented molecules of the extracellular DAMPs via PRRs and are the main elements of the innate
matrix such as hyaluronan, biglycan, and heparan sul- immune response. The family of Toll-like receptors (TLRs)
fate function as extracellular DAMPs.69-71 Regardless of are the most important PRRs for sensing tissue damage and
the intracellular or extracellular origin, DAMPs are activating the innate immune cascade.73 Experimental
 44 Principles of Liver Preservation 589

Primary Secondary Tertiary

• OH
trans.
metal
Spontaneous, H2O2
SOD
Cl, Br
HOCl
e MPO HOBr
• NO
O2• 

NOX, NOS
KC, SEC, • OH
XO,
PMN, pH < pKa
O2 ETC
platelet
ONOO
KC: iNOS, NOX ONOOH
SEC: iNOS, eNOS, NOX COa
KC, SEC,
PMN: iNOS, NOX, MPO CO3• 
PMN,
pH > pKa
Platelet: iNOS, NOX platelet
Scale of relative ROS/RNS toxicity
Nontoxic Toxic

FIGURE 44-8 n The formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the liver. ROS and RNS are
produced both enzymatically (NADPH oxidase [NOX], xanthine oxidase [XO]) and nonenzymatically (electron transport chain [ETC]).
The main sources of ROS/RNS production are sinusoidal endothelial cells (SECs), Kupffer cells (KCs), polymorphonuclear (PMN) cells,
and platelets. The reduction of O2 yields O2•−, which is quickly converted to downstream ROS (upper half of the figure) or RNS (bottom
half of figure). The ROS pathway ultimately gives rise to tertiary effector species such as the hydroxyl radical (•OH) or hypohalous
acids (HOCl, HOBr) in reactions catalyzed by transition (trans.) metals (Fenton reaction) or neutrophil-derived myeloperoxidase
(MPO), respectively. The formation of RNS occurs in the presence of •NO, creating the secondary RNS peroxynitrite, which at neutral
pH exists as a mixture of the pronated (ONOOH) and ionic (ONOO−) form. At the pH above its pKa of 6.8, ONOO− predominates and
reacts with CO2 to generate the carbonate radical (CO3•−). If the pH drops, the decay of ONOOH produces •OH via spontaneous
hemolytic fission. eNOS, Endothelial nitric oxide synthetase; iNOS, inducible macrophage-type nitric oxide synthetase; NADPH,
reduced form of nicotinamide adenine dinucleotide phosphate; NOS, nitric oxide synthetase; SOD, superoxide dismutase. (Modified
with permission from van Golen RF, van Gulik TM, Heger M. Mechanistic overview of reactive species-induced degradation of the endothelial
glycocalyx during hepatic ischemia/reperfusion injury. Free Radic Biol Med. 2012;52:1382-1402.)

evidence implicates TLR4 as the early key mediator of liver antigen-independent manner by upregulating “positive”
IRI.74-76 In murine models of liver IRI, signaling via TLR4, costimulatory pathways. CD4 T cells can promote liver IRI
but not TLR2, was required for the induction of intrahe- via CD154 without de novo antigen-specific activation, and
patic inflammation and hepatocellular damage.76 Further- innate immune-induced CD40 may trigger CD154-CD40
more, only one of the TLR4 downstream pathways engagement to facilitate tissue inflammation/injury.80
mediated by interferon regulatory factor-3 but not myeloid CD40 signaling can synergize with TLR4 in liver IRI in
differentiation factor 88 was indispensable for triggering the different aspects of the disease process. Because hepatocyte
inflammatory process.66 TLR9, an endosomal receptor rec- CD40 activation leads to their death, CD40 may also
ognizing self and bacterial DNA fragments, has recently enhance tumor necrosis factor-α– or ROS-induced liver
been shown to modulate liver IRI, and pharmacological tissue injury resulting from TLR4 activation.
inhibition of this receptor is a novel and potential clinical
application.77 The downstream activation of PRRs leads to Role of Reactive Oxygen and Nitrogen Species
production of cytokines, chemokines, and ROS/RNS that
are directly cytotoxic, amplifying the innate immune or acti- ROS/RNS are free radicals with one unpaired electron
vating the adaptive immune response to IRI. derived from molecular oxygen or nitrogen (Fig. 44-8).
The adaptive immune response to hepatic IRI is mainly ROS/RNS are highly reactive and toxic to cellular
mediated by T cells.66 Although the exact mechanism of components such as proteins, membrane lipids, and
T-cell activation is not completely understood, elements of DNA, but they also act as signal transducers in IRI. ROS/
the innate immune response have been proposed to trigger RNS can be generated by nonenzymatic (ETC) and
the adaptive immune response. Recent studies in T-cell– enzymatic (reduced form of nicotinamide adenine
and CD4-deficient mice have provided direct proof that dinucleotide phosphate [NADPH] oxidase, xanthine
T cells, particularly CD4 cells, are the key players in the oxidase, myeloperoxidase) pathways and have different
early hepatic IRI cascade.78,79 T cells function in an origins during the different phases of reperfusion.53 The
590 PART V Operation

40.00
35.00 Perfusion and addition of ice slush Hepatic artery anastomosis

30.00 Harvesting
Temperature (C)

25.00 Portal vein reperfusion

Transfer to back table
20.00 Warm saline perfusion

15.00 Insertion in cool-box

10.00 Transfer to back table

Insertion in abdominal cavity
5.00
0.00
00:00 02:00 04:00 06:00 08:00 10:00 11:00 11:30 12:00
Time (hh:mm)
FIGURE 44-9 n Direct intraparenchymal temperature measurement of a human donor liver from procurement to transplantation. (From
Villa R, Fondevila C, Erill I, et al. Real-time direct measurement of human liver allograft temperature from recovery to transplantation.
Transplantation. 81:483-486, 2006.)

superoxide anion O2•- is spontaneously or enzymatically demonstrated that simple cooling of kidneys enabled a
converted to hydrogen peroxide (H2O2). In the presence cold storage preservation of 12 to 13 hours. The rationale
of metal ions, H2O2 can be further catalyzed to the highly behind this principle is that most enzymes show a twofold
reactive hydroxyl radical OH• by the Fenton reaction. increase in activity for every 10° C rise in temperature
RNS are formed in the presence of O2•- and •NO creating (see Fig. 44-1), which results in a reduced metabolism at
peroxynitrite (ONOO−/ONOOH), which decays to OH• lower temperatures. Although the metabolic activity is
(see Fig. 44-8). In the very early reperfusion phase the significantly reduced at 0° to 4° C, experimental studies
main compartment of ROS/RNS production is the have shown that the liver still requires oxygen for
mitochondrion. As described earlier, the enormous metabolism.83
oxygen consumption immediately after reperfusion Hypothermia is induced during organ procurement by
results in oxidation of accumulated reduced form of arterial perfusion with chilled preservation solution after
nicotinamide adenine dinucleotide (NADH), excessive cross-clamping. The simultaneous application of ice slush
electron leakage from the mitochondrial ETC, and on the liver surface and in the abdominal cavity results in
formation of ROS/RNS.43,44 The mitochondrial-derived a rapid temperature drop from normal body temperature
ROS/RNS are deleterious in two ways because they are to 16° C (Fig. 44-9).23 Although the majority of experi-
harmful for both mitochondrial and cellular structures. mental and clinical studies refer to a cold storage tem-
Kupffer cells activated by DAMPs in the acute reperfusion perature of 4° C, real-time direct measurements of human
phase are the first immune cells that enzymatically liver allografts revealed that the intraparenchymal tem-
produce ROS via the NADPH oxidase. In addition, perature during cold storage in the ice box reaches a pla-
activated platelets and leukocytes that adhere rapidly to teau near 0° C instead of 4° C.23 There is evidence that
the endothelial surface via vWF, ICAM-1, and P-selectin low temperatures below 4° C can be guaranteed for nearly
release ROS/RNS, which have direct damaging effects 1 hour when the back-table preparation is performed
on the endothelial glycocalyx during reperfusion.53,81 after transportation in the ice box.23 Back-table prepara-
Polymorphonuclear (PMN) cells that migrate into the tion before placing the organ in the ice box is likely to
liver parenchyma during the chronic reperfusion phase result in liver core temperatures above 4° C. Considering
are probably the most important source of oxidative and that back-table trimming might last 1 to 2 hours, this
nitrosative damage. Activated PMN cells, which either technique would expose the liver to an undesired tem-
adhere to the endothelial surface in the acute phase of perature range. Experimental data demonstrate a better
reperfusion or are recruited as innate immune response outcome following cold storage at 0° C compared to 5° C
in the chronic phase of reperfusion, produce ROS in terms of reduced IRI and better early graft function.84
(NADPH oxidase, myeloperoxidase) and RNS (nitric Therefore back-table preparation should be performed
oxide synthetase). The release of ROS/RNS from Kupffer after transportation to provide the best hypothermic
cells and PMN cells causes further tissue destruction conditions.
during the acute and chronic reperfusion phase.
Preservation Solutions
The development of an effective preservation solution
ELEMENTS OF PRESERVATION has to address all major types of injuries during cold
Hypothermia preservation. The composition and addition of specific
ingredients aims to counteract the deleterious effects that
Hypothermia is the most important element of cold occur during cold preservation. According to Belzer and
preservation under anaerobic conditions. Calne et al82 Southard,85 the properties of an effective preservation
 44 Principles of Liver Preservation 591

solution are (1) prevention of hypothermia-induced cell the United States in 2002, although it is still used in
swelling and interstitial edema, (2) prevention of Europe.
electrolyte imbalance, (3) prevention of intracellular
acidosis, (4) reduction of oxidative damage by ROS, and University of Wisconsin Solution
(5) providing substrates for cellular energy metabolism.
The UW solution (ViaSpan) was developed by the
surgeon Folkert Belzer (Fig. 44-10) and the basic scientist
Collins Solution
In 1969 Collins developed a simple cold storage solution
for kidney preservation.86 This solution contains an
intracellular electrolyte composition with low sodium
and high potassium that aims to prevent transmembranous
fluid and electrolyte shifts (Table 44-1). The high
concentration of glucose in the solution provides osmotic
balance between the intracellular and extracellular space
and suppresses hypothermia-induced cell edema. Collins
used a phosphate buffer to prevent the intracellular
acidosis that is mainly caused by anaerobic glycolysis
during cold ischemia. The Collins solution was further
modified in Europe (Euro-Collins). The osmotic potency
of the Euro-Collins solution was increased by a higher
glucose concentration (195 versus 140 mmol/L).
Furthermore, magnesium sulfate was excluded because
the presence of magnesium and phosphate resulted in
formation of magnesium phosphate precipitates. Both
types of Collins solutions are effective for cold storage
preservation of kidneys for 24 to 30 hours. The Euro-
Collins solution was used by many transplant centers
throughout the world for many years. However, the
further development of new preservation solutions (UW,
histidine-tryptophan-ketoglutarate [HTK]) eliminated
FIGURE 44-10 n Folkert Belzer, who with James Southard intro-
the Euro-Collins, which disappeared from the market in duced the revolutionary University of Wisconsin solution.

TABLE 44-1 Composition of Cold Storage Solutions for Organ Preservation

Ingredients UW* Celsior HTK IGL-1 Collins‡
Na+ (mmol/L) 25-30 100 15 120 10
K+ (mmol/L) 125-130 15 10 30 115
Mg2+ (mmol/L) 5 13 4 5 30
Ca2+ (mmol/L) — 0.25 0.015 — —
Chloride (mmol/L) — 41.5 50 20 15
Phosphate (mmol/L) 25 — — 25 47.5
Sulfate (mmol/L) 5 — — 5 30
Bicarbonate (mmol/L) — — — — 10
Glucose (mmol/L) — — — — 140
Histidine (mmol/L) — 30 198 — —
Tryptophan (mmol/L) — — 2 — —
Glutaminic acid (mmol/L) — 20 — — —
α-Ketoglutarate (mmol/L) — — 1 — —
Lactobionic acid (mmol/L) 100 80 — 100 —
Mannitol (g/L) — 60 30 — —
Hydroxyethyl starch (g/L) 50 — — — —
Raffinose (mmol/L) 30 — — 30 —
Adenosine (mmol/L) 5 — — 5 —
Allopurinol (mmol/L) 1 — — 1 —
Glutathione (mmol/L) 3 3 — 3 —
Osmolarity (mOsm/L) 320 320 310 320 320
pH 7.4 7.3 7.2 7.4 7.0
Viscosity (cp)§ 5.70 1.15 1.80 1.28 N/A
*Additional ingredients are penicillin G, insulin, and dexamethasone.
†Additional ingredient is polyethylene glycol (0.03 mmol/L).
‡Euro-Collins has similar composition but with a higher glucose concentration (195 mmol/L) and omission of magnesium sulfate.
§Viscosity data refer to a temperature of 4° C.

HTK, Histidine-tryptophan-ketoglutarate; IGL-1, Institute George Lopez-1; UW, University of Wisconsin.

592 PART V Operation

James Southard at the University of Wisconsin in the intracellular Ca2+ concentration and the known negative
1980s1 and was introduced for clinical use in the United effects of elevated intracellular Ca2+ concentration for cell
States in 1987. This solution safely allowed extended survival.
preservation of human liver grafts to more than 15 hours
compared with the Euro-Collins solution.87 It made Histidine-Tryptophan-Ketoglutarate Solution
organ sharing across large distances possible, and liver
transplantation converted from an emergency to a The HTK solution (Custodiol) was initially developed as a
semielective procedure. Aside from the introduction of cardioplegic solution by the German physiologist Hans
cyclosporine, the development of preservation solution, Jürgen Bretschneider at the University of Göttingen in the
especially UW, is probably one of the most important early 1970s.88,89 In 1980 HTK solution was introduced as
factors in the evolution of liver transplantation. Although a preservation solution into clinical heart transplantation.
alternative preservation solutions have been developed, The solution has an intracellular sodium concentration
UW remains the gold standard for preservation of (15 mmol/L) and slightly elevated extracellular potassium
abdominal organs today. concentration (10 mmol/L) (see Table 44-1). This electro-
Although both Collins and UW solution use the same lyte constellation causes a decrease in cardiac electric activ-
buffer system (phosphate buffer) and have a similar ity and finally results in diastolic cardiac arrest. This
electrolyte composition (high potassium, low sodium) that solution uses the amino acid buffer histidine/histidine-
mimics the intracellular milieu, the formulation of UW HCl to maintain a physiological pH during hyperthermia
solution was different from that of Collins solution (see and anaerobic glycolysis. Mannitol was added as an osmotic
Table 44-1). Glucose was replaced by raffinose and membrane-impermeable macromolecule (182 Da) to pre-
lactobionic acid as osmotic membrane-impermeable vent hypothermia-induced cell swelling (see Table 44-2).
agents. Both molecules have a large molecular weight (594 The ingredients α-ketoglutarate and histidine serve as sub-
and 358 Da) and counteract the transmembranous water strates for the cellular energy metabolism, and tryptophan
shift to prevent cellular edema (Table 44-2). Hydroxyethyl was added as a membrane-protective agent. Although
starch was also added as an oncotic substance to prevent HTK solution was initially designed as a cardiac preserva-
expansion of the extracellular space. However, hydroxyethyl tion solution, it was successfully tested in clinical liver
starch confers the relatively high viscosity (5.70 cp) to UW preservation in Europe in the 1990s. In 2002 HTK was
solution, which is approximately four times higher than approved for liver preservation by the Food and Drug
water. Overall the electrolyte composition and the Administration (FDA) in the United States90 and is in
membrane-impermeable macromolecules in UW solution many centers the preferred solution for flushing and pres-
maintain the ionic and osmotic balance during hypothermia. ervation of livers from DCD because of its low viscosity.
Allopurinol was added as an inhibitor of xanthine oxidase,
which blocks the generation of ROS via the hypoxanthine- Celsior Solution
xanthine-uric acid pathway. The antioxidant glutathione
was added to neutralize ROS that are generated during Similar to HTK, Celsior solution (Celsior) was originally
reoxygenation at the time of reperfusion. UW solution developed for cold storage preservation in heart trans-
also includes adenosine, which serves as a substrate for the plantation.91 Although Celsior was developed with speci-
resynthesis of ATP on reperfusion. UW solution also fications similar to UW, the electrolyte composition of
omitted Ca2+ because of the extremely low physiological Celsior mimics the extracellular milieu in contrast to the

TABLE 44-2 Protective Strategy and Biochemical Function of Preservation Solution Ingredients
Protective Strategy Function Chemical Agents (Preservation Solution)
Prevention of intracellular edema Osmotic membrane-impermeable • Lactobionic acid (UW, Celsior, IGL-1)
macromolecules • Raffinose (UW, IGL-1)
• Mannitol (Celsior, HTK)
• Glucose (Collins)
Prevention of intracellular edema Intracellular electrolyte milieu • High K+, low Na+ (UW, Collins)
Prevention of intestinal edema Membrane-impermeable colloid • Hydroxyethyl starch (UW)
Maintaining physiological pH Buffer • Phosphate (UW, Collins)
• Histidine/histidine-HCl (HTK, Celsior)
• Bicarbonate (Collins)
Reduction of oxidative damage by Antioxidants/radical scavengers • Glutathione (UW, Celsior, IGL-1)
free radicals • Allopurinol (UW, IGL-1)
• Mannitol (HTK, Celsior)
Restoration of cellular energy Precursor substrate for energy • Adenosine (UW, IGL-1)
metabolism metabolism • α-Ketoglutarate (HTK)
• Histidine (HTK, Celsior)
• Glutamic acid (Celsior)
Maintaining cellular integrity Membrane stabilization • Dexamethasone (UW)
• Histidine (HTK, Celsior)
• Tryptophan (HTK)
 44 Principles of Liver Preservation 593

intracellular composition in UW (see Table 44-1). Simi- high costs, and the risk for hyperkalemia-induced cardiac
lar to UW, Celsior uses large membrane-impermeable arrest. Especially the last limitation requires liver flushing
macromolecules such as lactobionic acid and mannitol to before reperfusion. HTK and Celsior solution have the
maintain osmotic balance and prevent cell swelling advantages of low viscosity and low potassium, resulting
during cold storage (see Table 44-2). Celsior uses an in a better and faster flush and no need to flush before
amino acid buffer with histidine to prevent cellular reperfusion. These advantages stimulated transplant cen-
acidosis, and the amino acids histidine and glutamic acid ters to consider HTK or Celsior for liver preservation
serve as the cellular energy metabolism substrate. instead of UW. A recently published analysis of data from
Antioxidative protection is provided by the ingredients the United Network for Organ Sharing (UNOS) database
glutathione and mannitol. Celsior is a low-viscosity shows an increase in the use of HTK in deceased donor
solution, which theoretically provides a better flushing liver transplantation in the United States from 16.8% in
and wash-out during procurement than UW does. 2004 to 26.9% in 2008.93
Although HTK solution was initially designed as a Although many studies have been published
cardiac preservation solution, HTK was successfully comparing UW with HTK or Celsior solution, the
tested in clinical liver preservation in Europe in the number and quality of randomized controlled trials
1990s. Celsior was approved for liver preservation by the (RCTs) are surprisingly insufficient. To date only four
FDA in the United States in 1999. RCTs have been published comparing UW with HTK
or Celsior solution94-97 (Table 44-3). Only one of the
Which Preservation Solution Should Be four RCTs is of high quality.96 However, all RCTs
demonstrated equivalent graft and patient survival for
Used for Static Cold Preservation? UW and Celsior/HTK. Three RCTs also reported on
The first effective preservation solutions were developed posttransplant biliary complication rates.94,96,97 In these
for kidney preservation by Collins86 and Marshall92 in the trials UW was not associated with a higher biliary
1970s. Although the Collins and Marshall solutions pro- complication rate compared to HTK or Celsior solution
vided safe preservation of kidneys for 24 to 36 hours, both (see Table 44-3). Similar findings were reported by a
allowed only a safe short-term preservation (4 to recently published systematic literature review
8 hours) for liver allografts. The introduction of UW comparing the effect of preservation with UW versus
solution in the 1980s resulted in an almost complete HTK on posttransplant outcome.98 This review included
elimination of the Collins and Marshall solutions for liver mainly nonrandomized trials and reported equivalent
preservation.1 Initial clinical studies demonstrated that graft and patient survival for both preservation solutions
cold preservation times for livers could be safely extended in a meta-analysis approach. A significant difference for
to more than 15 hours.87 After that time, UW solution biliary complications could not be demonstrated by this
became the gold standard in liver transplantation for review. More recently the UNOS database analysis
many years. comparing UW (n = 12,613) and HTK (n = 4755)
Although HTK and Celsior solutions were designed preservation showed that preservation with HTK was
for heart preservation, both solutions have been tested associated with significantly increased graft loss, which
for liver preservation and challenged UW as the estab- was even more pronounced in DCD liver
lished cold storage solution for liver preservation. UW transplantation.93 In summary, the data show that there
solution has some disadvantages, such as high viscosity, is currently no proven evidence that Celsior or HTK is

TABLE 44-3 R
 andomized Trials Comparing Preservation Solutions in Deceased Donor Liver
Transplantation
Groups Sample Cold
(No. of Enrollment Size Ischemia Primary End
Author Patients) Period ­Calculation Time Point Findings
Erhard et al95 UW (30) 30 months No 663 min Not defined • Equivalent outcome for
HTK (30) 579 min graft and patient survival
Cavallari et al94 UW (90) Mar 1999- No 438 min Primary • No significant difference in
Celsior (83) Nov 2001 444 min dysfunction primary dysfunction
• Equivalent outcome for
biliary complications, graft,
and patient survival
Meine et al97 UW (65) Jan 2003- No 663 min Not defined • Equivalent outcome for
HTK (37) Aug 2004 579 min biliary complications, graft,
and patient survival
Garcia-Gil et al96 UW (51) Jan 2001- Yes 398 min Post-reperfusion • Higher rate of post-­
Celsior (51) Dec 2003 383 min syndrome reperfusion syndrome for
UW (5.9% vs 21.6%)
• Equivalent outcome for
biliary complications and
patient survival
594 PART V Operation

superior to UW in terms of biliary complications or ischemia.102-104 The underlying molecular mechanisms

graft and patient survival even in the light of the of IPC are complex and involve oxidative stress– and
theoretical advantages of a low-viscosity preservation tyrosine kinase–dependent mechanisms; other mediators
solution. As long as more high-quality RCTs are not such as nitric oxide (NO) and adenosine have also been
available, no evidence-based recommendation can be proposed.102,103,105,106 Several clinical studies have
given regarding which preservation solution is superior evaluated the effect of IPC on graft injury and patient
and should be preferred. All in all, there are no outcome (Table 44-4). The IPC protocols in these
fundamental differences between the presently used studies were heterogeneous with ischemia times of 5 to
preservation solutions. However, UW solution remains 10 minutes and reperfusion times ranging from 5 to 30
the gold standard as static cold storage solution in liver minutes before cross-clamping. The majority of the
transplantation in many centers. studies (six of eight) revealed decreased levels of
postoperative aspartate aminotransferase (AST) for
allografts undergoing IPC.107-112 Other positive findings
associated with IPC were reduced hepatocyte swelling110
NOVEL PRESERVATION STRATEGIES and neutrophil and CD41 infiltration112; less apoptosis107;
Ischemic Preconditioning of the Liver and suppressed transcriptional response to reperfusion
injury.111 However, most studies failed to demonstrate a
Ischemic preconditioning (IPC) describes the protective clinical benefit in terms of graft and patient survival. All
technique of applying a short period of ischemia fol- in all, the current evidence level does not support the
lowed by a short period of reperfusion before an extended routine use of IPC in liver transplantation. Perhaps
ischemic insult. This concept was first discovered in the marginal organs that are more vulnerable to IRI benefit
kidney and heart, in which IPC conferred protection more from IPC, as reported by two recent studies.110,115
against IRI.99,100 IPC has been initially tested in various
models of warm liver ischemia. Animals subjected to 5 to
10 minutes of ischemia followed by 10 to 15 minutes of
Pharmacological Conditioning of the Liver
reperfusion before prolonged ischemia showed reduced Pharmacological conditioning of the liver can be done in
liver injury and improved survival. Based on these obser- preconditioning or postconditioning transplant settings.
vations, the benefits of IPC in patients undergoing liver Preconditioning applies to pharmacological interventions
resection with inflow occlusion were initially reported in the donor or in the allograft before implantation/reper-
by Clavien et al.101 Subsequently the concept of IPC was fusion, whereas postconditioning intervenes during the
tested for cold ischemia in the settings of liver transplan- time of reperfusion. Although various agents have shown
tation. The protective effect of IPC was also demon- protective effects against IRI in experimental models, only
strated in experimental liver transplant models of cold a few have been tested in clinical randomized trials in liver

TABLE 44-4 Clinical Studies on Ischemic Preconditioning in Deceased Donor Liver Transplantation
IPC Protocol
No. of Patients Randomized (Ischemia/­ Protective
Author (Non-IPC/IPC) Trial Reperfusion) Findings for IPC Group IR Effects
Azoulay et al108 45/46 No 10/10 min ↓Postoperative AST but ↓early Yes
graft function
Koneru et al113 28/34 Yes 5/5 min No protective effects for No
ischemic preconditioning
Jassem et al112 14/9 No 10/30 min ↓Postoperative AST, ↓neutrophil Yes
and CD41 infiltration, ↓length
of intensive care unit stay
Cescon et al109 24/23 Yes 10/15 min ↓Postoperative AST and Yes
↓expression of inducible nitric
oxidase
Amador et al107 30/30 Yes 10/10 min ↓Apoptosis, ↓postoperative AST, Yes
and ↓reoperation rate
Koneru et al114 50/51 Yes 10/10 min ↑Postoperative AST and No
↑post-reperfusion IL-10 levels
but lower rate for acute
rejection
Jassem et al111 16/19 Yes 10/30 min ↓Postoperative AST and Yes
↓transcriptional response to
reperfusion injury
Franchello 44/30 Yes 10/30 min ↓Hepatocyte swelling, ↓Postop- Yes
et al110 erative AST in marginal
grafts, and ↓positive micro-
biological cultures

AST, Aspartate aminotransferase; IL-10, interleukin-10; IPC, ischemic preconditioning; IR, ischemia-reperfusion.
 44 Principles of Liver Preservation 595

transplantation (see Table 106-1). One of the early ran- the organ viability for up to 72 hours of extracorporeal
domized studies showed that the systemic bolus adminis- perfusion.122 In another experimental model, NOP res-
tration of prostaglandin I2 (epoprostenol) in the donor cued porcine liver grafts subjected to 60 minutes of warm
before cross-clamping resulted in a decreased hepatic ischemia, whereas nonperfused livers resulted in
IRI.116 The authors proposed improved sinusoidal perfu- nonfunction and recipient death after transplantation.124
sion as the underlying mechanism. Two other trials used In a more recently published study, NOP proved to be
immunosuppressive agents to minimize IRI.117,118 The superior to cold storage in porcine DCD livers in terms of
continuous treatment of the donor with methylpredniso- liver injury, synthetic graft function, cytokine and
lone resulted in significantly reduced hepatic graft injury proinflammatory response, and survival.126 Another
and lowered the rate of acute rejection.118 Thymoglobulin advantage of NOP is related to the group of steatotic
treatment started during the anhepatic phase and contin- donor livers. Two experimental studies demonstrated that
ued postoperatively with two single doses significantly NOP caused defatting of steatotic livers and metabolic
ameliorated IRI and improved the initial allograft func- conditioning.127,128 The concept of in situ NOP has been
tion.117 The underlying mechanism for this observation is tested in one clinical study only.129 Donors with irreversible
related to the suppression of the sterile inflammatory cardiac arrest before donation (DCD) were maintained
immune response after reperfusion. In particular, thymo- with normothermic extracorporeal membrane oxygenation
globulin will inhibit the adaptive immune response to IR until potential organ procurement. Ten of 40 patients
(see Fig. 44-7). This finding illustrates that the immuno- treated under this protocol donated their liver for
suppressive treatment that is used to prevent allograft transplantation. In this series one allograft developed
rejection also can be considered as treatment of IRI by sup- primary nonfunction and another hepatic artery
pressing the inflammatory immune response. Other phar- thrombosis. The other remaining livers displayed
macological strategies that resulted in less IRI are the reasonable postoperative graft function. Despite the
addition of a pancaspase inhibitor119 or blockade of benefits of NOP, this approach seems to lose its protection
P-selectin by inhibition of the ligand necessary for selectin when cold preservation is employed.130,131
activity.120 In the latter study, selectin blockade was accom-
plished by flushing the allograft after harvest with the Hypothermic Oxygenated Perfusion
ligand blocker. Another interesting concept is the intraop-
erative administration of inhaled NO at the time of trans- An alternative concept to NOP is hypothermic machine
plantation. A randomized trial demonstrated a reduction of perfusion (HMP) with or without oxygenation. The prin-
hepatocyte apoptosis and an improved restoration of ciple of hypothermic oxygenated protection is based on
allograft liver function when patients who underwent liver the deactivation of mitochondrial respiration and
transplantation received inhaled NO before and after decreased production of reactive oxygen species. In con-
reperfusion.121 In this study, inhaled NO was well toler- trast to NOP, HMP works with lower perfusion pres-
ated and did not cause any undesired cardiopulmonary sures and flow rates and uses modified colloid solutions
changes. Although the authors propose the downregula- instead of blood for perfusion. The benefit of HMP has
tion of endogenous NO production as the underlying been demonstrated in many experimental transplant
mechanism, the exact mechanism remains to be investi- models either as long-term (24 to 72 hours),132-134 inter-
gated. Currently three large RCTs (NCT01172691, mediate (3 to 7 hours),135,136 or short-term (1 to 2 hours)
NCT00948194, NCT00582010) are running in the perfusion.137,138 A short-term application of oxygenated
United States evaluating the protective effects of inhaled HMP appears to be an attractive approach for the clinical
NO in liver transplantation (http://www.clinicaltrials.gov). setting. In a novel study using porcine allografts, 1 hour
of HOP before implantation conferred protection to
nonviable DCD grafts in terms of improved bile flow,
Machine Perfusion better ATP recovery, reduction of posttransplant necro-
Machine perfusion of donor liver grafts before implanta- sis, and improved survival.137
tion may safely extend ischemia times and minimize the The concept of hypothermic perfusion was recently
IRI in extended criteria donor organs. This concept has tested in the first clinical trial in patients undergoing
been extensively investigated in experimental rodent and orthotopic liver transplantation.139 In this study 20 patients
pig models either as normothermic (NOP) or hypother- received allografts that were treated by hypothermic per-
mic oxygenated perfusion (HOP) and has been tested in fusion for 3 to 7 hours. The comparison of this group to a
limited clinical trials. matched cold storage group revealed significantly lower
rates of allograft dysfunction (5% versus 25%) and shorter
hospital stay (10.9 versus 15.3 days) for the hypothermic
Normothermic Oxygenated Perfusion
perfusion group. Livers preserved with HMP had
NOP has the advantage of physiological organ perfusion significantly reduced expression of proinflammatory
that is close to the in situ situation. This method, which cytokines and ICAM-1.140 Another clinical trial tested
uses supplemented blood as perfusate, allows real-time oxygenated HOP in patients undergoing liver
assessment of viable liver function by measuring oxygen transplantation with DCD organs. The study showed that
consumption, bile flow, and urea synthesis.122-125 A signifi- oxygenated HOP was well-tolerated and protective against
cant advantage is that the perfused organ may be main- IRI and DCD-associated injury.141 These encouraging
tained for an extended period of time. One experimental experimental and first clinical results using machine
study using porcine livers showed that NOP maintained perfusion indicate its great potential and future clinical
596 PART V Operation

applications to improve the outcome of patients who 10. Spitzer AL, Lao OB, Dick AA, et al. The biopsied donor liver:
receive extended criteria donor organs, with the end result incorporating macrosteatosis into high-risk donor assessment.
Liver Transpl. 2010;16:874-884.
of expanding the donor pool. 11. Baccarani U, Adani GL, Isola M, et al. Steatosis of the graft is a
risk factor for posttransplantation biliary complications. Trans-
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12. Durand F, Renz JF, Alkofer B, et al. Report of the Paris consensus
meeting on expanded criteria donors in liver transplantation.
Pearls and Pitfalls Liver Transpl. 2008;14:1694-1707.
13. Diamant AL, Babey SH, Wolstein J, et al. Obesity and diabetes:
• Graft injury is manifested on reperfusion but is the result two growing epidemics in California. Policy Brief UCLA Cent
of accumulated organ damage acquired in prepreserva- Health Policy Res. 2010:1-12.
tion, preservation, and rewarming periods. 14. Nguyen DM, El-Serag HB. The epidemiology of obesity. Gastro-
• Many grafts suffer prepreservation injury, which is mainly enterol Clin North Am. 2010;39:1-7.
related to underlying liver disease (steatosis), cardiopul- 15. Wertheim JA, Petrowsky H, Saab S, et al. Major challenges limit-
monary arrest, and hypotension in the donor. Livers from ing liver transplantation in the United States. Am J Transplant.
donation after cardiac death donors experience warm 2011;11:1773-1784.
16. Cywes R, Mullen JB, Stratis MA, et al. Prediction of the outcome
ischemia as part of the prepreservation injury. of transplantation in man by platelet adherence in donor liver
• Cold preservation injury is mainly due to the effects of allografts. Evidence of the importance of prepreservation injury.
cold on the microcirculation. Cold activates the sinu- Transplantation. 1993;56:316-323.
soidal endothelial surface, which makes it adherent for 17. de Vera ME, Lopez-Solis R, Dvorchik I, et al. Liver transplanta-
platelets and leukocytes. tion using donation after cardiac death donors: long-term follow-
• The accumulated organ injury, which is manifested on re- up from a single center. Am J Transplant. 2009;9:773-781.
perfusion, initiates a sterile inflammatory immune r­esponse, 18. Ho KJ, Owens CD, Johnson SR, et al. Donor postextubation hypo-
which amplifies local tissue destruction and triggers the acti- tension and age correlate with outcome after donation after cardiac
vation of cell death programs. death transplantation. Transplantation. 2008;85:1588-1594.
19. Hong JC, Yersiz H, Kositamongkol P, et al. Liver transplantation
• Although University of Wisconsin solution is the standard using organ donation after cardiac death: a clinical predictive index
preservation solution in many centers, histidine-tryptophan- for graft failure-free survival. Arch Surg. 2011;146:1017-1023.
ketoglutarate (HTK) and Celsior solutions achieve similar 20. Cameron AM, Ghobrial RM, Yersiz H, et al. Optimal utilization
results for static cold preservation of the liver. of donor grafts with extended criteria: a single-center experience
• There is growing experimental evidence that machine in over 1000 liver transplants. Ann Surg. 2006;243:748-753:dis-
perfusion might be superior to static cold storage for liver cussion 53-55.
preservation. 21. Dutkowski P, Oberkofler CE, Slankamenac K, et al. Are there
• Primary nonfunction is usually due to multiple risk fac- better guidelines for allocation in liver transplantation? A novel
tors for poor function being combined in one patient. score targeting justice and utility in the model for end-stage liver
disease era. Ann Surg. 2011;254:745-753:discussion 53.
When a known risk factor such as steatosis is present, 22. Rana A, Hardy MA, Halazun KJ, et al. Survival outcomes follow-
all other adjustable risk factors such as cold preservation ing liver transplantation (SOFT) score: a novel method to predict
time and rewarming time should be minimized. patient survival following liver transplantation. Am J Transplant.
• After 60 minutes, a minute of rewarming time has a much 2008;8:2537-2546.
greater injurious effect than a minute of rewarming time 23. Villa R, Fondevila C, Erill I, et al. Real-time direct measurement
   before 60 minutes has elapsed. of human liver allograft temperature from recovery to transplan-
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model. Transplantation. 2011;92:289-295. hypothermic oxygenated perfusion (HOPE) protects nonviable
128. Nagrath D, Xu H, Tanimura Y, et al. Metabolic preconditioning liver allografts donated after cardiac death. Ann Surg. 2009;250:
of donor organs: defatting fatty livers by normothermic perfusion 674-683.
ex vivo. Metab Eng. 2009;11:274-283. 138. Dutkowski P, Furrer K, Tian Y, et al. Novel short-term hypo-
129. Fondevila C, Hessheimer AJ, Ruiz A, et al. Liver transplant using thermic oxygenated perfusion (HOPE) system prevents injury in
donors after unexpected cardiac death: novel preservation proto- rat liver graft from non-heart beating donor. Ann Surg. 2006;244:
col and acceptance criteria. Am J Transplant. 2007;7:1849-1855. 968-976:discussion 76-77.
130. Reddy S, Greenwood J, Maniakin N, et al. Non-heart-beating 139. Guarrera JV, Henry SD, Samstein B, et al. Hypothermic machine
donor porcine livers: the adverse effect of cooling. Liver Transpl. preservation in human liver transplantation: the first clinical
2005;11:35-38. series. Am J Transplant. 2010;10:372-381.
131. Reddy SP, Bhattacharjya S, Maniakin N, et al. Preservation of 140. Guarrera JV, Henry SD, Chen SW, et al. Hypothermic machine
porcine non-heart-beating donor livers by sequential cold storage preservation attenuates ischemia/reperfusion markers after liver
and warm perfusion. Transplantation. 2004;77:1328-1332. transplantation: preliminary results. J Surg Res. 2011;167:e365-e373.
132. Kamada N, Calne RY, Wight DG, et al. Orthotopic rat liver trans- 141. Dutkowski P, Schlegel A, de Oliveira M, et al. HOPE for human
plantation after long-term preservation by continuous perfusion liver grafts obtained from donors after cardiac death. J Hepatol.
with fluorocarbon emulsion. Transplantation. 1980;30:43-48. 2014;60:765-772.
133. Pienaar BH, Lindell SL, Van Gulik T, et al. Seventy-two-hour
preservation of the canine liver by machine perfusion. Transplan-
tation. 1990;49:258-260.
134. Tamaki T, Kamada N, Wight DG, et al. Successful 48-hour pres-
ervation of the rat liver by continuous hypothermic perfusion
with haemaccel-isotonic citrate solution. Transplantation. 1987;43:
468-471.
 CHAPTER 45

Recipient Hepatectomy
and Grafting
Göran B.G. Klintmalm • Ronald W. Busuttil

CHAPTER OUTLINE

CLASSIC TECHNIQUE HEPATIC ARTERY

PORTAL VEIN BILE DUCT
PIGGYBACK TECHNIQUE SUMMARY

According to conventional clinical and surgical stan- also a more sophisticated technique of dissection. Today
dards of the early 1960s, removal of a diseased liver and the entire dissection is performed with electrocautery in a
replacing it with a working, undamaged one was a con- coagulation mode, most commonly directly by the sur-
cept that, although visionary and sound, had a low prob- geon or by the assistant cauterizing on the surgeon’s dis-
ability of being successfully executed. Only because of secting tonsil clamp. Whereas suture ligation was used
the technical brilliance and stubborn perseverance of for all vessels during the recipient hepatectomy, it is now
Thomas E. Starzl did the experiment continue and reserved for only major vascular and tissue structures.
slowly develop into the refined surgical procedure that Third, the introduction of venovenous bypass and its
we know today. To perform liver replacement in an early implementation in the operation have provided a
environment of unsophisticated hemodynamic monitor- certain equanimity to the conduct of the operation,
ing, slow turnaround of biochemical and coagulation thereby providing a more suitable atmosphere for the
monitoring profiles, inadequate blood component education of liver transplant trainees. A fourth advance-
replacement therapy, and crude surgical instruments ment is an adaptable technique of using either the classic
that did not even include atraumatic needles is almost orthotopic procedure or the caval-sparing transplant
beyond comprehension. During the last 1½ years of (piggyback). Fifth, the use of modern mechanical retrac-
Starzl’s liver transplant program at Colorado General tors permits an unrestricted, nontiring visualization of
Hospital (1979 to 1980) in Denver, the fastest procedure the field, which allows the procedure to be performed
took 14½ hours, and only cases lasting longer than with only two assistants. In Denver, fellows and residents
20 hours were considered poor from a technical point of hanging for dear life onto the retractors were rotated
view. The preoperative blood order for type and cross- every 2 to 4 hours or until they dropped to give the best
match for 15 units of packed cells was designated for possible exposure. Nonetheless, most adult patients
opening the abdomen, during which time the blood bank required a thoracotomy to allow access to the suprahe-
would have the opportunity to cross-match and supply patic vena cava, a procedure that is now virtually never
more blood for the remainder of the case. used.
Since these pioneering times, innumerable improve- Liver transplantation today is performed principally
ments have been made, each one making a small contri- with two different techniques: the classic technique with
bution that, as a whole, has transformed today’s liver vena cava interposition and a piggyback technique1 that
transplant procedure into an evolutionary descendant leaves the native cava behind. Venovenous bypass is not
that barely resembles its ancestor. Of the factors that have mandatory with either one. Until 1983, liver transplanta-
done the most to develop liver transplantation from an tion was performed by what we now call the classic tech-
experimental undertaking to a therapeutic procedure, we nique, which is when Starzl and coworkers developed the
first list the development of anesthesia, including central bypass.2 The bypass maintains cardiovascular stability
hemodynamic monitoring and coagulation control. We and normal hemodynamics to a degree that caval-side
believe that anesthesiologists are the unsung heroes of occlusion is unable to do; it requires fewer intraoperative
this operation, and they deserve much credit. Second, the fluid transfusions and results in a diminished frequency of
introduction of electrocautery, the argon beam coagula- reperfusion syndrome and a less edematous posttrans-
tor, and new hemostatic agents created not only a safe plant patient. Furthermore, it is most helpful in the high
technique of controlled coagulation of bleeding areas but Model for End-Stage Liver Disease (MELD) patient who

600
 45 Recipient Hepatectomy and Grafting 601

FIGURE 45-2

surgeon has a direct perpendicular view of the suprahe-

patic vena cava; at times, complete or partial xiphoidec-
FIGURE 45-1 tomy may be necessary. With this incision, exposure is
excellent, and of more than 6000 patients, only 2 required
extension into the chest via a median thoracotomy.
is receiving vasopressors and/or in need of hemodialysis A mechanical retractor is placed with the blades under
at the time of transplantation. The most important indi- both costal margins to pull the rib cage laterally and ante-
cation for the piggyback technique may be cases in which riorly to spread the aperture (Fig. 45-2). The falciform
a small donor liver with a narrow cava is to be trans- ligament is divided, and the tissue with all the collaterals
planted into a large recipient in whom the narrow donor along the falciform ligament and the midline fascia are
cava causes clinically significant stenosis. Another impor- removed up to the xiphoid, thereby totally preventing
tant advantage of the piggyback technique is in difficult further collateral bleeding and obstruction of the field
retransplantation, when the vena cava is embedded in an from the tissue mass itself. The fatty tissue below the
inflamed retroperitoneum. upper midline extension often contains large collaterals
For a technically adroit surgeon, surgical time and from the umbilical vein that should be controlled with
blood loss with the piggyback technique may approach ligatures and entirely removed, which is done without
that of the classic technique with the use of venovenous blood loss if the correct tissue plane is found. On opening
bypass. In a regular transplant procedure using the classic the rectus sheath, a ligature placed on the round liga-
technique, we expect the patient to be anhepatic on ment, when left long and “draped” over the retractor
bypass for 40 to 50 minutes with a warm ischemia time of ring, can serve as excellent exposure to the porta hepatis.
the graft of approximately 25 to 30 minutes. Of note, The falciform ligament is divided all the way down to
both authors of this chapter routinely use the classic tech- the suprahepatic vena cava, and the left triangular liga-
nique in the vast majority of transplants. ment is then opened with the cautery. Frequently, col-
lateral veins are present at the very tip of the left lateral
segment that require ligature for hemostasis. The left
CLASSIC TECHNIQUE lateral segment is then retracted up out of the wound and
to the right. The gastrohepatic ligament is now visualized
After the patient has been carefully positioned on the and requires either cautery division or suture ligation,
table, prepared, and draped, the abdomen is opened via a depending on the extent of the collateral vessels. Obvi-
bilateral subcostal incision with midline extension (Fig. ously, if an accessory left hepatic artery is present, it must
45-1), so appropriately named the Mercedes incision by Sir be ligated and divided.
Roy Calne. Except for the superficial skin incision, the The anteroinferior edge of the liver or the ligated
skin, subcutaneous tissue, and muscle layers are opened round ligament is now lifted up by an assistant to allow an
with the electrocautery unit. The right-sided incision is unobstructed view of the porta hepatis (Fig. 45-3). The
extended far enough laterally to allow a horizontal view dissection is carried down to the hepatic artery, which is
into the vena cava. The left-sided incision is shorter and then divided above its bifurcation. Before division we find
extends beyond the lateral border of the rectus. If spleno- it helpful to isolate the common hepatic and gastroduo-
megaly is present, care should be taken to avoid making denal arteries and place an atraumatic vascular bulldog
this incision very long because the spleen is then easily clamp on the common hepatic artery. This maneuver
injured, which could possibly cause serious bleeding and prevents dissection of the hepatic artery, which can occur
necessitate an otherwise unnecessary splenectomy. The if the artery is simply ligated distally.3 This maneuver vir-
midline incision is extended to the point at which the tually eliminates initial dissection of the hepatic artery.
602 PART V Operation

FIGURE 45-3 FIGURE 45-4

We then proceed to the right side of the porta hepatis back into the hepatic fossa and expose the left side of the
and divide the common duct. Normally it is unnecessary vena cava by retracting the left lateral segment and the
to divide the cystic duct separately; however, division caudate lobe to the right. The peritoneal reflection is
above the cystic duct entrance can easily be accomplished opened longitudinally along the vena cava with cautery. In
when necessary to preserve sufficient length of the com- most cases, the retrohepatic caval tissue can be taken down
mon duct. In more than 95% of patients with an acces- with finger dissection. Any resistance to such dissection
sory right hepatic artery, it traverses posterior to the usually signifies retrohepatic collaterals entering the vena
common bile duct and is divided when present. We then cava, which require ligation. With this dual-sided
complete the dissection around the portal vein. In many approach, the posterior aspect of the retrohepatic cava can
cases the dorsal pancreatic vein drains into the anterior be quickly and safely liberated from the retroperitoneum.
portion of the portal vein and must be divided and ligated. At this juncture the patient is prepared for venovenous
If adhesions to the liver are present after previous bypass by cannulation of the femoral vein. Cannulation is
operations or from spontaneous bacterial peritonitis, they performed via the Seldinger technique in the groin by
are taken down with electrocautery. The tip of the elec- using a premade kit (Medtronic, catalog No. 96530-015).
trocautery is run parallel to the liver surface at all times, We use wire-reinforced cannulas, 15F for the femoral
never venturing more than 1 mm from the liver surface vein. Forced cannulation is contraindicated. The position
but never violating the liver capsule. The liver is to be of the wire is easily checked by palpation of the infrahe-
“shaved.” In cases in which the liver is encased in adhe- patic vena cava. The return cannula is inserted by the anes-
sions, it is often easier to commence with dissection of the thesia team into the right intrajugular vein by using a 12F
lateral aspects of the right lobe followed by dissection of wire-reinforced cannula (Medtronic, catalog No. 96830-
the stomach and duodenum from segments II and III 012) with a pediatric arterial kit (Argon Medical, catalog
before venturing into the porta hepatis. No. 401135B). This cannula is always inserted when the
In an uncomplicated case we now proceed to dissect patient has been intubated before preparing the abdomen.
the right triangular ligament (Fig. 45-4). This dissection is An alternative option is to cut down directly on the axillary
performed completely with cautery, beginning at the lat- vein (usually the left) and the left saphenofemoral junction
eral inferior aspect and dividing the ligament carefully all and then insert 20F and 18F cannulas, respectively.
the way into the vena cava. If there are technical problems Once the cannulas have been introduced and secured,
with an unusual amount of collaterals, scarring, and we proceed to final dissection of the portal vein. The por-
inflammation, this part of the procedure is deferred until tal vein is secured with the left hand and cleaned with
after the patient is placed on total venovenous bypass. scissors by simply pushing the tissue away longitudinally
With the portal vein transected, the anterior aspect of the along the vein (Fig. 45-5, A). The portal vein is then
infrahepatic inferior vena cava (IVC) is exposed to allow clamped as high in the hilum as possible and divided.
easy circumferential mobilization for placement of a vas- Three Moynihan (tonsil) clamps are attached to the end
cular clamp. If the portal vein is not transected at this of the portal vein and held straight up by the assistants. A
point, the vena cava is dissected in an inferior-to-superior surgeon who controls the portal vein with the left hand
direction with cautery. The right adrenal vein is ligated introduces the 28F to 36F wire-reinforced cannula
and divided. At this time we allow the right lobe to fall (Edwards Lifesciences) with the right hand and keeps it in
 45 Recipient Hepatectomy and Grafting 603

A
A B

B
C D FIGURE 45-6
FIGURE 45-5

place as the first assistant secures it with tape (see Fig.

45-5, B).
An alternative way to cannulate the portal vein is to
ligate the portal vein up in the hilum and, after placing
tape around the portal vein to control the vein where it
emerges from the neck of the pancreas, make a transverse
cut in the distal end of the portal vein to allow the portal
vein cannula to be introduced (see Fig. 45-5, C). The can-
nula is secured with tape and tied down, thereby complet-
ing the portal vein cannulation, and the transverse
incision of the portal vein is now completed to divide the
portal vein in its entirety (see Fig. 45-5, D).
Venovenous bypass is now started (Fig. 45-6, A). The
entire cannulization process for venovenous bypass usu-
ally requires 5 to 10 minutes.
In cases in which the portal vein is injured or, even
more important, when dense adhesions with large collat-
eral veins are surrounding the liver, the inferior mesen-
teric vein can be used for bypass purposes. For the inferior
mesenteric vein a No. 20 cannula is usually sufficient and
needs to be introduced only 2 to 3 cm. If it is advanced
further, the tip often goes out into the portal vein and
makes portal vein clamping very difficult later (see Fig.
45-6, B).
In patients with organized portal vein thrombus, a for- FIGURE 45-7
mal thrombendvenectomy can be performed in the
majority of situations to remove thrombus all the way to ensure portal venous inflow to the liver (Fig. 45-8).
down into the superior mesenteric vein (SMV) under Patients with extensive portal vein repairs or conduits are
manual control (Fig. 45-7). In patients with portal vein administered low-molecular-weight dextran at 25 mL/hr
thrombosis, partial or complete, utmost care should be for 1 or 2 days and then acetylsalicylic acid, 81 mg/day,
taken to avoid any further traumatization of the portal for 3 months.
vein. In cases in which avoidance of further trauma is Vascular clamps are now placed on the suprahepatic
impossible, portal vein venous conduits need to be used vena cava and the lower infrahepatic vena cava (Fig. 45-9).
604 PART V Operation

FIGURE 45-10

Figure 45-10. With the use of 3-0 or 2-0 monofilament

polypropylene suture (Prolene; Ethicon, Somerville, NJ),
FIGURE 45-8 the bare area is sutured in the direction of the arrows and
back to the starting point, as numbered 1, 2, and 3. Care
should be taken to ensure that the needle passes superfi-
cially under the bottom of the entire wound to obtain
hemostatic control. In many cases this can be done before
liver removal.
In patients with difficult dissections the vena cava can
be clamped above and below the liver before all the right-
sided and retrohepatic dissection is performed (Fig. 45-11,
A). The dissection can now be concluded quickly (see Fig.
45–11, B). In such cases it is often expedient to retain the
dorsal side of the vena cava to eliminate the need for elab-
orate hemostatic control of the retrocaval tissue.
The suprahepatic vena cava is now prepared by open-
ing the right, middle, and left hepatic veins into a com-
mon cloaca of the IVC (Fig. 45-12). All phrenic vein ostia
are oversewn with 4-0 polypropylene and the knots
placed outside the suprahepatic vena cava cuff. The liver
is now brought onto the field. By placing a lap in the
hepatic fossa, the liver receives support from below to
prevent it from sinking down too far into the wound;
FIGURE 45-9 however, with oversized allografts, as is seen more fre-
quently today, this is often not necessary.
Corner stitches are placed on the two opposing ends
Care should be taken to place these clamps horizontally (Fig. 45-13, A), and a stay suture may be placed in the
and with the liver in its normal anatomical position to middle for retraction of the posterior wall. The suprahe-
prevent rotation of the vessels. The suprahepatic vena patic vena cava anastomosis is performed with 3-0 poly-
cava clamp should be placed on the very edge of the dia- propylene; care is taken to ensure perfect intimal
phragmatic reflection to avoid phrenic nerve injuries. adaptation. The dorsal suture is run to the right-sided
We now divide the vena cava while taking care to stay suture and just one bite beyond and anterior to it.
retain as much of the right, middle, and left hepatic veins The midline stay suture is removed, and the front wall
as possible and pull the veins up by almost cutting into closure is completed in a simple running suture fashion.
the liver substance (Fig. 45-10). The lower cava is then When the anastomosis is finished, a 1- to 1.5-cm
divided as far proximal as possible. The previously ligated “growth factor” is tied in. The lateral stay suture is tied
retrocaval tissue is divided and the liver removed. down securely to prevent the anastomosis from separat-
To achieve hemostasis in the hepatic fossa, the bare ing as the growth factor is taken up by expansion of the
area can be reperitonealized, as shown in the inset of vessel at the time of reperfusion (see Fig. 45-13, B).
 45 Recipient Hepatectomy and Grafting 605

B
FIGURE 45-11 B
FIGURE 45-13

FIGURE 45-14

FIGURE 45-12 excessively high concentrations of intravascular potassium

left from the preservation solution. When the organ is
cooled down for preservation, the sodium-potassium pump
A portal flush with normal saline or lactated Ringer’s is inhibited, allowing the high concentration of intracellu-
solution and 25 g of albumin per liter is run through the lar potassium to leak out into the vascular space. The infra-
portal vein during the completion of the infrahepatic vena hepatic vena cava is sewn in exactly the same manner as
cava (Fig. 45-14). Such flushing is needed to empty the used for the suprahepatic vena cava, usually with 4-0 poly-
graft of air to prevent air emboli, as well as to remove the propylene, and a 1.5-cm growth factor is included.
606 PART V Operation

these elevations have normalized, the portal vein is com-

pletely opened. It usually takes three or four partial
decompressions before the vein is completely open.
After the surgeon makes sure that there is no significant
bleeding from the vena cava, portal vein, or its anastomo-
ses, the systemic bypass is discontinued and the cannula
removed from the groin to allow blood in the bypass sys-
tem to be reinfused into the patient. When the portal vein
is unusable, which is extremely rare because of the increased
application of thrombendvenectomy, a portal venous con-
duit is used (see Fig. 45-8). In such cases, arterial recon-
struction and reperfusion of the liver are performed before
the portal conduit is sewn in. For the portal venous con-
duit, a donor iliac vein is the preferable conduit. The SMV
is most commonly used for inflow and is accessed at the
base of the colon mesenterium. After the SMV has been
FIGURE 45-15 identified and side-occluded, the venous conduit, which
should have already been anastomosed to the donor portal
vein and pulled behind the stomach in front of the pan-
Care must be taken to prevent too long a vena cava. creas through a tunnel in the colon mesenterium toward
Excessive length of vena cava is the main cause of folding the SMV, should now be anastomosed with running 6-0
and kinking, which can cause formidable postoperative polypropylene. It should be pointed out that when the
problems that require extraordinarily difficult recon- side-occluding clamp on the SMV is released, there must
structions at a later stage. be an outflow already established from the venous conduit.
Otherwise, the anastomosis line may rupture completely
and cause an immediate catastrophe. Sometimes, large col-
PORTAL VEIN lateral veins can be found in the subhepatic area, either
along the minor curvature of the stomach or as a collateral
If venovenous bypass is used, the portal bypass cannula is to the liver, that can be used for the donor portal vein anas-
now clamped, and only the systemic venovenous bypass is tomosis instead of a mesenteric venous conduit.
continued. The cannula is removed from the portal vein,
and an atraumatic clamp is carefully placed proximally on
the portal vein (Fig. 45-15). The donor portal vein is now PIGGYBACK TECHNIQUE
shortened to the appropriate length. One should not cut
the recipient portal vein shorter than 1 cm because length With the falciform, gastrohepatic, and left and right tri-
should be conserved in the event that retransplantation angular ligaments taken down, the hepatic hilum is dis-
becomes necessary. A laparotomy pad is placed against sected out and the hepatic artery, common duct, and
the right hemidiaphragm to prevent kinking of the portal portal vein are divided. If necessary, we proceed to veno-
vein anastomosis. The portal vein is sutured with running venous bypass or perform an end-to-side portocaval
6-0 polypropylene, and the inverting stitch in the back shunt. The portal vein is rotated slightly counterclock-
wall also includes a growth factor that is three quarters of wise, which facilitates its approximation to the vena cava.
the portal vein diameter. If size must be adjusted to either The anastomosis is sewn with running 5-0 monofilament
the donor or the recipient portal vein, a fish-mouth suture (Fig. 45-16). With the inferior liver surface com-
reconstruction is recommended. There are several meth- pletely exposed, the dissection is continued in the plane
ods to reperfuse the liver after portal venous reconstruc- between the cava and the liver. We use titanium surgical
tion: (1) reperfusion through the portal vein with or clips for small retrohepatic veins (Fig. 45-17). Veins
without vena cava venting, (2) opening of the IVC fol- larger than 3 to 4 mm are ligated with silk. Once the liver
lowed by portal vein reperfusion, and (3) reperfusion is removed, all clips and ligatures are secured by 3-0 or
through the portal vein and hepatic artery simultane- 4-0 silk sutures. The right hepatic vein is clamped,
ously. To date no randomized trial has conferred superi- divided, and oversewn.
ority to any of these methods. Furthermore, a randomized The left and middle veins are clamped and divided to
trial conducted at the University of California at Los allow the liver to be removed from the wound. When
Angeles (UCLA) has shown that venting through the dividing the right, middle, and left hepatic veins, we
vena cava before portal vein reperfusion does not result in divide them as far into the liver as practical. The most
a lower incidence or decreased severity of reperfusion expeditious way to clamp the hepatic veins is to side-
syndrome. However, venting through the intrahepatic occlude the vena cava with a Satinsky clamp (Fig. 45-18).
IVC with 250 to 400 mL portal vein blood does ensure Depending on the anatomy, we connect the hepatic veins
washout of the high K+-containing preservation solution. into a common cloaca and extend the cava incision dis-
It is our preference to release the portal vein clamp slowly tally 3 to 4 cm. At this time the donor liver is brought into
with an eye on the electrocardiogram to monitor the pro- the field. The donor cava is cut down longitudinally in
cedure. We usually open the portal vein in stages after the back 3 to 4 cm from the proximal cava to create two
any T-wave segment elevations have reversed. Once corresponding orifices. Great care should be taken to
 45 Recipient Hepatectomy and Grafting 607

FIGURE 45-18

FIGURE 45-16

FIGURE 45-19

completion. We then sew the right side of the anastomosis

from the inside in a running fashion and complete it on the
left side with an outside approach (Fig. 45-19).
At this point the portal vein reconstruction is per-
formed in normal fashion (see earlier). For reperfusion
we usually begin by opening the portal vein and flushing
air and intravascular high-potassium fluid out of the liver
FIGURE 45-17 through the open end of the distal portion of the donor
cava. The distal end, controlled by two stay sutures, is
clamped when the flush seems adequate.
ensure that the anterior wall of the donor cava is long At this time the recipient cava clamp is opened to
enough to attach to the recipient hepatic veins. If there is establish normal venous return. The distal end of the
any tendency for stretching of the donor hepatic veins in donor cava is oversewn with running 4-0 monofilament
the anastomosis, a Budd-Chiari–type syndrome may suture.
result that is very difficult to correct.
The large anastomosis is sewn with 3-0 or 4-0 monofila-
ment suture. It is easily done by placing the right lobe down HEPATIC ARTERY
into the hepatic fossa and lifting the left lobe up to expose
the two cavas. A stitch at each end of the anastomosis (cra- Successful hepatic artery reconstruction is crucial for
nial, caudal) makes it easy to outline the suture line for graft function, and a variety of methods can be used. In
608 PART V Operation

A B

C D A B
FIGURE 45-20

principle, the type of reconstruction with regard to spe-

cific recipient and donor arteries is secondary to achiev-
ing excellent inflow and outflow at the first anastomosis.
In routine cases a Carrel patch of donor aorta or the celiac
artery is anastomosed end to end to the recipient com-
mon hepatic artery or to a branch patch of the bifurcation
between the gastroduodenal and the hepatic artery proper
(Fig. 45-20, A). The arterial anastomosis is sewn with 6-0
or 7-0 polypropylene, and a one-half-diameter growth
factor is tied in place to provide full expansion of the arte- C D
rial anastomosis without any constriction. If the gastro- FIGURE 45-21
duodenal artery is large, as could occur if it is providing
significant vascular supply or if stenosis of the celiac
artery is present, it is left untouched. The donor celiac Arterial reconstruction varies greatly depending on
artery is then sewn end to side (see Fig. 45-20, B). When the particular circumstances of each patient. Quite fre-
performing end-to-side anastomoses, no growth factor is quently in the case of dual blood supply to the liver from
tied in. Instead, the corner stay suture is tied, the arteries an accessory right hepatic artery and a hepatic artery
are unclamped, and after the anastomosis has settled proper, the accessory right hepatic artery stemming from
down to a comfortable size, the running suture is tied the superior mesenteric artery is dominant. In such cases
carefully so that the anastomosis is not pulled up and con- the donor celiac artery is anastomosed to the recipient
stricted. In donor livers with an accessory right hepatic accessory right hepatic artery. Usually the donor hepatic
artery, the artery is divided, and a Carrel patch is fash- artery lies most comfortably when pulled over in front of
ioned from the superior mesenteric artery (SMA) and the portal vein down to the right side for the anastomosis
then sewn to the donor splenic artery stump with 6-0 (Fig. 45–21, A). When the recipient hepatic artery is
polypropylene (see Fig. 45-20, C). In some cases we will insufficient, the donor celiac artery can be anastomosed
complete the reconstruction of the replaced right hepatic directly to the supraceliac recipient aorta. This approach
artery after reperfusion and sew the replaced right hepatic to the aorta is more commonly performed for pediatric
artery end to end to the donor gastroduodenal artery with transplants than for adult transplants (see Fig. 45-21, B).
interrupted 7-0 monofilament sutures (see Fig. 45-20, D). When there is no acceptable common hepatic artery or
The reason for this sequence in selected cases is to pre- right hepatic artery to which the donor celiac artery can
vent a malrotation of the replaced right hepatic artery be anastomosed, a donor iliac artery conduit is used. This
that can occur if the reconstruction is performed on the procedure is performed by exposing the infrarenal aorta
back table. just above the inferior mesenteric artery. After the aorta
In some patients, despite a perfect technical result, is side-occluded, the iliac arterial conduit is sewn end to
inflow is inadequate because of compression of the celiac side with 5-0 polypropylene. The conduit is then tun-
axis by the arcuate ligament. This complication is dem- neled through the transverse mesocolon and pulled
onstrated by marked respiratory variation and can be behind the stomach in front of the pancreas and up
documented by flow measurement. In this situation the toward the liver hilum, where it is anastomosed end to
celiac artery must be dissected proximal to the aorta and end to the donor celiac artery with 6-0 polypropylene.
the arcuate ligament cut. The illustrations (see Fig. 45-20, When the arterial conduit is sewn to the aorta before
A and B) also show the electrodynamic flow probes it is attached to the donor celiac artery, the conduit is
(Cliniflow II; Carolina Medical Electronics, East Bend, completely mobile and access for completion of the anas-
NC) used to ensure that adequate revascularization has tomosis is made easier (see Fig. 45-21, C). When exten-
been achieved by measuring flow rates at the end of the sive scarring is found around the stomach or the pancreas,
procedure. it is sometimes advantageous to curve the arterial conduit
 45 Recipient Hepatectomy and Grafting 609

lateral to the pancreas after first mobilizing the duode-

num. The attachment to the aorta is the same as for the
shorter conduit, but after the aortal anastomosis is com-
pleted, the arterial conduit is pulled laterally—with care
taken to not traumatize the pancreas—and up toward the
hepatic hilum behind the duodenum (see Fig. 45-21, D).

BILE DUCT
After the gallbladder is removed, the common duct is
shortened proximal to the cystic duct. Usually a lap is
placed superior to the liver to push the liver down to
approximate the donor and recipient ducts better (Fig.
45-22). It is important to prevent redundancy of the bile
duct because redundancy is an important cause of bili-
ary obstruction in the postoperative period. The donor
cystic duct, if allowed to remain to preserve common
duct length, has to empty freely into the remaining
common duct to prevent the development of cytoclesis,
which can compress the duct and cause biliary obstruc-
tion and serious long-term consequences. If the cystic
duct does not empty into the common duct, it has to be FIGURE 45-22
excised. The biliary anastomosis is sewn with inter-
rupted or running 6-0 monofilament absorbable suture,
polydioxanone (PDS; Ethicon, Somerville, NJ), or
polyglyconate (Maxon; Covidien, Mansfield, MA). Over
the past 2 years the UCLA group has been using a run-
ning technique for the biliary anastomosis with success-
ful results. We have not used a T tube since 1997. For
the first year we experienced some leaks; however, our
current biliary complication rate is half of what it was B
previously with T tubes. A great advantage is the disap-
pearance of duct obstruction from sphincter spasm and
leaks when the T tube is pulled. If a T tube is used, it is
brought out of the bile duct with a purse-string suture, A
as shown in Figure 45-22.
If there is any discrepancy in bile duct size (Fig. 45-23,
A) or if both donor and recipient ducts are of normal or
small size, we prefer to side-cut the small one; if equal in
size, we cut both sides (see Fig. 45-23, B). With equally
sized normal or small ducts, the side-cut is performed to C
compensate for the tissue that is effectively lost in the
FIGURE 45-23
suture line and prevent a stricturing effect of the suture
line. If one of the ducts, usually the recipient, is exces-
sively large, which is frequently seen in patients with pre- The jejunostomy is sewn in two layers with polyglactin
vious cholecystectomies, a part of the large duct is closed (Vicryl; Ethicon, Somerville, NJ) and silk, and the distal
with running or interrupted 6-0 polypropylene suture; end of the stapled Roux-en-Y is oversewn with an extra
the duct opening is left large enough to accommodate the layer of silk. In patients with sclerosing cholangitis, the
donor duct, which is then sewn in the usual fashion with Roux-en-Y is always brought retrocolic to permit colec-
interrupted 6-0 polydioxanone suture (see Fig. 45-23, C). tomy in the later stage if necessary. We use biliary drains
In patients with very small donor common ducts or only if there is concern with bleeding or possible bile leak-
with extraordinarily large biliary collateral veins, we pre- age. The choledochojejunostomy is sewn with interrupted
fer to perform a choledochojejunostomy. In patients with 5-0 polydioxanone. We noticed that in a few patients the
a thrombosed portal vein or Budd-Chiari syndrome, the use of 6-0 polydioxanone resulted in early dehiscence by
huge venous collaterals that parallel the bile duct can absorption of the suture. The feeding tube is secured in
cause excessive blood loss and make performance of the the anastomosis by a single chrome-cut stitch into the
choledochocholedochostomy difficult because collateral bowel mucosa wall and through the catheter to prevent it
veins can completely encase the common duct. Using a from coming out before the abdomen is even closed.
stapler, we divide the jejunum approximately 20 to 30 cm After the catheter has been brought out through the
distal to the ligaments of Treitz and then construct a bowel lumen, a tunnel is created by oversewing the serosa
40-cm defunctionalized Roux-en-Y limb (Fig. 45-24). via a Witzel technique for approximately 5 cm to prevent
610 PART V Operation

Abdominal drains, which were once routine, are now

used selectively. The Baylor group has noted fewer prob-
lems with fluid balance and serum albumin and no differ-
ence in wound infections in the absence of drains.
Postoperative ascites is seen no more commonly now
than previously.

SUMMARY
The procedures as explained provide only the initial
guidelines for the recipient hepatectomy and implanta-
tion of the graft. The secret of this operation, as for all
surgery, is to have complete mastery of the anatomy to
avoid wandering into places or structures where one is
not supposed to be. Even the most minute, careless move
can have a devastating impact on the outcome of liver
transplantation. Nothing supplants experience and tech-
nical expertise for the final result. One cannot overem-
phasize the need for precise atraumatic dissection
conducted with dispatch. A ponderous, hesitant tech-
FIGURE 45-24 nique invariably results in greater bleeding and more
complications.

any leakage. The feeding tube is then brought out REFERENCES

through a separate incision in the abdominal wall. The 1. Tzakis A, Todo S, Starzl TE. Orthotopic liver transplantation with
feeding tube is removed after 4 to 6 weeks. We have not preservation of the inferior vena cava. Ann Surg. 1989;210:649–652.
2. Denmark SW, Shaw Jr BW, Starzl TE, et al. Veno-venous bypass
experienced any leaks after having removed the feeding without systemic anticoagulation in canine and human liver trans-
tube from the choledochojejunostomy. By placing the plantation. Surg Forum. 1983;34:380–382.
stent, we have good access and control of the bile duct in 3. Duffy J, Busuttil RW. Vascular Complications of Orthotopic Liver
the postoperative period. An alternative to the external Transplantation: Experience in over 4,200 Patients. J Am Coll Surg.
2009;208(5):896–903.
stent is an internal one created by placement of a small
Silastic catheter, which is allowed to pass spontaneously
into the bowel lumen.
 CHAPTER 46

Anesthesia for Liver

Transplantation
Michael Ramsay

CHAPTER OUTLINE

MARGINAL DONORS Recipient Care

Pharmacokinetics and Pharmacodynamics
THE RECIPIENT
Monitoring
PREOPERATIVE ASSESSMENT
INTRAOPERATIVE ANESTHESIA
Pathophysiology of Liver Disease
Rapid Infusion Devices
Liver Cirrhosis
Thermal Homeostasis
Central Nervous System
Cardiovascular System ANESTHESTIC TECHNIQUES
Pulmonary System THREE PHASES OF ORTHOTOPIC LIVER
Pulmonary Hypertension and TRANSPLANTATION
Hepatopulmonary Syndrome Preanhepatic Phase
Renal Function Anhepatic Phase
Hepatorenal Syndrome Venovenous Bypass
Coagulation Disorders Neohepatic Phase
Metabolic Disorders
Portal Hypertension FLUID MANAGEMENT

FULMINANT HEPATIC FAILURE POSTOPERATIVE CARE

ANESTHESIA CARE PEDIATRIC ASPECTS

Donor Management Living Donor Liver Transplantation

Liver transplantation is a very successful and effective (http://www.unos.org) have produced the specific require-
treatment for many different disorders of the liver. ments for providing anesthesia services for liver transplant
Improved techniques in surgery, anesthetic management, procedures.
donor organ procurement, preservation, immunosup- A director of liver transplant anesthesia must be able
pression, and perioperative care have resulted in many to establish a clear communication channel between the
centers reporting a 1-year survival rate for some recipient transplant anesthesiology service and services from
groups of nearly 90%. Increasing survival rates have led other disciplines that participate in the care of liver
to the performance of a greater number of liver trans- transplant patients. The types of activities to be involved
plants and to broadened indications for transplantation. in include perioperative consultations, participation in
The numbers of transplant centers are expanding as the the candidate selection process, attendance at morbid-
demand increases and the numbers of trainees graduating ity and mortality conferences, and development of
increases. The result of this is that many anesthesiologists intraoperative guidelines based on existing knowledge.
involved in the management of liver transplants may have The director of anesthesiology for liver transplantation
limited experience. The goal of this chapter is to provide must be a designated member of the transplant team
a comprehensive up-to-date manual to serve as a refer- and is responsible for establishing internal policies for
ence resource for anesthesia providers. A further resource participation of the department of anesthesiology in the
for the reader is the International Liver Transplantation perioperative care of liver transplant patients. These
Society Web site (http://www.ilts.org), which maintains a policies are developed in the context of the institutional
current database of the literature, interactive discussions, needs, transplant volume, and quality measures.The
and educational monographs. director must be a diplomat of the American Board of
The American Society of Anesthesiologists (http://www. Anesthesiology (or hold an equivalent foreign certifi-
asahq.org) and the United Network for Organ Sharing cate). Applicants for a directorship who are not board

611
612 PART V Operation

certified must attain this status within 2 years of split liver donor; donation after cardiac death; and cold
approval as director. Clinical responsibilities of the ischemia time. Now other criteria have been added: ICU
director should include but are not limited to the follow- stay with ventilator for more than 7 days, body mass index
ing: preoperative assessment of transplant candidates, greater than 30, steatotic liver greater than 40%, serum
participation in candidate selection, intraoperative man- sodium level above 165 mmol/L, serum glutamic-pyruvic
agement, postoperative management, participation in the transaminase (SGPT) greater than 105 units/L, serum
selection committee, consultation preoperatively with glutamic-oxaloacetic transaminase (SGOT) greater than
subspecialists as needed, and participation in morbidity 90 units/L, and serum bilirubin level greater than
and mortality conferences. 3 mg/dL. The placement of an extended criteria donor
The director of transplant anesthesia must have expe- graft into a high-risk recipient may result in a very chal-
rience demonstrated by one of the following: lenging procedure.
1. Fellowship training in critical care medicine, car-
diac anesthesiology, or pediatric anesthesiology
that includes the perioperative care of at least 10 THE RECIPIENT
liver transplant patients
2. Experience within the last 5 years in the periopera- The major disorders leading to transplantation are end-
tive care of at least 20 liver transplant recipients in stage chronic liver disease, acute fulminant liver failure,
the operating room or intensive care unit (ICU). primary liver malignancy, and certain liver-based meta-
Experience acquired during postgraduate (resi- bolic disorders such as Wilson’s disease and α1-antitrypsin
dency) training does not count for this purpose deficiency. In the latter category the donor liver not only
3. A minimum of 8 hours of Accreditation Council for replaces a damaged organ but also provides a source for
Graduate Medical Education category 1 credits in the missing enzyme or protein. The contraindications for
transplant-related educational activities earned liver transplantation include active extrahepatic infec-
within the most recent 3-year period tions and extrahepatic malignancy. Viral hepatitis, alco-
The director is responsible for maintaining a team of holic liver disease, and neoplasm are the most frequent
well-credentialed anesthesiologists, and a basic template causes for transplantation but remain challenging because
could be as follows: Liver transplant anesthesiologists will the original disease frequently recurs unless adjunct ther-
have undergone a fellowship in transplant anesthesia or apy is provided.6-8
have been involved in the anesthesia care of 12 liver The introduction of the Model for End-Stage Liver
transplant recipients or be proctored in at least 5 liver Disease (MELD) scoring system and Pediatric End-Stage
transplant procedures with sign-off by the director.1 Liver Disease (PELD) scoring system for the pediatric
population has allowed organs to be transplanted based
on medical urgency with a goal of reducing waiting list
MARGINAL DONORS mortality.9 The MELD score is based on three labora-
tory results: serum bilirubin and creatinine concentra-
Lack of suitable donors is the current rate-limiting factor tions together with the international normalized ratio
for performing more liver transplants. This has resulted (INR) (Table 46-1). These laboratory values are predic-
in increasing numbers of marginal donors that are now tive of 3-month mortality. These critically ill patients,
being used, and also many liver grafts are now surgically with multiple-organ dysfunction and severe metabolic
divided to supply two recipients. The impact on the anes- and coagulation disorders, present a significant challenge
thesiologist and the operating room team is that this sur- to the anesthesiologist.
gery is again becoming an emergent procedure that keeps The concept of a team approach to the care of the liver
the cold ischemia time of the donor organ to a minimum. transplantation patient is an important factor in the
This timing causes the surgery to be performed fre- development of a successful program. This approach
quently in the middle of the night, when support teams starts with the preoperative selection and preparation of
may not be readily available. To meet the demand for the patients and includes all facets of the perioperative
organs and to address cultural reasons for the lack of a care. Good communication among surgeon, hepatolo-
deceased donor organ supply, living donor procedures gist, pulmonologist, cardiologist, nephrologist, intensiv-
are increasing. The number of living donors providing ist, anesthesiologist, nursing staff, and patient coordinators
right or left lobes of their livers for adult or pediatric provides the basis for an optimal care team and a success-
patients may complicate the logistics of the procedures ful program.10
because two anesthesia teams need to be available at the
same time. This scenario requires significant preparation
and resources by the perioperative team.2 TABLE 46-1 T
 hree-Month Mortality According
The use of extended criteria or marginal donors has to MELD Score*
lead to criteria being put together to assess the risk of
using these less-than-optimal grafts; one of the first MELD score 9 or less 10-19 20-29 30-39 ≥40
scores to be validated was the Donor Risk Index.3,4,5 The In hospital 4% 27% 76% 83% 100%
Donor Risk Index includes only donor and transplant Outpatient 2% 6% 50%
parameters found to significantly influence outcomes *The MELD score: 10 × (0.957 × loge [creatinine] + loge [bilirubin] +
adversely after liver transplantation. These parameters 1.12 × loge [INR]).
included the donor’s age, race, height, and cause of death; MELD, Model for End-Stage Liver Disease.
 46 Anesthesia for Liver Transplantation 613

PREOPERATIVE ASSESSMENT these livers may be well preserved, whereas in others

severe liver dysfunction may be present.
Anesthesia management of the liver transplant recipient The metabolic function of the liver includes the pro-
may involve taking into consideration a severely debili- cessing of carbohydrates, fats, proteins, and other sub-
tated patient with multiple organ system malfunctions. stances, including drugs. The end pathway for most
There may be alterations in physiological and pharmaco- carbohydrates is the conversion of glucose to produce
logical responses, a severe coagulopathy, encephalopathy, energy in the form of adenosine triphosphate, carbon diox-
cardiomyopathy, respiratory failure, massive abdominal ide, and water. The liver also plays a critical role in protein
ascites and pleural effusions, renal dysfunction, and metabolism, including amino acid deamination and forma-
severely deranged serum electrolyte levels, together with tion of urea and plasma proteins. Combining two mole-
an emergent situation. The patient may have been admit- cules of ammonia with carbon dioxide forms urea, and this
ted from home, having been evaluated months before the can readily pass out of the liver and be excreted by the kid-
time the donor organ becomes available. The clinical sta- neys. Failure of this process will cause an accumulation of
tus may have changed significantly from the time of ini- ammonia in the body and resultant ill effects. The plasma
tial evaluation until admission to hospital for the liver proteins produced by the liver include albumin and many
transplantation. An acute deterioration in the status of of the coagulation factors. The hepatocytes also secrete
the patient may advance the patient on the waiting list or bile salts, cholesterol, and conjugated bilirubin that are
be serious enough to warrant admission to the ICU and excreted into the intestinal lumen and are essential for the
to obtain the next available organ. Consequently, a care- absorption of fats and fat-soluble vitamins A, D, E, and K.
ful preoperative assessment is necessary in the often short
time available before transplantation.
Significant portopulmonary hypertension (see
Liver Cirrhosis
Chapter 39) may have developed in the months spent Cirrhosis is a serious and progressive pathological disease
waiting for the availability of an organ. The patient may that eventually results in hepatic failure. It usually is the
have been admitted in fulminant liver failure and be in result of chronic viral disease or chronic alcoholic disease,
the ICU. The patient may be comatose and require dialy- although now because of the epidemic of morbid obesity,
sis, mechanical ventilation, and intracranial pressure nonalcoholic fatty liver disease is becoming more preva-
(ICP) monitoring. The pathophysiological processes of lent. Hepatocyte necrosis is followed by fibrosis and nod-
end-stage liver disease may affect all major organ systems, ular regeneration. Distortion of the liver’s normal cellular
and therefore the anesthetic management must include and vascular architecture obstructs portal venous flow
measures for the optimal protection of all these organs, as and leads to portal hypertension and impairment of the
well as the liver. Occasionally a patient may present with liver’s synthetic and metabolic functions that results in
a hepatocellular carcinoma and still have good synthetic widespread endothelial dysfunction resulting in multior-
liver function. gan system dysfunction. Most patients will eventually
develop jaundice and ascites. Cirrhosis is generally asso-
Pathophysiology of Liver Disease ciated with four major clinical complications: variceal
hemorrhage from portal hypertension, which may be
A good understanding of the pathophysiology of end- exacerbated by a profound coagulopathy, intractable fluid
stage liver disease is required to be able to develop an retention in the form of ascites, and pleural effusions, and
optimal care plan for the patient undergoing transplanta- all this compounded by the hepatorenal syndrome (HRS),
tion (Table 46-2). The pathological condition of the liver cirrhotic cardiomyopathy, and hepatic encephalopathy.
will depend on the diagnosis and indication for liver The severity of liver dysfunction is the focus of two clas-
transplantation. Genetic causes may affect more than just sification systems: the Child-Turcotte-Pugh (CTP) sys-
one major organ; an example is amyloidosis, with which tem, which most non–liver transplant anesthesiologists
significant cardiac amyloidosis may also occur. Hepato- will be familiar with, and the MELD score, which is used
cellular cancers may develop especially in the presence of for the allocation of liver organs. The CTP score relies on
chronic viral hepatitis. The synthetic function of some of ascites, encephalopathy, prothrombin time, serum albu-
min and total bilirubin levels, and the INR (Table 46-3).
The 3-month mortality for a patient with a CTP score
TABLE 46-2 Etiology of Liver Problems of 5 to 6 points is 4%; 7 to 9 points, 14%; and 10 to 15
points, 51%.
• Chronic viral hepatitis: B and C
• Hepatocellular cancer The MELD score is a more precise calculation that is
• Alcohol based on serum creatinine and bilirubin levels and the
• Nonalcoholic fatty liver disease INR (see Table 46-1). Both scores assess the patient’s risk
• Autoimmune: autoimmune hepatitis, primary biliary for death.
cirrhosis, primary sclerosing cholangitis
• Hemochromatosis
• Drugs (methotrexate, amiodarone, acetaminophen)
• Cystic fibrosis, α1-antitryptin deficiency, Wilson's disease
Central Nervous System
• Vascular problems (portal hypertension with or without Cirrhosis of the liver is associated with varying degrees of
liver disease) encephalopathy. It may be characterized by changes in
• Cryptogenic
• Others: sarcoidosis, amyloidosis, schistosomiasis mental status and fluctuating neurological signs—asterixis
and hyperreflexia. Mild encephalopathy has been found
614 PART V Operation

in up to 84% of patients with chronic liver failure.11 The drugs such as diazepam; therefore this group of agents
encephalopathy appears to be related to both the amount should be avoided in patients with encephalopathy because
of hepatocellular damage and the degree of shunting of hepatic coma may be precipitated.15 The reversal agent
portal blood away from the liver. This allows the accumu- flumazenil may improve the mental status of the hepatic
lation of toxins such as ammonia, mercaptans, short-chain encephalopathy patient.16,17 The liver performs a critical
fatty acids, and phenol, causing deleterious effects on the role in protein metabolism: the deamination of amino
brain. Spectral electroencephalogram (EEG) analysis acids, and the formation of urea, by combining two mole-
provides reliable quantitative information in the evalua- cules of ammonia with carbon dioxide. The kidneys may
tion of subclinical encephalopathy.12 The intraoperative then excrete the urea produced. The failure of the liver to
use of a brain function monitor that displays a multichan- convert ammonia to urea results in the accumulation of
nel EEG can guide the management of anesthesia in this ammonia, which exacerbates the encephalopathy. The
set of patients, who may be very sensitive to anesthetic liver is also responsible for the formation of plasma pro-
agents and changes in cerebral hemodynamics. The basic teins with the exception of immunoglobulins. This
patterns of the EEG—awake, sedated, surgical anesthesia, includes not only the coagulation factors but also albumin,
burst suppression, and isoelectricity—are easily recog- which is responsible for maintaining a normal plasma
nized by the practitioner and aid in managing the patient’s oncotic pressure and also the transport of a number of
hemodynamics and anesthesia delivery (Fig. 46-1).13 drugs. Therefore a reduction in serum albumin level will
The pathogenesis of hepatic encephalopathy has been allow edema formation and also an increase in the unbound
associated with increased γ-aminobutyric acid (GABA) fraction of many drugs.
neurotransmitter in the brain.14 This excess GABA neu- The patient in fulminant hepatic failure may develop
rotransmitter effect may be potentiated by benzodiazepine deep coma, severe brain edema, and a marked increase in
ICP. The anesthetic management of the comatose patient
with raised ICP is greatly facilitated by the presence of an
TABLE 46-3 The Child-Turcotte-Pugh Score ICP monitor. However, because of the risk for bleeding in
this patient population, many neurosurgeons defer place-
Score ment of the monitor. An aggressive correction of the
coagulopathy is required before the placement of a moni-
1 2 3
toring device. The administration of fresh frozen plasma
Prothrombin time (sec) 1-4 5-6 >6 may be all that is needed, but when this is inadequate,
prolonged recombinant activated factor VII will temporarily correct
Encephalopathy 0 1-2 3-4 the coagulopathy of liver failure and allow the placement
Ascites Slight Moderate Severe of an ICP monitor.18 As the encephalopathy becomes
Bilirubin (mg/dL) <2 2-3 >3 worse and the patient becomes slowly obtunded, early
Albumin (g/dL) >3.5 2.8-3.5 <2.8 intervention to maintain and secure the airway and oxy-
International normalized <1.7 1.8-2.3 >2.3 genation is indicated. Cerebral edema is best monitored
ratio
and controlled by the direct measurement of ICP. Intra-
The 3-month mortality for a patient with a Child-Turcotte-Pugh Score operative periods of increased risk are when hemody-
of 5-6 points is 4%; 7-9 points, 14%; and 10-15 points, 51%. namic instability occurs and at the time of the new graft

Raw EEG patterns:

Awake

Sedated

Surgical
anesthesia

Burst
suppression

Isoelectricity
1 second

FIGURE 46-1 n Electroencephalographic (EEG) patterns at different stages of anesthesia. (From Kertai MD, Whitlock EL, Avidan MS. Brain
monitoring with electroencephalography and the electroencephalogram-derived bispectral index during cardiac surgery. Anesth Analg.
2012;114:533-546.)
 46 Anesthesia for Liver Transplantation 615

reperfusion. Very small changes in hemodynamics may the brain include controlled hypothermia to 34° C and the
cause major changes in cerebral perfusion pressure. The use of osmotic diuretics and barbiturate or propofol coma.
aim of anesthetic management is to keep the ICP less than
20 mm Hg, the cerebral perfusion pressure more than
50 mm Hg, and the mean arterial pressure more than
Cardiovascular System
60 mm Hg. At reperfusion of the new liver graft, a signifi- The cardiovascular system should be carefully evaluated.
cant infusion of acid and inflammatory, vasodilating cyto- It has been recognized for more than 50 years that a high
kines may enter the circulation, together with an increase cardiac output state with extremely low systemic vascular
in cardiac output, resulting in an acute elevation in ICP. resistance (SVR) typically is present with liver cirrhosis.20
The infusion of a bolus of sodium pentothal or propofol at This state can make the assessment of ventricular func-
this time, guided by the ICP, may counter this effect.19 tion difficult to interpret accurately. A reduced afterload
Mild hyperventilation may be helpful by causing hypo- can allow a ventricle that is functioning poorly to appear
capnia, resulting in cerebral vasoconstriction; however, to be functioning well. This is important to know because
this technique is controversial. Maintaining cerebral per- severe cardiomyopathy is frequently associated with liver
fusion pressure is critical at this time, and an ICP trans- cirrhosis.21 Cardiomyopathy has been reported to exist to
ducer together with intra-arterial pressure and central some degree in all patients with liver cirrhosis.22 Cardio-
venous pressure monitoring are vey useful management myopathy may result in impaired contractility, especially
tools. The use of cerebral function monitors that display under stress conditions, and altered diastolic relaxation. It
the cortical electrical activity of the brain may be helpful also presents as a blunted responsiveness to β-adrenergic
adjuncts in management. The prevention of volume over- receptor agonists because of diminished β-receptor func-
load and the increase in central venous pressure can be tion that may be exacerbated by the chronic use of
facilitated by the early introduction of continuous venove- β-receptor blocking agents (Fig. 46-2). The cardiomy-
nous hemodialysis. Other measures that can help protect opathy may be further compromised in the alcoholic


Noradrenaline K K
5-Hydroxytryptamine K K -Adrenergic MUSCARINIC MUSCARINIC
Neuropeptide Y K Receptor Receptor M1 Receptor M2, M3
Angiotensin II
K channel
Endothelin-1

Impaired Adenylyl
coupling cyclase
Reduced
content in K K
 Gs
membrane K K Impaired Phospholipase-C
phospholipids signaling

cAMP

Sarcoplasmic Reticulum

RyR2 Ca2-ATPase

2 Myosin-action
Ca2 Ca cross bridge
Ca2Ca2
Gap junction

Gap junction

FIGURE 46-2 n Downregulation of the β-receptor in cirrhosis. ATPase, Adenosine triphosphatase; cAMP, cyclic adenosine monophos-
phate; Gs, G proteins; RyR2, ryanodine receptor Ca2+ release channels. (From Zardi EM, Abbate A, Zardi DM, et al. Cirrhotic cardiomyopa-
thy. J Am Coll Cardiol. 2010;56:539-549.)
616 PART V Operation

Reduced cardiac Compensatory CARDIAC

function phase FAILURE

CO CO

Hyperdynamic state Hypotension

Cardiac failure sign and
Clinical findings Hyperdynamic state Palpitations
symptoms
Tachycardia Pulmonary edema
Bundle branch block
Multiple extrasystoles ST-segment depression
ECG abnormalities QT prolongation
QT prolongation Electrical and mechanical
dyssynergy
Prolonged isovolumetric - Enlarged left atrium
relaxation time (>80 msec)
Echocardiographic Prolonged isovolumetric - Decreased wall motion
Decreased pattern
findings relaxation time
of contractility - Increased wall thickness
Diastolic dysfunction Systolic dysfunction

FIGURE 46-3 n The progression of cirrhotic cardiomyopathy. CO, Cardiac output; ECG, electrocardiographic. (From Zardi EM, Abbate A,
Zardi DM, et al. Cirrhotic cardiomyopathy. J Am Coll Cardiol. 2010;56:539-549.)

patient by the presence of an alcoholic cardiomyopathy.22 of diastolic dysfunction and normalization of the cardiac
The performance of a transjugular intrahepatic portosys- response to stress.
temic shunt stent placement will result in a sudden Because the upper age limit for liver transplantation
increase in cardiac output and may precipitate cardiac is being extended in most centers and is now based on
failure in the cardiomyopathic patient. Similarly, because physiological age as opposed to chronological age, care-
this is a high–cardiac output cardiomyopathy, reperfusion ful screening for coronary artery disease (CAD) is nec-
of the liver graft at the time of transplantation, which essary because the prevalence of this disease increases
usually results in a further acute increase in cardiac out- with age.25 In the past it was thought that there was
put, may precipitate ventricular dysfunction, both right reduced CAD in cirrhotic patients.26-28 However,
and left, causing graft dysfunction.23 recent data demonstrate a significant incidence of severe
Cirrhotic cardiomyopathy is characterized by an CAD in up to 16% of liver transplant candidates older
increased cardiac output, attenuated response to inotro- than 50 years.29 The presence of CAD in patients
pic stimuli, mild chamber dilatation, and repolarization undergoing liver transplantation is greater than in the
changes. The examination by echocardiography may general population and has been reported to increase
initially be interpreted as normal cardiac function the mortality rate to 50% and the morbidity rate to
because of the significant reduction in afterload caused 81%.30,31 Therefore there should be close screening of
by the low systemic vascular resistance. However, on at-risk liver transplant candidates for CAD and a low
closer examination both systolic and diastolic dysfunc- threshold for performing a dobutamine stress echocar-
tion may be demonstrated. The diagnostic features are diogram.32-34 If ischemia is producible, a coronary arte-
an early to late diastolic filling ratio (E/A ratio) of less riogram should be obtained. If the coronary arterial
than 1, a prolonged deceleration time above 200 msec, a obstructive lesions can be dilated and a bare-metal stent
prolonged isovolumetric relaxation time of more than placed, liver transplantation may be an acceptable-risk
80 msec, enlarged left atrium, overall decreased pattern procedure.
of contractility, decreased wall motion, increased wall Occasionally angioplasty is not a viable option, and the
thickness, resting ejection fraction below 50%, left ven- decision must be made as to whether coronary artery
tricular ejection time that is prolonged greater than 0.44 bypass grafting or liver transplantation should be per-
seconds (rate corrected) (Fig. 46-3).24 If cardiomyopathy formed first or if they should be performed together.35
is suspected, a dobutamine stress echocardiogram may Cardiac surgery in the patient with severe liver dysfunc-
be performed to assess ventricular function. Any patient tion may result in an exacerbation of the preexisting
who presents for liver transplantation and is found to coagulopathy and potentially a decrease in liver blood
have a low cardiac index and elevated filling pressures flow, precipitating fulminant liver failure. Conversely,
must be closely examined for the presence of a cardio- the unavoidable major hemodynamic changes that may
myopathy. However, the most common cause of a low occur during liver transplantation make this option very
cardiac index in the immediate preoperative period is hazardous if it is undertaken first. This therapeutic
hypovolemia. The cirrhotic cardiomyopathy does dilemma requires close consultation among the cardiolo-
improve after liver transplantation with disappearance gist, anesthesiologist, and surgeon. The role of coronary
 46 Anesthesia for Liver Transplantation 617

Normal hemodynamics. Pulmonary

artery pressure, cardiac output, PVR,
and PCWP are normal.
A
PAH. Elevated pulmonary artery
pressure caused by increased PVR
with normal cardiac output and PCWP.
B
High-flow condition. Elevated
pulmonary artery pressure caused by
increased cardiac output but normal
C PVR and PCWP.

Pulmonary venous hypertension.

Elevated pulmonary artery pressure
caused by increased PCWP, normal
cardiac output and PVR.
D
FIGURE 46-4 n Pathophysiology of portopulmonary hypertension. PAH, Pulmonary artery hypertension; PCWP, pulmonary capillary
wedge pressure; PVR, pulmonary vascular resistance. (From Safdar Z, Bartolome S, Sussman N. Portopulmonary hypertension: an update.
Liver Transpl. 2012;18:881-891.)

artery bypass surgery is a risk-benefit decision that will Pulmonary System

depend on the severity of the liver disease. The at-risk
patient should receive a dobutamine stress echocardio- Ventilation may be restricted by massive abdominal asci-
gram so that CAD, ventricular function, and valvular tes compressing the diaphragm and by large bilateral
function can be assessed and to determine if the pulmo- pleural effusions. The mortality of patients with end-
nary artery pressures are normal or elevated. Plotkin stage liver disease who develop adult respiratory distress
et al36 demonstrated that the dobutamine stress echocar- syndrome is reported to be 100% unless transplantation
diogram had a sensitivity of 100%, a specificity of 90%, a is performed.39 Circulating endotoxins, the result of the
positive predictive value of 100%, and a negative predic- liver disease, may initiate an inflammatory cascade, caus-
tive value of 100% when evaluating liver transplant can- ing a panendothelial injury that causes multiorgan dys-
didates with cardiac risk factors. These data support the function. Cirrhotic patients present with diffuse bilateral
use of the dobutamine stress echocardiogram as a screen- pulmonary infiltrates and poor pulmonary compliance.
ing tool for CAD in those liver transplant patients when This clinical picture of adult respiratory distress syn-
indicated by the guidelines of the American College of drome is thought to be the result of a sepsis syndrome
Cardiology and the American Heart Association.37 The and not active sepsis, which could be a contraindication
data supporting the administration of perioperative to transplantation. Successful resolution of adult respira-
β-blockers to patients undergoing surgery with a risk for tory distress syndrome has followed orthotopic liver
coronary ischemia is compelling and should be applied to transplantation.40
liver transplant recipients who meet the criteria.38 Many
liver recipients are already taking β-blockers as treatment Pulmonary Hypertension and
for portal hypertension. The combination of a cirrhotic
cardiomyopathy and the administration of β-blockers can
Hepatopulmonary Syndrome
make catecholamine responses very blunted during liver These pathological entities are discussed in detail in
transplantation. Chapter 39. The key to understanding the clinical signifi-
The monitoring of the cardiovascular system should cance of high pulmonary artery pressure is to determine
include intra-arterial and central venous pressure sensors. if it is the result of increased vascular resistance, cardiac
The role of the pulmonary artery catheter is controver- failure, volume overload, or high cardiac output (Fig.
sial, but it can detect previously undiagnosed pulmonary 46-4).41 The management then follows protocols.
hypertension and cardiomyopathy and may be used to
guide the administration of vasopressors and volume in Renal Function
the face of hypotension. The differentiation among hypo-
volemia, low SVR, and poor ventricular function can be An adequate volume of urine production is critical to the
critical. The transesophageal echocardiogram (TEE) intraoperative management of the liver transplant patient.
offers a comprehensive assessment of volume status, Volume overload, if allowed to occur, results in conges-
together with left and right ventricular function. In tion and eventual failure of the new liver graft. Good
patients with pulmonary hypertension who are undergo- urine output enables proper management of volume
ing liver transplantation, the TEE can provide essential changes associated with the correction of coagulopathy.
information on right ventricular function. On the rare Satisfactory renal function assists in maintaining electro-
occasion when pulmonary emboli occur, the TEE can be lyte and acid-base homeostasis. Acute elevations in serum
critical in early diagnosis and management. potassium levels may occur from the rapid transfusion of
618 PART V Operation

units of old red blood cells and from the reperfusion of increased antidiuretic hormone activity, leading to
the new liver graft. The role of monitors of cardiac out- sodium and water retention that is often accompanied by
put and volume state can be essential for optimizing renal a decreased effective plasma volume. Water retention is
perfusion and preventing congestion of the new liver greater than sodium retention, resulting in hyponatre-
graft. The TEE can provide good information on the mia.42 Secondary aldosteronism also occurs, making
cardiac chamber sizes and supplement information pro- hypokalemia and total body potassium depletion com-
vided by the pulmonary artery catheter. mon. Serum creatinine level is a significant component of
Patients with liver cirrhosis frequently have renal dys- the MELD score, which determines the position of the
function because of prerenal azotemia or intrinsic renal recipient on the waiting list for an organ; therefore many
disease. Prerenal azotemia may be the result of chronic recipients will have impaired renal function. Those
hypovolemia caused by long-term diuretic use and may patients with reversible disease such as HRS should
be treated by volume expansion. Liver disease is also asso- recover renal function after transplantation, but those
ciated with increased renin-angiotensin activity and patients who have severe renal damage may require a
renal transplant at the same time as the liver transplant.
Acute renal dysfunction occurs in up to 78% of liver
transplant recipients intraoperatively.43 Perioperative
TABLE 46-4 C
 auses of Perioperative Acute
acute kidney injury may be the result of prerenal, intrinsic
Kidney Injury
renal, postrenal, and exogenous factors (Table 46-4 and
Prerenal Absolute or relative renal hypoperfusion; Fig. 46-5).44
hepatorenal syndrome
Intrinsic renal Glomerular, tubular, vascular, or interstitial
damage: ischemia, hypoxia, ischemia/
Hepatorenal Syndrome
reperfusion injury, inflammation, and Renal dysfunction may also present as HRS, in which
hypotension
there is no parenchymal damage, but there is profound
Postrenal Abdominal compartment syndrome,
obstruction of ureters or bladder hypoperfusion of the kidney caused by vasoconstriction
Exogenous Drug induced: calcineurin inhibitors in the setting of systemic and splanchnic arterial vasodila-
tation in patients with advanced cirrhosis.45-47 HRS

Ischemic insult Systemic inflammation Sepsis

• Lipopolysaccharide/endotoxin

Hemodynamic injury Prerenal Toxic injury

• Decreased filtration pressure • Hypoxic injury • Bacterial toxins

perfusion pressure • Oxidative stress • Cytokine-induced injury
renal vascular resistance • Endothelial dysfunction • Efferent arteriolar
• Ischemia-reperfusion • Nitric oxide vasodilation
• RAAS activation • TGF activation
• Necrosis • Microcirculatory dysfunction
• Microthrombosis • Apoptosis
• Backleak • Endothelial injury
• Tubular casts • White-cell adhesion
• Tubular obstruction
• Loss of polarity
• Edema

Renal cell injury

Necrosis
Apoptosis
ry
Sublethal inju

Renal cell regeneration

FIGURE 46-5 n Pathogenesis of acute kidney injury as a result of ischemia. RAAS, Renin-angiotensin-aldosterone system; TGF, tubulo-
glomerular feedback. (From Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Lancet. 2012;380:756-766.)
 46 Anesthesia for Liver Transplantation 619

diagnosis is based on the absence of primary renal disease, and retransfusing it back to the patient. In this manner,
proteinuria, hypovolemia, and renal hypoperfusion. It is volume and potassium can be removed, and the patient
characterized by normal urinary sediment, low urinary undergoes hemoconcentration.
sodium level (<10 mEq/L), azotemia, and oliguria. It is Indications for instituting continuous venovenous
important that hypovolemia be ruled out (Table 46-5). hemodialysis during liver transplantation include anuria
HRS is reversible with liver transplantation but may or severe oliguria, hyperkalemia, hyponatremia, severe
progress to acute tubular necrosis that is not reversible metabolic acidosis, volume overload with poor response
and could be treated by a combined liver-kidney trans- to diuresis, and abdominal compartment syndrome.44
plant. Increased sympathetic tone in the renal vasculature Acute kidney injury during liver transplantation contrib-
plays an important role in the development of this syn- utes significantly to the incidence of postoperative renal
drome. Adequate volume replacement is essential in these failure.53 Even mild kidney injury, defined as a rise in
patients.48 serum creatinine level above 0.5 mg/dL, is associated
Endogenous production of creatinine is reduced with with reduced patient and graft survival.43 Therefore mea-
end-stage liver disease, and therefore serum creatinine sures to maintain renal perfusion and protect the kidney
level may not reflect the severity of the renal dysfunction. during liver transplantation are essential. Should venove-
The patient’s prerenal status must be closely assessed, nous bypass be used intraoperatively to decompress the
because reduced plasma volume may exist from chronic venous system and maintain cardiac output during the
use of diuretics. Aggressive rehydration may be necessary anhepatic phase? The published data do not support
to provide and maintain an effective intravascular volume using or not using bypass.54,55 Maintaining renal perfu-
and prevent renal hypoperfusion. Perioperative oliguria sion is essential and may be very challenging when faced
should be treated initially as prerenal in origin and a fluid with massive blood loss and the reperfusion syndrome.56,57
challenge administered. Using an albumin volume expan- Vasopressors that have shown some improvement in
sion and a renal dose infusion of dopamine, together with renal perfusion and blood pressure during liver trans-
a mannitol infusion, may optimize urine output in the plantation include norepinephrine, vasopressin, and
patient with HRS. A dopamine infusion, however, is not methylene blue (Fig. 46-6).58-60 Methylene blue may
protective of the kidney in this clinical situation.49 The cause severe serotonin toxicity if administered to patients
role of an infusion of fenoldopam, a dopamine-1 recep- receiving serotonin reuptake inhibitors.61
tor agonist, shows great promise not only in renal pro-
tection but also by improving mesenteric perfusion and
new liver graft vascular perfusion.50 A completely differ-
Coagulation Disorders
ent approach that is also being examined is the role of The patient with liver disease may develop major coagu-
splanchnic vasoconstriction in improving HRS. Vaso- lation abnormalities primarily as a result of depressed
pressin analogues terlipressin and ornipressin are under- synthetic function. Frequently splenomegaly, nutritional
going clinical trial.51,52 deficiencies, and variceal bleeding coexist and result in an
If the patient is unresponsive to therapy, early institu- associated thrombocytopenia and anemia. The liver is
tion of intraoperative continuous venovenous hemodi- responsible not only for producing many coagulation
alysis should be considered. It can easily be accomplished factors—I, II, V, VII, VIII, IX, X, XI, XII, and XIII—but
in the operating room and greatly facilitates fluid and also for synthesizing coagulation inhibitors, fibrinolytic
electrolyte management. If it is not available, all units of proteins, and their inhibitors. It also clears all activated
banked blood should be washed before infusion to coagulation and fibrinolytic enzymes.
reduce the potassium load. The cell-saver blood salvage The liver functions as an important modulator of the
system can be used to do this directly in the operating coagulation balance, preventing hypercoagulation or
room. The cell-saver system can also be used to “hemo- hypocoagulation and modulating fibrinolysis. An altera-
dialyze” the patient by drawing off blood through a tion in this fine-tuning by the presence of liver disease
large-bore central catheter, washing it in the cell saver, can result in a coagulopathy caused by hypocoagulation,
excessive fibrinolysis, or a hypercoagulable state, result-
ing in thrombosis or disseminated intravascular coagula-
TABLE 46-5 International Ascites Club tion (DIC).62 Metabolic and pharmacological events may
Proposed Diagnostic Criteria for also affect the clotting mechanism. Citrate toxicity from
Hepatorenal Syndrome transfusion of blood and blood products may cause a pro-
found reduction in ionized calcium levels. Heparin, both
1 Cirrhosis with ascites endogenous and exogenous, may not be cleared, which
2 Serum creatinine >1.5 mg/dL may result in decreased coagulation. Normothermia is
3 No improvement in serum creatinine after 2 days of essential in maintaining the integrity of the coagulation
volume expansion with albumin system. Table 46-6 lists the types of factors synthesized.
4 Absence of shock The severity of the coagulopathy is related to the
5 No recent treatment with nephrotoxic drugs extent of the liver disease; therefore prolongation of the
6 Absence of parenchymal kidney disease as indicated prothrombin time is a guide to the state of liver function.
by proteinuria >500 mg/day When the disease is more severe, dysfibrinogenemia
From Salerno F, Gerbes A, Gines P, et al. Diagnosis, prevention and
develops and the fibrinolytic system is activated.62 Acti-
treatment of hepatorenal syndrome in cirrhosis. Gut. 2007;56: vated proteins such as tissue plasminogen activator are
1310-1318. not cleared easily by the diseased liver63 (Table 46-7).
620 PART V Operation

A B C
Patient #1 Patient #2 Patient #3
3.0 6 8
Phenylephrine (mic/kg/min)
2.5 6 Epinephrine (mic/kg/min)
2.0 Vasopressin (U/hr)
Vasopressor dose

4 Dopamine (mic/kg/min)
1.5 Epinephrine (mic/kg/min)
1.0 4
Norepinephrine (mic/kg/min) 2
0.5
0.5 Dobutamine (mic/kg/min) 0.15
0.4 2
0.3 0.10
0.2 0.05
0.1
0.0 0 0.00
0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100

150 150 150

Blood pressure (mm Hg)

100 100 100

50 50 50
SBP SBP SBP
DBP DBP DBP
0 0 0
0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100
Minutes Minutes Minutes

MB MB MB
FIGURE 46-6 n Hemodynamic effects of methylene blue. DBP, diastolic blood pressure; MB, methylene blue 100-mg intravenous bolus;
SBP, systolic blood pressure. (From Cheng SS, Berman GW, Merritt GR, et al. The response to methylene blue in patients with severe
hypotension during liver transplantation J Clin Anesth. 2012;24:324-328.)

This hyperfibrinolytic state can be monitored in the labo-

TABLE 46-6 Liver Coagulation Factor Synthesis ratory by elevated fibrin split products, D-dimers, and
Procoagulant factors II, VII, IX, X, V, VIII, XI, fibrinogen
reduced euglobulin-lysis time. The thromboelastogram
(TEG) and rotational thromboelastography (ROTEM)
Anticoagulant factors Antithrombin, protein C, protein S reveal the typical spindle trace of fibrinolysis.
Fibrinolytic factors Plasminogen, plasminogen The differentiation between fibrinolysis and DIC by
activator inhibitor-1
laboratory tests is difficult because of an overlap in the
Others Thrombopoietin, protein Z
results. TEG and ROTEM are essential monitoring tools
in liver transplantation management because they pro-
vide a visual display of the dynamic function of clot for-
mation and deformation so that differentiation between
TABLE 46-7 Hemostatic Changes in Cirrhosis
fibrinolysis and DIC can be made. Thrombocytopenia
Changes Impairing Changes Promoting frequently occurs as a result of splenomegaly and a reduc-
Hemostasis Hemostasis tion in thrombopoietin, folic acid deficiency, and exces-
Low platelet count Increased levels of factor VIII
sive platelet consumption, especially if DIC is present.
Impaired platelet function and von Willebrand factor In programs where the transfusion of blood or blood
Decreased levels of factors Decreased levels of products is routine, the prophylactic administration of
II, V, VII, IX, X, XI protein C, protein S, antifibrinolytic therapy may be cost effective, but the risk
Quantitative and qualitative protein Z, antithrombin, for thrombosis exists if a hypercoagulable state exists or
abnormalities in alpha-macroglobulin, DIC is present. The differentiation between severe fibri-
fibrinogen heparin cofactor II
nolysis and DIC is not easy, and case reports exist of mas-
Decreased levels of Decreased levels of
α2-antiplasmin and TAFI plasminogen sive thrombosis and thromboembolism—venous, arterial,
Increased levels of plasma and intracardiac—associated with the use of aprotinin
t-PA not balanced by during liver transplantation.64,65 The state of coagulation
PAI-1 should be monitored both by laboratory testing and by
intraoperative viscoelastic tests, which include TEG and
PAI-1, Plasminogen activator inhibitor-1; TAFI, thrombin-activated
fibrinolysis inhibitor; t-PA, tissue plasminogen activator.
ROTEM. These instruments allow the state of coagula-
tion in whole blood to be monitored and can provide
early indication of the presence and severity of fibrinoly-
sis.66 In this manner antifibrinolytic agents can be accu-
rately administered.
 46 Anesthesia for Liver Transplantation 621

200/450 = 0.44 210/300 = 0.70 increase glucose levels. Close control of blood glucose
700 levels perioperatively may improve outcomes.68
600 Hyponatremia is not infrequently seen in patients with
end-stage liver disease. The cause may be multifactorial—
ETP (FUXmin)
500
450 for example, the result of aggressive diuretic therapy,
400
especially the administration of spironolactone, together
300 300 with the inability of the kidney to excrete free water. Mild
200 200 210 hyponatremia (serum Na+ >125 mEq/L) may be well tol-
100
erated, but lower levels of sodium may be associated with
cerebral edema and central pontine myelinosis, particu-
0 larly if the serum Na+ is allowed to increase rapidly during
No TM TM No TM TM the perioperative period. The management of hyperkale-
Controls Cirrhotics mia can become a significant problem during liver trans-
FIGURE 46-7 n Normal thrombin generation in patients with cir- plantation. Patients may present with high serum K+
rhosis when measured with the addition of thrombomodulin levels as a result of renal insufficiency, the use of potas-
(TM). ETP, Endogenous thrombin potential. sium-sparing diuretics, and the presence of metabolic aci-
dosis. The administration or blood and blood products
Normal thrombin generation may occur in patients that contain significant concentrations of potassium, espe-
with severe cirrhosis (Fig. 46-7).67 Therefore the treat- cially the more aged units, may compound hyperkalemia
ment of coagulation defects should be based on sound intraoperatively. At the time of new graft reperfusion a
information and a review of the surgical field. The only significant influx of potassium into the circulation may
therapies that need to take place in the absence of signifi- occur and can be sufficiently severe to cause a cardiac
cant bleeding are the correction of a reduced ionized cal- standstill. Control of hyperkalemia includes the mainte-
cium level by the administration of calcium chloride, the nance of good diuresis and the judicious use of calcium
use of antifibrinolytic agents if lysis is detected, and prot- chloride, sodium bicarbonate, and insulin/glucose ther-
amine administration to reverse the presence of heparin. apy. If these measures are inadequate, the institution of
Maintenance of body temperature is also necessary for continuous venovenous hemodialysis should be consid-
effective coagulation. The reduction of other clotting ered. Preoperative plans must be made to handle potential
factors causing a prolonged prothrombin time or partial fluid overload and hyperkalemic situations in patients
thromboplastin time, hypofibrinogenemia, or thrombo- with impaired kidney function.
cytopenia need not be treated if surgical bleeding is not a
problem. These parameters slowly become corrected as Portal Hypertension
the new graft develops optimal function and splenic
hypertension is relieved. The use of blood products to Portal hypertension may be severe in cirrhotic patients,
treat on the basis of laboratory data without good clinical and this severity may be ameliorated before transplanta-
judgment is not justified. tion by surgical placement of a portosystemic shunt or by
the interventional radiologist in the percutaneous place-
ment of a transjugular intrahepatic portosystemic shunt.69
Metabolic Disorders This latter procedure may be performed with the patient
Derangements in acid-base homeostasis and electrolyte given general anesthesia or monitored anesthesia care.
balances are common in the patient presenting for liver Adequate monitoring and timely access to laboratory and
transplantation. Respiratory acidosis may be the result of blood bank services are essential and must be available in
an altered level of consciousness caused by encephalopa- the radiology department. Creation of a portosystemic
thy or cerebral edema and should be managed by early shunt may precipitate hepatic encephalopathy. Esopha-
intervention with endotracheal intubation and mechani- geal varices are common and may present an increased
cal ventilation to prevent further brain swelling and pro- risk for bleeding with the placement of a nasogastric tube
tect the airway. Metabolic acidosis may be seen when or a transesophageal echocardiograph probe.
there is renal dysfunction or hypotension. It is usually
caused by lactic acid accumulation. Therapy with sodium
bicarbonate may be individualized, depending on current FULMINANT HEPATIC FAILURE
hemodynamics, presence of hyperkalemia, and serum
sodium levels. The presence of a well-functioning graft Fulminant liver failure results from severe hepatocellular
following liver transplantation will result in metabolism injury and necrosis. It occurs in 3% to 6% of patients
of lactic acid and correction of the acidosis, as well as with severe liver disease. Hepatic encephalopathy devel-
development of a metabolic alkalosis if there has been ops early, together with deep jaundice. Laboratory find-
aggressive bicarbonate treatment. ings include hyperbilirubinemia, marked elevation of the
Glucose-insulin metabolism becomes deranged in serum aminotransferase concentration, hypoglycemia,
severe liver disease, and hypoglycemia may be seen in the hyperammonemia, and hypoalbuminemia. Severe coagu-
severely ill patient before transplantation. Blood glucose lopathy develops because there is impaired liver synthesis
levels tend to increase during liver transplantation, of coagulation factors; a prolongation of the prothrombin
because glucose is provided with units of banked blood, time is a sensitive index of hepatocyte dysfunction.
and glycogenolysis in the new graft can significantly Depressed liver gluconeogenesis results in increased
622 PART V Operation

anaerobic metabolism and generation of lactic acid, cre- epoprostenol as a microcirculatory vasodilator.75 Vaso-
ating a severe metabolic lactic acidosis. A variceal hemor- pressin and terlipressin have been shown to reduce mor-
rhage into the gastrointestinal tract causes increases in tality related to variceal bleeding.76 However, they may
serum ammonia levels because the liver is unable to be associated with cerebral hyperemia in patients with
incorporate ammonia into urea, and this worsens the severe encephalopathy.77
encephalopathy. The clinical manifestations of fulminant hepatic fail-
Because some patients in fulminant liver failure ure are profound jaundice, encephalopathy, cerebral
recover, guidelines for the selection of patients for ortho- edema, coagulopathy, and multiple organ system failure.
topic liver transplantation were developed so that trans- The cerebral edema becomes irreversible if treatment
plantation can occur before grade IV coma sets in.70,71 cannot control an ICP of more than 25 mm Hg or a cere-
Criteria for going ahead with orthotopic liver transplan- bral perfusion pressure of less than 50 mm Hg. Periop-
tation include any three of the following variables: erative goals are to maintain cerebral circulation, systemic
younger than 10 years or older than 40 years, non-A, hemodynamics, acid-base balance, and metabolic/elec-
non-B hepatitis, halothane hepatitis, idiosyncratic drug trolyte homeostasis. Introducing bioartificial liver sup-
reaction, jaundice for at least 7 days before the onset of port systems and the use of xenografts as a bridge to
encephalopathy, prothrombin time greater than 50 sec- transplantation have improved survivability in some
onds, and serum bilirubin level greater than 300 mmol/L. cases.
Arterial ketone body ratio is a predictor of prognosis in
fulminant liver failure.72
Most patients who progress to grade IV encephalopa-
thy experience cerebral edema, which is optimally man-
ANESTHESIA CARE
aged with direct monitoring of ICP. Perioperative use of Donor Management
direct ICP monitoring, with the ability to drain cerebro-
spinal fluid, may reduce morbidity and mortality rates Because the demand for donor organs continues to
associated with liver transplantation and cerebral edema. increase, it is imperative to salvage even marginal organs.
As ICP increases, systemic hypertension and decerebrate The anesthesiologist has an important role to play in this
posturing may be seen. Once the patient develops grade care because hemodynamic heterogeneity in donors is
III (stupor) or grade IV (coma) encephalopathy, airway common.78 Intensive management of the donor, using all
control and ventilation are indicated because there is a the monitoring sensors and laboratory facilities that are
risk for pulmonary aspiration. Elevation of the patient’s used on living patients, is well justified and provides opti-
head 25 degrees and maintenance of cerebral perfusion mal organs to the donor pool. Invasive monitoring,
pressure by supporting systemic arterial blood pressure, together with cardiac output assessment, may optimize
reducing central venous pressure, and avoiding agitation donor management. Normal blood pressure alone does
are essential. The role of ICP monitoring is controversial not indicate adequate organ perfusion. With acceptable
but helpful if it can be obtained so that the cerebral perfu- hemodynamics ensured, organ perfusion may be opti-
sion pressure can be accurately monitored and main- mized and vasopressor administration minimized. With
tained above 50 mm Hg.73 increasing experience it has been found that no arbitrary
In patients for whom death is imminent and for whom maximal vasopressor dose exists as long as hemodynamics
a donor liver has not become available, total hepatectomy are maintained.79 Crystalloid infusions may be used as
has been performed to eliminate the toxic effects of a fluid replacement unless the hematocrit is less than 21%,
necrotic liver. The liver is removed, and a portacaval at which time the use of erythrocyte infusions may be
shunt is performed to decompress the portal system. The indicated.
inferior vena cava (IVC) is left intact, and the hepatic
veins are ligated. Patients have been shown to improve
with less metabolic acidosis and a reduced need for vaso- Recipient Care
active drugs and have undergone transplantation success-
Pharmacokinetics and Pharmacodynamics
fully up to 72 hours after becoming anhepatic.74 Once the
patient has become anhepatic the hemodynamics rapidly The most important contributor to the plasma protein
stabilize because the vasoactive toxins are excluded from binding of drugs is albumin. In chronic liver disease, as
the circulation. hypoalbuminemia develops, there are fewer drug-binding
Apart from cerebral edema, which is the major cause sites available; therefore free drug concentration increases,
of death in fulminant liver failure, major gastrointestinal resulting in enhanced distribution and higher concentra-
hemorrhage, bacterial infection, kidney failure, circula- tion at the site of action. This effect may be offset by
tory collapse, hypoglycemia, and severe acidosis may all increased clearance of the drug.
be fatal. To maintain normoglycemia, an infusion of 10% In the liver the sinusoids provide a large surface area
glucose may be necessary. Severe metabolic acidosis, a where drugs can diffuse into the hepatocytes. The intrin-
function of tissue hypoxia and lactic acidosis, is often sic clearance and extraction of a drug depends on the
impossible to reverse even with bicarbonate infusions. number of enzyme systems present and the rate at which
Blood pressure may be maintained with epinephrine or they perform. During development of portosystemic
norepinephrine infusions but may be at the expense of shunts, liver blood flow may decrease. Drug metabolism
tissue perfusion and may make lactic acidosis worse. This is reduced as effective liver blood flow decreases and
effect may be mitigated by the addition of an infusion of microsomal activity is depressed. A close relationship
 46 Anesthesia for Liver Transplantation 623

exists between liver blood flow and metabolic rate for

Monitoring
those drugs with a high intrinsic clearance and extraction
ratio (e.g., propofol, lidocaine, and fentanyl). Those Liver transplantation is likely to cause massive fluid shifts,
drugs that have low intrinsic clearance and extraction are blood loss, hemodynamic instability, coagulation disor-
unaffected by liver blood flow (e.g., diazepam and ders, electrolyte and acid-base disorders, and difficulties
phenobarbital). in maintaining body temperature. Consequently, careful
The enzyme complex cytochrome P-450 system plays monitoring and the availability of measures to maintain
a major role in drug metabolism. Each distinct P-45O hemostasis, normothermia, and normovolemia are essen-
protein is the product of a unique gene. Each gene tial. Adequate assistance is necessary, as is access to point-
appears to be independently regulated and selectively of-service laboratory equipment or the presence of a “stat
inducible.80 Agents such as phenobarbital and alcohol can laboratory,” so that current data are obtained. Rapid
cause induction to function at a much higher level of analyses of basic electrolytes, glucose, arterial blood
activity, so other unrelated drugs are metabolized at a gases, ionized calcium and magnesium levels, as well as
much greater rate (e.g., thiopentone, diazepam, pan- hemostasis profiles—hematocrit, prothrombin time, par-
curonium). Acute viral hepatitis, alcoholic cirrhosis, and tial thromboplastin time, fibrinogen, platelet count,
pericentral cirrhosis are associated with a 30% to 50% thrombin clot time, fibrin split products, and D-dimers—
decrease in P-450 levels, in contrast to chronic hepatitis are required. The perioperative use of TEG or ROTEM
and primary biliary cirrhosis, which generally spare this allows an accurate assessment of the quality of the clot-
system.81 Consequently the response of the patient to ting system to be made in real time.
anesthetic drugs may be unpredictable, and the use of Hemodynamic monitoring consists of a multichannel
cerebral function monitors during surgery may be help- electrocardiogram, direct arterial blood pressure, central
ful. The effects of disturbed liver function on drug dispo- venous pressure and often pulmonary artery pressures
sition may be contradictory. Clearance may be increased with cardiac output determinations and hemodynamic
because of induction of the cytochrome P-450 enzyme profiles. TEE can be helpful in the management of car-
complex but decreased as a result of reduced liver blood diac function, volume status, and monitoring for the
flow, reduced hepatocellular mass, deranged liver metab- presence of intracardiac emboli. Heparin is not added to
olism, or decreased level of plasma enzymes such as cho- the flush solution of monitoring catheters because the
linesterase. The effect of reduced portal extraction is to small amounts of heparin may not be metabolized by the
reduce “first-pass” metabolism of orally administered liver and can affect coagulation.
drugs, leading to greater bioavailability. Pulmonary status is monitored by end-tidal carbon
Different disease entities have different combinations dioxide analysis, pulse oximetry, serial arterial blood gas
of these disturbances, and each patient presents with an measurements, and compliance assessments. End-tidal
individual pattern of dysfunction. Some derangements nitrogen and carbon dioxide monitoring by mass spec-
will have opposing effects that tend to be self-canceling, trometry can aid in the diagnosis of air emboli and in the
whereas others may be additive. Therefore drug actions assessment of adequate ventilation.
should be carefully monitored with titration of drug to Cerebral function monitoring may provide useful data
effect. in assessing depth of anesthesia and cerebral well-being.
Morphine has a normal clearance in cirrhotic patients, These patient populations have varied responses to anes-
and it is probable that there is extrahepatic glucuronida- thetic drugs and are more susceptible to unexpected lev-
tion of morphine and it is likely to be metabolized at all els of anesthesia. Reperfusion of the liver graft can
degrees of liver insufficiency. Meperidine shows a marked produce temporary isoelectric cerebral activity. Cerebral
reduction in clearance. Fentanyl and sufentanil show no function monitors that display the raw EEG signal are
changes in clearance or protein binding in cirrhosis.82 the most helpful in guiding management.
Muscle relaxants show a varied response to liver dys- TEG and ROTEM provide a graphic display of visco-
function. Succinylcholine action is prolonged as plasma elastic clot strength, allowing a virtual assessment of the
cholinesterase levels are reduced. Pancuronium has a quality of coagulation. The TEG tracing can be described
50% increase in volume of distribution, causing lowered by reporting measured parameters (Fig. 46-8). Reaction
plasma concentrations; however, it also has decreased time is the time from the start until the amplitude of the
clearance, which causes an increase in elimination half- trace is 2 mm. The K value is the time from the end of
life of approximately 3 to 5 hours. Vecuronium and reaction time to the point at which amplitude is 20 mm.
rocuronium are dependent on liver excretion and there- The α-angle is formed by the tangential slope of the graft
fore have an increased elimination half-life with liver dis- from the initial point of divergence. It is possible to
ease. They can be used as pharmacodynamic probes to observe fibrinolysis by observing the maximal amplitude
assess new graft primary function.83,84 Atracurium is decrease more rapidly than normal. The graph, calcu-
degraded normally with end-stage liver disease; how- lated parameters, and normal ranges may be displayed on
ever, laudanosine, a principal metabolite and central ner- a computer screen.
vous system stimulant, is dependent on the liver for
clearance.
Cardiovascular drugs should generally be administered INTRAOPERATIVE ANESTHESIA
in reduced doses. Lidocaine and procainamide, β-blockers,
calcium channel blockers, and metoclopramide all have Adequate venous access must be obtained so that massive
reduced clearance in patients with cirrhosis. rapid transfusions may be administered if necessary.
624 PART V Operation

10 millimeters

TEG value descriptions:

Reaction time (min) (4–8) 5.8

Kinetics (speed) (min) (1–4) 2.2
Angle (α) (47–74) 61.3
Maximum amplitude (mm) (55–73) 56.5
Predicted maximum amplitude (6.0K–13.2K) 0.0
Tensile clot strength (d/sc) (0–15) 6.5K
Estimated percent lysis (%) (–3–3) 0.0
Clot build speed (mm) (0–8) 56.2
Coagulation index N/A –0.8
Lysis after 30 min (%) N/A 0.0

FIGURE 46-8 n Thromboelastogram of patient undergoing liver transplantation. TEG, Thromboelastogram.

Large-bore peripheral and central venous catheters may similar warming capabilities, but more rapid flow rates
be placed in the upper part of the body because fluid were achieved by the Level 1, and better air detection and
given through lower body venous catheters may be lost in air elimination were achieved by the Belmont system
the surgical field or obstructed in passage to the heart. A (Fig. 46-9).85 When these devices are used, cardiac filling
radial arterial catheter is inserted for continuous blood pressures must be observed closely because volume over-
pressure monitoring and access for arterial blood gas load can occur rapidly. Banked blood units contain
measurement. Following induction of anesthesia, a sub- increasingly high levels of potassium as they age so that a
clavian triple-lumen catheter may be placed, which may dangerously high level of serum potassium may occur
be useful postoperatively as well as intraoperatively. A with resulting cardiac arrest if these units are transfused
single large-bore catheter or two catheters are placed rapidly.
percutaneously in the right internal jugular vein if veno- The older units of banked blood may be washed
venous bypass is contemplated: one, a 12F catheter, is before use, which can be achieved easily in the operating
used for rapid volume replacement and as the return limb room by a red cell–saving device. In a dire emergency
of a venovenous bypass circuit; the other internal jugular the cell saver can be connected directly to the rapid infu-
catheter is used as a pulmonary artery catheter intro- sion device reservoir so that salvaged blood can be trans-
ducer. A pulmonary artery catheter, although not used in fused directly back into the patient. Blood salvage
all centers, may prove valuable in diagnosing pulmonary systems help reduce the demand on the blood bank.
hypertension and managing hemodynamic instability. All A system that washes the red cells before retransfusion,
fluids should pass through warming devices to assist in such as the cell saver, is preferable. The cell saver may be
temperature maintenance. A rapid infusion system may used safely in all patients except those with malignant
be necessary for those times when massive blood loss tumors in whom the risk is uncertain. There is the pos-
occurs. sibility that in patients with hepatocellular carcinoma
that there could be hematogenous spread of tumor cells.
With routine use of the cell saver, there is no risk for
Rapid Infusion Devices trace heparinization of the patient if the blood is aspi-
Infusion of large volumes of warmed blood and blood rated with 20,000 units of heparin per liter of saline, and
products at high flow rates may be required if blood loss no risk for infection has been demonstrated.86 Alterna-
is rapid and severe. Available units include the Level 1 tively, salvaged blood may be anticoagulated with an
rapid infusion (SIMS Level 1, Inc., Rockland, MA) sys- infusion of adenosine-citrate-dextrose at 6 mL/min.
tem Model H1025 and the Belmont instrument fluid The cell saver may also be used for exchange autotrans-
management system Model FMS 2000 (Belmont Instru- fusion in patients who present with elevated blood levels
ment Corp., Billerica, MA). A recent comparison between of ammonia, lactate, and potassium as a result of renal
the Level 1 and the Belmont systems demonstrated failure.
 46 Anesthesia for Liver Transplantation 625

-D
Top (#2)
socket
Pump head
Heat Heat Display tubing
exchanger Pressure exchanger Fluid out
guide transducer detector
(behind pressure (behind pump
Heat chamber) head tubing)
exchanger
Pressure
Bottom (#1) chamber Power
socket switch
In-line
C air detector
Fluid
pump
Output infrared
Gas temperature
vent probe
E (inside case) Valve
(#3) C45
vent
holder Input infrared
Patient temperature
line D probe
(inside case)

A B
FIGURE 46-9 n A, The SIMS Level 1 H1025. B, The Belmont Instrument Model FMS 2000. (From Comunale ME. A laboratory evaluation of the
Level 1 Rapid Infuser (H1025) and the Belmont Instrument Fluid Management System (FMS 2000) for rapid transfusion. Anesth Analg.
2003;97:1064-1069.)

Thermal Homeostasis ANESTHESTIC TECHNIQUES

Thermal homeostasis is essential during liver transplan- A modified rapid-sequence induction technique is used in
tation. Major heat loss occurs after induction of anesthe- the majority of patients. Preoxygenation is followed by
sia, when the patient is exposed and prepared, during the the administration of propofol (1.5 mg/kg). Intubation is
anhepatic phase, and at the time of reperfusion, when the assisted by muscle relaxation with vecuronium or
cold, preserved organ is placed in circulation. Hypother- rocuronium, and cricoid pressure is applied until the air-
mia affects all organ systems and causes reversible platelet way is secured. Anesthesia is maintained with isoflurane
dysfunction that could potentiate or cause coagulopathy. in an air-oxygen mixture, supplemented with fentanyl.
There is a generalized slowing of the cardiac conduction Isoflurane provides an optimal relationship between liver
system and a decrease in the ventricular fibrillation oxygen supply and demand; however, in this extensive
threshold. These effects on the heart are especially procedure this may be only a theoretical consideration,
important at the time of reperfusion, when bradycardia and any of the newer volatile agents are satisfactory.
and ventricular ectopy are not uncommon. Coronary The use of muscle relaxants that are metabolized by
vasospasm, presumed secondary to placing the cold graft the liver, such as vecuronium or rocuronium, should be
beneath the diaphragm near the heart, has been accompanied by monitoring of neuromuscular block with
observed.87 Routine methods of thermal regulation a nerve stimulator.
include maintaining an ambient room temperature as Ventilation is set to provide a low tidal volume and
warm as tolerable; using thermal drapes for the lower inspiratory pressure and at least 5 cm H2O of positive end-
extremities and head, fluid-warming devices, and a heated expiratory pressure to maintain adequate alveolar ventila-
humidifier; and placing a forced-air warming device over tion, particularly of the lower lobes, and to reduce the risk
the upper and lower extremities. If venovenous bypass is for venous air embolism from the liver bed. Positioning and
used, a heater placed in the circuit can effectively main- padding the patient require particular care. Padding should
tain body temperature, but care must be taken not to heat be checked meticulously at all pressure points because of
the circuit above body temperature because coagulation the potential length of the surgery. Extra padding should be
of the blood in the system may be initiated. available to protect the arms from surgical retractors.
626 PART V Operation

A high incidence of brachial plexus neuropathy in macrophages from releasing interleukin-1, thereby initi-
posttransplantation liver patients and living related ating immunosuppression.
donors has been reported despite excellent padding. The anhepatic phase has variable considerations
The cause appears to be multifactorial, including depending on the use of venovenous bypass. Patients
cyclosporine-induced neuropathy and the surgical without venovenous bypass can be expected to have a
retraction of the costal margin to gain exposure of the major decrease in venous return at the time of clamping
liver, compressing the thoracic outlet in those patients the IVC unless there is a well-developed intact shunt sys-
with narrowed outlets. tem from long-standing portal hypertension or a “piggy-
A nasogastric tube is placed atraumatically, and the back” technique that is used when the vena cava is only
stomach is kept decompressed. An enteric feeding tube is partially occluded. This decrease in venous return can be
placed for postoperative hyperalimentation. treated with volume and vasopressors. The decrease in
cardiac output combined with obstruction of the IVC
may lead to a decrease in kidney perfusion, and oliguria is
THREE PHASES OF ORTHOTOPIC LIVER not uncommon. The use of venovenous bypass counters
TRANSPLANTATION these effects to some degree.

The anesthetic management of the operation can be con-

sidered with respect to three phases: preanhepatic, anhe-
Venovenous Bypass
patic, and neohepatic. The preanhepatic phase includes Some centers do not routinely use venovenous bypass
dissection and isolation of infrahepatic and suprahepatic because of concerns regarding potential complications,
vena cava, exposure of the porta hepatis and hilar struc- such as air embolism, thromboembolism, and increased
tures of the liver, and preparation for venovenous bypass surgical time. Many transplant centers, however, do use
when used. The anhepatic phase begins with isolation of venovenous bypass routinely during the anhepatic phase
the liver and extends until the time of reperfusion of the to improve venous return and reduce congestion of the
donor liver. The neohepatic phase begins at reperfusion intestines, improve renal perfusion, and delay the devel-
and lasts until the end of the procedure. opment of metabolic acidosis. In patients with severe
portal hypertension, venovenous bypass may be set up
earlier in the procedure to decompress the portal system
Preanhepatic Phase and to reduce blood loss.
During the preanhepatic phase both overt and covert The femoral vein and portal vein are cannulated.
blood losses can occur, particularly in patients with portal Blood is drained from these catheters, run through a cen-
hypertension. Massive volumes of ascitic fluid may be trifugal constrained vortex pump, and returned to the
drained, and volume shifts must be anticipated and cor- patient by way of the internal jugular vein. This process
rected. Heavy bleeding may be encountered at any time, may be safely completed without heparin or heparin-
and readiness to transfuse massively at any time must be bonded tubing, provided that flow rate on bypass is kept
maintained. At the start of the case, 3 units of packed red at greater than 1000 mL/min. Air entrainment may occur
cells and 3 units of fresh-frozen plasma may be cross- if the draining venous cannulas are not tightly tied into
matched. If excessive bleeding is encountered, additional their respective veins; therefore there is an advantage to
products can be ordered. During the preanhepatic phase, using a system that includes an air detector. The venove-
before venovenous bypass, only correction of preexisting nous circuit may be heated up to body temperature to
coagulopathies accompanied by clinically significant maintain body temperature effectively. Demonstration of
bleeding and an abnormal TEG should be attempted. a decreased right ventricular end-diastolic volume is an
Platelet counts as low as 20,000/mm3 may be well toler- indication that venovenous bypass is not as efficient as a
ated in some patients, and transfusion of platelets is not patent IVC at maintaining venous reurn.88 Markers of
required. The use of citrate-rich blood products may kidney perfusion, however, are preserved with the use of
result in the development of reduced levels of ionized cal- venovenous bypass.48 The liver is extracted, and meticu-
cium and ionized magnesium. These electrolytes should lous hemostasis is obtained. The argon beam coagulator
be monitored closely and replaced as necessary. Hypo- is effective in aiding hemostasis, but application of the
tension may occur secondary to surgical manipulation in beam to the underside of the diaphragm can cause cardiac
addition to hypovolemia and blood loss. Potential com- arrhythmias, even ventricular tachycardia. After comple-
pression of major vessels during dissection can lead to a tion of the caval anastomoses, portal bypass is discontin-
reduction in venous return. Vigilance regarding the sur- ued, and the portal vein is anastomosed. The reduction in
gical field can allow proper diagnosis. The hepatic artery venous return may require volume loading at this time.
is ligated, followed by the portal vein, and the anhepatic At the completion of this anastomosis, venovenous bypass
stage is entered. is discontinued and the suprahepatic and infrahepatic
IVC and portal vein are opened, reperfusing the new
graft. Venovenous bypass is then discontinued.
Anhepatic Phase Alternatively, if bypass is not used, the hepatic vein
The suprahepatic and infrahepatic IVC are clamped, and pedicle is parachuted down onto the vena cava, the portal
the liver is removed. During the anhepatic phase, in vein is anastomosed, and reperfusion occurs.
preparation for the new graft entering circulation, a large During the lower vena caval anastomosis, the liver is
dose of corticosteroids is given. The steroids prevent flushed with room temperature normal saline and albumin
 46 Anesthesia for Liver Transplantation 627

solution through the portal vein. This process of irrigation conversion of xanthine dehydrogenase to xanthine oxi-
flushes the preservation solution, metabolites, and air from dase. Mannitol, also infused at the time of reperfusion,
the donor liver. After the portal anastomosis is completed, can act as a free-radical scavenger. Other free-radical
the clamps are removed from the IVC, and the portal vein scavengers, such as superoxide dismutase and catalase,
clamp is slowly removed while closely monitoring the may be considered. Prostaglandin E1 has been reported
hemodynamic state. Reperfusion of the graft liver via the to improve the survival of livers that appeared marginal
portal vein marks the beginning of the neohepatic phase. at reperfusion.91 The effect of prostaglandin E1 on vas-
cular endothelium may enhance perfusion of the graft
both generally and in areas of “no reflow.”
Neohepatic Phase The anesthesiologist must take care after reperfusion
The initial period of the neohepatic phase is a critical not to cause volume overload in the patient. Congestion
time marked by the potential development of reperfusion of the liver graft can seriously impair graft function.
syndrome, which is characterized by hypotension, brady- Surgically the remainder of stage three involves the
cardia, and arrhythmias; rarely seen are circulatory col- hepatic artery anastomosis and biliary anastomosis. The
lapse and ventricular fibrillation. Pulmonary artery hepatic artery is reconstructed by an end-to-end anasto-
pressures are also observed to increase, and right ventric- mosis. Hepatic artery flow is a critical factor in determin-
ular dysfunction has been observed.23,56,89 The cause ing survival of the graft. Blood flow in the hepatic artery
appears to be the sudden circulatory influx of a cold, and portal vein is measured using an electromagnetic
acidic, hyperkalemic volume into the right atrium. flow probe. If the hepatic arterial flow is inadequate (<400
Minor reperfusion syndromes require no treatment; mL/min), improvement is sought by using various
major episodes may require vasopressors and occasionally maneuvers such as injection of papaverine directly into
resuscitation. Hypocalcemia contributes to cardiac dys- the vessel. Hepatic arterial flow in a graft liver is pressure
function; therefore ionized calcium is normalized before dependent; therefore systemic pressure should be main-
reperfusion. Calcium should be given with caution to the tained at this time. If flow remains inadequate, the hepatic
hypokalemic patient because it can precipitate arrhyth- artery may be reconstructed by an aortohepatic graft
mias in this setting. The portal vein clamp should be using vessels obtained from the donor. In these cases the
released slowly because this method decreases the bolus anesthesiologist must anticipate the effects of either par-
effect and lessens the likelihood of a severe reperfusion tial or total clamping of the aorta.
syndrome. Careful observation of pulmonary artery tem- The biliary anastomosis is performed either as a direct
perature, T-wave amplitude on the electrocardiogram, end-to-end connection or as a choledochojejunostomy
pulmonary artery pressure, and systemic blood pressure via Roux-en-Y limb. During this phase the anesthesiolo-
as the portal vein is unclamped can guide the speed of gist’s major concerns are rewarming and correction of
unclamping of the portal vein. Alternatively, the suprahe- coagulopathy. Heparin effect and fibrinolysis may be
patic vena cava can remain clamped and the infrahepatic observed after reperfusion and can be treated with prot-
anastomosis left partially open so that the initial blood amine, aminocaproic acid, or tranexamic acid, respec-
perfusing the liver by way of the portal vein is shed into tively. Antifibrinolytic therapy should be guided by TEG
the wound. The suprahepatic vena cava is then opened, data because this appears to be the most sensitive monitor
and the infrahepatic vena cava anastomosis is completed. of fibrinolysis. Cryoprecipitate, fresh-frozen plasma, or
This technique of nonsystemic reperfusion of the trans- platelets may also be needed to correct a coagulopathy at
planted liver reduces significantly the incidence of reper- this time.
fusion syndrome.90 Signs of a well-functioning graft include good hepatic
Bolus doses of epinephrine have been used effectively arterial flow, early bile formation, increasing body tem-
to treat reperfusion syndrome. Large doses of norepi- perature, improvement in coagulation status, correction
nephrine have also been used effectively in some cases of of acidosis, a decrease in potassium level, and an increase
severe cardiovascular collapse. Norepinephrine may pro- in carbon dioxide production.
vide better support of SVR and perfusion of vital organs,
particularly if cardiac massage is required. The effects of
reperfusion syndrome and treatment modalities to over- FLUID MANAGEMENT
come it on the donor liver are not well elucidated. Suc-
cessful subsequent liver function, however, has been The most common cause of a low cardiac output at the
observed in all of the situations just described. Reperfu- start of liver transplantation is hypovolemia. Good vol-
sion is associated with an increase in cardiac output, a ume replacement is required for adequate tissue perfu-
reduction in SVR, a decline in systemic blood pressure, sion, and more especially for adequate renal perfusion. A
and an increase in pulmonary artery pressure. Low-dose non–lactate-balanced electrolyte solution can be used as
vasopressor support may be required early in the neohe- maintenance fluid. This solution will not exacerbate lac-
patic stage. tic acidosis in patients with little or no liver function.
Some livers appear marginal at reperfusion. Free- Fluid administration is guided by hemodynamic moni-
radical formation is considered contributory to this toring and urine output. In the absence of diuretics or
problem. The addition of allopurinol to the University kidney failure, a urine output of 0.5 to 1 mL/kg/hr or
of Wisconsin preservation solution may be part of the greater is a good indicator of adequate fluid load and car-
reason for its efficacy, because allopurinol can prevent diovascular function. If the patient becomes oliguric, a
the release of some free radicals by inhibiting the fluid challenge is most often the first option indicated.
628 PART V Operation

Continued oliguria after adequate fluid administra- Postoperative pain control is an important part of
tion, as evidenced by monitoring of filling pressures or postoperative care, and pain medication should not be
cardiac volume, may indicate a need to optimize cardiac withheld because of fear that the new graft may not be
performance (cardiac output) through pharmacological functioning fully. However, the drug doses should
measures, or it may respond to diuretics such as furose- be individualized until the degree of liver function can be
mide or mannitol. Intraoperative continuous venovenous assessed. Patient-controlled analgesia pumps provide a
hemodialysis is useful in liver transplant recipients with good system of intravenous narcotic in small boluses
impaired renal function who require ongoing transfu- delivered on patient command. This system of on-
sions to treat a coagulopathy. In these patients the vol- demand provision of narcotic allows for the titration of
ume of products necessary to correct the coagulopathy an effective and safe dose of analgesic regardless of the
may lead to fluid overload together with hyperkalemia. level of liver function.
Continuous venovenous hemodialysis can prevent and
treat this situation. Volume overload will cause liver con-
gestion and dysfunction of the new graft and must be PEDIATRIC ASPECTS
avoided.
Children with end-stage liver disease experience a nutri-
tional deficit and growth retardation. Because children
POSTOPERATIVE CARE with reduced nutritional reserves are less able to handle
the demands of liver transplantation, nutritional support
After liver transplantation, patients are transferred to the should be part of the pretransplant protocol. Children
ICU for postoperative care. If the operation has been account for approximately 10% of the liver transplants
uneventful and the graft is functioning well, routine mon- performed in the United States.
itoring of vital signs, fluid balance, coagulation, and liver The indications may be divided into five categories:
function is all that is required. Patients are ventilated chronic liver diseases—biliary atresia, Alagille syn-
until they fully recover from anesthesia and are then extu- drome; metabolic diseases—α1-antitrypsin deficiency,
bated. This may be performed safely in many patients at Crigler-Najjar syndrome; acute liver failure—
the end of the procedure on the operating room table or autoimmune, viral; malignancy—hemangioendotheli-
on arrival in the ICU.92 oma; and miscellaneous—Budd-Chiari syndrome.95 The
Primary nonfunction of the graft as a result of injury severity of the liver disease and position on the waiting
or acute rejection is demonstrated by failure of the coagu- list is determined by the PELD score, which is based on
lation system to normalize and marked elevation in liver serum bilirubin level, prothrombin time, albumin level,
enzyme levels followed by encephalopathy. The hepatic growth failure, and age less than 1 year. The anesthesia
artery is studied by Doppler ultrasonography to ensure technique is similar to that in adults, but in many smaller
that it has remained patent. If no flow is detected, the children the information provided by a pulmonary artery
patient undergoes emergent reexploration, and the catheter is not of great help. It is better to use volume
hepatic artery is reconstructed. This early intervention catheters for venous access and to measure central
can salvage the graft and prevent the need for venous pressure as a guide to fluid management.
retransplantation. Donor livers are obtained from living donors, reduced-
Patients with preoperative HRS can be expected to size livers, and split liver organs, all of which present spe-
have a reasonable recovery of kidney function after a suc- cific challenges. Venovenous bypass is not used in
cessful liver transplantation. The introduction of calci- children and infants because they generally tolerate
neurin inhibitors for immunosuppression, although explantation well, provided that volume replacement has
improving the survival of liver grafts, has increased the been adequate. A “piggyback” technique allows some
incidence of kidney dysfunction. The major cause of venous return through the vena cava. Temperature con-
death after transplantation is infection.93 Consequently trol is essential and can be provided by good fluid warm-
an aggressive prophylactic regimen against both bacterial ing and forced-air warming devices. Occasionally in
and fungal organisms should be instituted. children, and rarely in adults, abdominal wall closure may
Sepsis and retransplantation are major risk factors for be impossible because of the large size of the donor liver.
the development of adult respiratory distress syndrome.94 This may be remedied by either downsizing the liver by
Associated with infection and graft failure, multiple organ resection of a lobe or creating a silo on the abdominal
system failure is an important factor contributing to wall so that a temporary closure can be made.
death. The most common complication after transplantation
Postoperative hemorrhage may be the result of surgi- in the pediatric patient is hepatic artery thrombosis. This
cal bleeding or a coagulopathy. Early intervention is war- is reported in the range of 5.7% to 8.4%.96
ranted so that large blood clots or collections do not
accumulate and result in ongoing coagulopathy or as a
nidus for infection or fibrinolysis.
Living Donor Liver Transplantation
Hypertension is seen in more than 50% of posttrans- Living donor liver donation is the major source of organs
plantation patients and requires treatment. The risk for a for recipients in Asia. The anesthetic management of the
cerebrovascular accident is increased in the early postop- donor has a focus on minimizing risk to the donor and
erative period because some degree of bleeding tendency providing an optimal graft for the recipient. Right or left
exists. hepatic lobes may be resected. The anesthetic is managed
 46 Anesthesia for Liver Transplantation 629

to maintain optimal perfusion of the graft, avoiding con- 14. Bakti G, Fisch HU, Karlaganis G, et al. Mechanics of the excessive
gestion while maintaining a good perfusion. A low central sedative response of cirrhosis to benzodiazepines: model experi-
ments with triazolam. Hepatology. 1987;7:629-638.
venous pressure of less than 5 cm H2O will reduce blood 15. Basile AS, Hughes RD, Harrison PM, et al. Elevated brain concen-
loss but must be carefully balanced with maintaining trations of 1,4benzodiazepines in fulminant hepatic failure. N Engl
good hemodynamics. Good postoperative analgesia may J Med. 1991;325:473-478.
be obtained by using multimodal anesthesia or epidural 16. Dursun M, Caliskan M, Canonic F, et al. The efficacy of flumazenil
in subclinical to mild hepatic encephalopathic ambulatory patients.
techniques. A prospective, randomized, double-blind, placebo-controlled
study. Swiss Med Wkly. 2003;133:118-123.
17. Barbara G, Di Lorenzo G, Soldini M, et al. Flumazenil for hepatic
encephalopathy grade III and IVa in patients with cirrhosis: an
Pearls and Pitfalls Italian multicenter double-blind, placebo-controlled, cross-over
study. Hepatology. 1998;29:1338-1339.
• Treat the patient, not the laboratory data. 18. Shami VM, Caldwell SH, Hespenheide EE, et al. Recombinant
• Carefully assess right ventricular function. activated factor VII for coagulopathy in fulminant hepatic failure
• A congested graft will not function. compared with conventional therapy. Liver Transpl. 2003;9:
• Maintain normothermia. 138-143.
• Tightly control blood glucose, serum potassium, and ion- 19. Brajtbord D, Parks RIP, Ramsay MAE, et al. Management of acute
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Anesthesiology. 1989;70:139-141.
• The thromboelastogram is the key virtual monitor of the 20. Kowalski HJ, Abelmann WH. The cardiac output at rest in
coagulation system. Laennec’s cirrhosis. J Clin Invest. 1953;32:1025-1033.
• Ensure adequate vascular access. 21. Liu H, Song D, Lee SS. Cirrhotic cardiomyopathy. Gastroenterol
• Maintain excellent urine output. Clin Biol. 2002;26:842-847.
• Be vigilant in identifying the rare patient who is hyperco- 22. Lee SS. Cardiac abnormalities in liver cirrhosis. West J Med.
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• Administer antifibrinolytic agents to treat identified fibri- 23. Ramsay M. The Reperfusion syndrome: Have we made any Prog-
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13. Kertai MD, Whitlock EL, Avidan MS. Brain monitoring with perioperative mortality and myocardial infarction in high-risk
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41. Safdar Z, Bartolome S, Sussman N. Portopulmonary hypertension: 65. Fitzsimons MG, Peterfreund RA, Raines DE. Aprotinin administra-
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42. Arroyo V, Gines P, Jirnenez W, Rodes J. Ascites, renal failure, and plantation: report of two cases. Anesth Analg. 2001;92:1418-1421.
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45. Nadim MK, Kellum JK, Davenport A, et al. Hepatorenal Syn- 69. Conn HO. Transjugular intrahepatic portal-systemic shunts: “The
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47. Salerno F, Gerbes A, Gines P, et al. Diagnosis, prevention and or not to transplant. Neth J Med. 1991;38:131-141.
treatment of hepatorenal syndrome in cirrhosis. Gut. 2007;56: 72. Saibara T, Onishi S, Gone J, et al. Arterial ketone body ratio as a
1310-1318. possible indicator for liver transplantations in fulminant hepatic
48. Gunning TC, Brown MC, Swygert TH, et al. Perioperative renal failure. Transplantation. 1991;51:782-786.
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Transplantation. 1991;51:422-427. derangements in acute liver failure: pathophysiology and manage-
49. Swygert TH, Roberts LC, Valek TR, et al. Effect of intraoperative ment. Semin Liver Dis. 1996;16:379-388.
low-dose dopamine on renal function in liver transplant recipients. 74. Husberg BS, Goldstein RM, Klintmalm GB, et al. A totally failing
Anesthesiology. 1991;75:571-576. liver may be more harmful than no liver at all: three cases of total
50. Carey RM, Siragy HM, Ragsdale NV, et al. Dopamine-1 and hepatic devascularization in preparation for emergency liver trans-
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53. Nadim MK, Genyk YS, Tokin C, et al. Impact of the etiology of cerebral hyperemia by the administration of terlipressin in acute
acute kidney injury on outcomes following liver transplantation: liver failure with severe encephalopathy. Hepatology. 2004;39:
acute tubular necrosis versus hepatorenal syndrome. Liver Transpl. 471-475.
2012;18:539-548. 78. Duke PK, Ramsay MAE, Paulsen AW, et al. Intraoperative hemo-
54. Sakai T, Matsusaki T, Marsh JW, et al. Comparison of surgical dynamic heterogeneity of brain dead organ donors. Transplant
methods in liver transplantation: retrohepatic caval resection with Proc. 1991;23:2485-2486.
veno-venous bypass(VVB) versus piggy back (PB) with VVB versus 79. Mor E, Klintmalm GB, Gonwa TA, et al. Use of marginal donors
PB without VVB. Transpl Int. 2010;23:1247-1258. for liver transplantation: A retrospective study of 365 liver donors.
55. Gurusamy KS, Koti R, Pamecha V, et al. Veno-venous bypass ver- Transplantation. 1992;53:383-386.
sus none for liver transplantation. Cochrane Database Syst Rev. 80. Watkins PB. Role of cytochromes P450 in drug metabolisms and
2011;3:CD007712. hepatotoxicity. Semin Liver Dis. 1990;10:235-250.
56. Paugam-Burtz C, Kavafyan J, Merckx P, et al. Postreperfusion syn- 81. Farrell GC, Cooksley WGE, Powell LW. Drug metabolism in
drome during liver transplantation for cirrhosis: outcome and pre- liver disease: activity of hepatic microsomal metabolizing enzymes.
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57. Haase M, Bellomo R, Story D, et al. Effect of mean arterial pres- 82. Chauvin M, Ferrier C, Haberer JP, et al. Sufentanil pharmacoki-
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bypass on postoperative acute kidney injury. Nephrol Dial Trans- 83. Lukin CL, Hein HAT, Swygert TH, et al. Duration of vecuronium
plant. 2012;27:153-160. induced neuromuscular blockade as a predictor of liver allograft
58. Bellomo R, Wan L, May C. Vasoactive drugs and acute kidney dysfunction. Anesth Analg. 1995;80:526-533.
injury. Crit Care Med. 2008;36:S179-S186. 84. Marcel RJ, Ramsay MAE, Hein HAT. Duration of rocuronium
59. Wagener G, Kovalevskaya G, Minhaz M, et al. Vasopressin defi- induced neuromuscular block during liver transplantation: a pre-
ciency and vasodilatory state in end-stage liver disease. J Cardiotho- dictor of primary allograft function. Anesth Analg. 1997;84:
rac Vasc Anesth. 2011;25:665-670. 870-874.
60. Cheng SS, Berman GW, Merritt GR, et al. The response to meth- 85. Comunale ME. A laboratory evaluation of the Level 1 Rapid
ylene blue in patients with severe hypotension during liver trans- Infuser (H1025) and the Belmont Instrument Fluid Management
plantation. J Clin Anesth. 2012;24:324-328. System (FMS 2000) for rapid transfusion. Anesth Analg. 2003;97:
61. Stanford SC, Stanford BJ, Gillman PK. Risk of severe serotonin 1064-1069.
toxicity following co-administration of methylene blue and sero- 86. Brajtbord D, Paulsen AW, Ramsay MAE, et al. Potential problems
tonin reuptake inhibitors: an update on a case report of post- with auto-transfusion during hepatic transplantation. Transplant
operative delirium. J Psychopharmacol. 2010;24:1433-1438. Proc. 1989;21:2347-2348.
62. Hambleton J, Leung LL, Levi M. Coagulation: Consultative 87. Ramsay MAE, Takaoka F, Brown M, et al. Coronary artery vaso-
hemostasis. Hematology Am Soc Hematol Educ Program. 2002: spasm following placement of a cold liver graft during orthotopic
335-352. liver transplantation. Anesth Analg. 1989;69:854-855.
 46 Anesthesia for Liver Transplantation 631

88. De Wolf AM, Begliomini B, Gasior TA. Right ventricular function 93. Park GR, Gomez-Arnau J, Lindop MJ, et al. Mortality during
during orthotopic liver transplantation. Anesth Analg. 1993;76: intensive care after orthotopic liver transplantation. Anaesthesia.
562-568. 1989;44:959-963.
89. Ventricular dysfunction does occur during liver transplantation. 94. Takaoka F, Brown MR, Paulsen AW, et al. Adult respiratory dis-
Transplant Proc. 1991;23:1924-1926. tress syndrome following orthotopic liver transplantation. Clin
90. Brems JJ, Triff H, McHutchinson J, et al. Systemic versus nonsys- Transpl. 1989;3:294-299.
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527-529. liver transplantation. Mt Sinai J Med. 2012;79:1990213.
91. Greig PD, Woolf GM, Abecassis M, et al. Prostaglandin E, for 96. Diamond IR, Fecteau A, Millis JM, et al. SPLIT Research Group.
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Proc. 1989;21:3360-3361. a report from Studies of Pediatric Liver Transplantation. Ann
92. Mandell MS, Lezotte D, Karn I, et al. Reduced use of intensive Surg. 2007;246:301-310.
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Transpl. 2002;8:676-681.
 CHAPTER 47

Imaging Techniques for Partial

Grafting
Victor Sai • Steven S. Raman

CHAPTER OUTLINE

IMAGING MODALITIES Donor Liver Volume Analysis

Multidetector Computed Tomography, Quantification of Macrovesicular Steatosis
Computed Tomography Angiography, and Hepatic Vascular Anatomy Analysis
Computed Tomography Cholangiography Hepatic Arterial Anatomy
Magnetic Resonance Imaging Portal Venous Anatomy
Magnetic Resonance Angiography Hepatic Venous Anatomy
Magnetic Resonance Biliary Anatomy Evaluation
Cholangiopancreatography
COMPREHENSIVE MAGNETIC RESONANCE
IMAGE INTERPRETATION IMAGING
Exclusion of Underlying Hepatic Pathological
Conditions

Preoperative imaging plays a crucial role in optimizing recent years, however, dual-energy CT cholangiography
outcomes and minimizing risks involved with partial liver (CTC) has demonstrated potential to replace MRCP for
grafting. The primary goals of imaging are to understand biliary anatomy, which would allow MDCT/CTA/CTC
donor vascular and biliary anatomy, identify variant anat- to serve as the sole preoperative imaging modality along
omy, assess hepatic segmental volumes, and exclude with MRI/MRA/MRCP.
underlying hepatobiliary pathological conditions. Donors
with inadequate liver volume, detectable pathology, or
anatomical variations that may require extensive vascular Multidetector Computed Tomography,
or biliary reconstruction may not be selected for living Computed Tomography Angiography, and
related liver transplantation.
Computed Tomography Cholangiography
Hepatic CTA is comparable to conventional angiography
IMAGING MODALITIES for evaluation of arterial anatomy2 and can be performed
on a 16-, 64-, 128- or higher detector row MDCT scan-
Advancements in multidetector computed tomography ner. The optimal protocol includes a noncontrast sequence
(MDCT) scanner technology have obviated the need for and postcontrast sequences in the arterial, portal venous,
invasive angiography to assess vascular anatomy. Com- and venous phases. The noncontrast sequence can be
puted tomography angiography (CTA) can provide accu- acquired with 5-mm collimation thickness, arterial phase
rate assessment of hepatic segmental volumes and arterial with 0.5- to 1.25-mm slice collimation at peak arterial
anatomy and also exclude liver masses and underlying enhancement, and portal venous and venous phases with
steatosis. Improvements in magnetic resonance imaging 1- to 2.5-mm collimation. Three-dimensional (3-D)
(MRI) and magnetic resonance angiography (MRA) have hepatic arteriograms, portal venograms, and hepatic veno-
made it possible to accurately assess underlying liver grams can then be rendered with any one of several types
pathological conditions and vascular anatomy as a poten- of commercially available software.
tial replacement for MDCT and CTA. At the same time CT cholangiography can be performed using intrave-
magnetic resonance cholangiopancreatography (MRCP) nously administered biliary contrast agents such as iodip-
can further delineate biliary anatomy,1 which is more dif- amide meglumine (Cholografin), which can result in
ficult to visualize by computed tomography (CT). In excellent depiction of the bile ducts. This is usually

634
 47 Imaging Techniques for Partial Grafting 635

performed 15 minutes after the administration of the bili- and of significant diffuse hepatic disease (such as cirrho-
ary contrast agent. The source images are then recon- sis, steatosis, hemosiderosis, and hemochromatosis).
structed and easily visualized by 3-D rendering.
Donor Liver Volume Analysis
Magnetic Resonance Imaging Volume analysis of the donor right and left lobes is neces-
MRI provides accurate evaluation of the liver paren- sary to ensure adequate right lobe function in the recipi-
chyma and detection of focal lesions and can be per- ent and sufficient left lobe reserve in the donor. The
formed on a 1.5- or 3-T magnetic resonance (MR) residual liver volume in the donor should exceed 35% of
magnet with a torso phased-array coil. Breath-hold axial the total liver volume.4,5 Previous studies have suggested
T1-weighted in-phase and opposed-phase gradient-echo that a graft weight–to–body weight ratio should be
and T2-weighted images are acquired to assess for diffuse greater than or equal to 0.8; however, recent analyses
liver disease, particularly steatosis, and to rule out focal have suggested that the data supporting this are weak.6
lesions that would render the allograft unacceptable for After MDCT or MR imaging is performed, analysis of
transplantation. the segmental volumes is performed on a 3-D worksta-
tion with a volumetric software package (Fig. 47-1). The
results are accurate with maximal deviation from true vol-
Magnetic Resonance Angiography ume estimated to be less than 10%.7
MRA can be performed on the same 1.5- or 3-T MR
magnet. Intravenous gadolinium contrast is adminis-
tered, and a 3-D gradient-echo sequence is usually
Quantification of Macrovesicular Steatosis
acquired with generation of subtraction arteriograms and Assessing the presence of donor macrovesicular steatosis
venograms. MRA provides accurate assessment of the is important because severe macrovesicular steatosis
hepatic vasculature despite poorer definition of smaller (>60%) is associated with a greater than 60% risk for
vessels because of larger slice thicknesses and increased allograft nonfunction/dysfunction after transplanta-
motion degradation from longer acquisition times. The tion.8,9 Moderate macrovesicular steatosis (30% to 60%)
performance of MRA has been demonstrated to be com- may also result in decreased hepatocyte degeneration and
parable to CTA for evaluation of hepatic vascular anat- higher rates of graft nonfunction, dysfunction, and isch-
omy in living donors.3 emic injury.10 However, survival data from patients trans-
planted with moderately steatotic livers have not been
Magnetic Resonance significantly different from that of patients transplanted
with mildly steatotic livers.11 Despite this there are well-
Cholangiopancreatography documented risks to transplantation with moderately to
MRCP can also be performed on the same 1.5- or 3-T severely steatotic livers, for which preoperative hepatic
MR magnet, and images can be obtained without contrast core biopsy remains the gold standard for quantitation.
using breath-hold, heavily T2-weighted, half-Fourier The use of CT or MRI may decrease the need for biopsy
rapid acquisition with relaxation enhancement sequence, in donors with severe (>60%) macrovesicular steatosis,
usually in either the axial/coronal planes with contiguous however.12-14
thin sections (3 to 5 mm) or rotating (coronal and off- The liver attenuation index (LAI) has been developed
coronal) slabs of variable thickness (3, 5, 7, and 10 cm). to prospectively predict the degree of macrovesicular ste-
The vertical axis of the common hepatic duct is used as atosis. The LAI is defined as the difference between mean
the center of rotation in coronal/off-coronal thick slabs.
Alternatively, contrast-enhanced MR cholangiography
using hepatobiliary-specific agents such as gadoxetate
disodium (Eovist) or gadobenate dimeglumine (Multi-
Hance) can be performed for higher resolution images
using a 3-D gradient-echo sequence. This also leads to
better image quality because of shorter acquisition times
and better patient cooperation.

IMAGE INTERPRETATION
Exclusion of Underlying Hepatic
Pathological Conditions
First and foremost, underlying hepatic pathological con-
ditions of the donor should be excluded. MDCT of the Whole liver 2400CC
liver allows detection of benign (cysts, hemangioma, and Right lobe 1575CC Left lobe 814CC
focal nodular hyperplasia), intermediate (hepatic ade- FIGURE 47-1 n Volumetric hepatic lobar analysis performed on a
noma), and malignant (hepatocellular carcinoma, cholan- GE workstation demonstrates the computer-generated whole
giocarcinoma, or hepatic metastases) focal liver lesions liver and lobar volumes.
636 PART VI Split and Living Donor Transplantation

hepatic and mean splenic CT attenuations on noncon- sequence for assessing steatosis is the T1 dual-phase gra-
trast CT in Hounsfield units (HU): dient-echo, whereby the degree of steatosis has been
found to correlate with the percentage signal loss from
LAI = Mean Hepatic Attenuation (HU) the in-phase to opposed-phase sequence. The fat fraction
− Mean Splenic Attenuation (HU) (FF) has been developed as a formula for calculating the
degree of steatosis17:
An LAI greater than 5 HU reliably predicted donor
livers without significant histological macrovesicular ste- FF = SIP − SOP /2 * SIP
atosis (≤5% steatosis). An LAI between −10 HU and 5
HU predicted mild to moderate macrovesicular steatosis where SIP is the signal intensity of a region of interest
(5% to 30%), which is a relative contraindication for (ROI) on the in-phase images and SOP is the signal
transplantation. An LAI less than −10 HU reliably pre- intensity of a similar ROI on the opposed-phase images.
dicted moderate to severe macrovesicular steatosis Figure 47-3 shows an example of severe macrovesicular
(>30%), which is a contraindication for transplantation. steatosis.
Figure 47-2 shows that there is a high degree of correla- Although the exact fat fraction cutoff for abnormal
tion between histological macrovesicular steatosis and liver fat has not been definitively established, a fat frac-
CT LAI.12 If CT LAI predicts severe macrovesicular ste- tion of 5.56% has been found to be the 95th percentile
atosis, the need for biopsy may be excluded. However, if cutoff in a group of patients with no risk factors for ste-
LAI is normal, biopsy may still be required to detect atosis.18 A fat fraction of less than 1.5% reliably predicts
underlying subclinical diffuse liver disease, including donor livers without significant histological macrovesicu-
hemosiderosis. lar steatosis (≤5% steatosis).14
MRI has also proven to be highly reliable in assessing There are confounding factors to fat fraction calcula-
hepatic steatosis, with study results showing stronger cor- tion using the T1 dual-phase gradient-echo method, one
relation with histological steatosis grade than that from of the most common of which is T2* decay from con-
CT13,15 and sensitivity/specificity of around 70% to comitant iron deposition disease. T2* correction
90%.14,16 The most widely used and accurate MRI decreases the likelihood that the fat fraction will be
underestimated because of the presence of iron. Other
30 confounding factors include the scanner platform used
and the specific imaging parameters.
20
MR spectroscopy has been studied extensively and can
10 also estimate the fat-fraction fairly well if appropriate
0 corrections are performed. More advanced MRI tech-
LAI (HU)

10 niques have also been developed to calculate the proton

20 density fat fraction, which is emerging as potentially the
most reliable method to estimate true fat fraction.
30
40
50 Hepatic Vascular Anatomy Analysis
60 Hepatic Arterial Anatomy
0 20 40 60 80 100
Histological steatosis (%) Anatomical variations of hepatic artery branching and ori-
FIGURE 47-2 n Linear graph demonstrates a high correlation
gin are common; the largest series to date demonstrated
between the liver attenuation index (LAI) and histological mac- variant arterial anatomy in 24.3% of 1000 patients under-
rovesicular steatosis. going liver harvesting.19 The hepatic arterial variants are

SI  425 SI  75

A B
FIGURE 47-3 n In-phase (A) and opposed-phase (B) gradient-echo images in a 31-year-old woman demonstrate significant decrease in
signal intensity (Si) from in-phase to opposed-phase images, compatible with diffuse steatosis. The calculated fat fraction is (425 −
75)/425*2 = 36.8%, suggestive of severe steatosis.
 47 Imaging Techniques for Partial Grafting 637

classified according to the Michels classification and are It is important to identify the arterial variations
as follows20: because preservation of all arteries supplying the right
Type 1: Normal; proper hepatic artery arises from the lobe is necessary to prevent postoperative ischemia in
common hepatic artery and divides distally to form the recipient. At the same time preservation of the
the right and left hepatic arteries (75.7%) (Fig. artery to segment IV is essential to ensuring adequate
47-4) regeneration of the remaining left lobe in the donor. If
Type 2: Replaced or accessory left hepatic artery aris- a segment IV artery arises from the right hepatic artery,
ing from the left gastric artery (9.7%) (Fig. 47-5) the division of the right hepatic artery must be distal to
Type 3: Replaced or accessory right hepatic artery the origin of the segment IV artery. Findings from
arising from the superior mesenteric artery (10.6%) CTA have correlated closely with conventional cathe-
(Fig. 47-6) ter angiography and operative findings, essentially
Type 4: Replaced or accessory left hepatic artery plus obviating the need for more invasive conventional
replaced or accessory right hepatic artery (2.3%) angiography.
(Fig. 47-7)
Type 5: Common hepatic artery arising from the Portal Venous Anatomy
superior mesenteric artery (1.5%)
Type 6: Common hepatic artery arising from the Variant portal venous anatomy is much less common
aorta (0.2%) than variant arterial anatomy, reported in approximately

RHA LHA
LGA
CHA

PHA
PHA
GDA CHA

GDA

FIGURE 47-4 n Three-dimensional volume-rendered computed

tomography angiography in a 52-year-old male potential liver FIGURE 47-6 n Three-dimensional volume-rendered computed
donor demonstrates normal hepatic arterial anatomy. CHA, tomography angiography in a 30-year-old male potential liver
Common hepatic artery; GDA, gastroduodenal artery; LHA, left donor demonstrates a big accessory right hepatic artery (white
hepatic artery; PHA, proper hepatic artery; RHA, right hepatic arrow) from the superior mesenteric artery (gray arrow). CHA,
artery. Common hepatic artery; GDA, gastroduodenal artery; LGA, left
gastric artery; PHA, proper hepatic artery.

CHA
LGA

FIGURE 47-5 n Three-dimensional volume-rendered computed FIGURE 47-7 n Three-dimensional computed tomography angi-
tomography angiography in a potential donor demonstrates a ography of a potential liver donor demonstrates an aberrant ori-
replaced left hepatic artery (arrow) from the left gastric artery gin of segment IV (white arrow) artery from the right hepatic
(LGA). CHA, Common hepatic artery. artery (gray arrow).
638 PART VI Split and Living Donor Transplantation

15% to 20% of the population.21-23 Some portal vein

variations include trifurcation (confluence of right poste-
Biliary Anatomy Evaluation
rior, right anterior, and left to the main portal vein) (Fig. Anatomic variants of the biliary system should be identi-
47-8), right anterior originating from the left portal vein, fied preoperatively to minimize the risk for biliary leak.
and left anterior originating from the right anterior por- Huang et al26 classified the variants of right lobe ductal
tal vein. These variations require dual anastomoses to the drainage into five types:
right and left portal vein in the recipient, whereas con- 1. Normal bifurcation (62.6% of normal population)
ventional bifurcation anatomy requires only a single (Fig. 47-10)
anastomosis. 2. Trifurcation (19%) (Fig. 47-11)
3. Right posterior duct drainage into the left main
Hepatic Venous Anatomy duct (11%) (Fig. 47-12)
4. Low-lying right posterior duct drainage into the
It is important to identify the branching pattern of the common hepatic duct (5.8%) (Fig. 47-13)
middle hepatic vein and hepatic venous variants to 5. Low-lying right posterior duct drainage into the
ensure that the graft can be adequately drained. The cystic duct (1.6%)
branching pattern of the middle hepatic vein affects the
location of the hepatectomy plane. Hepatic venous con-
gestion can occur as a result of decreased venous out-
flow compared to portal inflow because the middle
hepatic vein is not transplanted from living donors. The
degree of congestion has been shown to be accurately
predicted preoperatively using a CT-based quantitative
assessment.24
Common hepatic venous variants include an acces-
sory inferior right hepatic vein and an aberrant segment
VIII vein. The accessory inferior right hepatic vein
drains the posteroinferior portion of the right lobe
directly into the inferior vena cava in 68% of cases (Fig.
47-9). This aberrant vein requires special attention if it is
larger than 5 mm and should be preserved during sur-
gery to prevent the risk for graft malfunction. A large
aberrant segment VIII vein draining significant portions
of the anterior right lobe into the middle hepatic lobe
must also be identified preoperatively if it is larger than FIGURE 47-9 n Axial computed tomography hepatic venography
demonstrates a large accessory inferior hepatic vein (arrow)
5 mm; this variant requires additional surgical steps to draining the posteroinferior portion of the right lobe into the
prevent medial sector venous congestion.25 Additional inferior vena cava.
anastomoses of these major hepatic veins must be per-
formed to ensure the proper hepatic drainage in the
recipient after transplantation.

FIGURE 47-10 n Three-dimensional volume-rendered computed

FIGURE 47-8 n Three-dimensional computed tomography por- tomography cholangiogram shows normal biliary anatomy with
tography of a 44-year-old potential liver donor demonstrates normal bifurcation (white arrow) of a normal-sized common bile
trifurcation of the main portal vein (arrow). duct (gray arrow) and intrahepatic bile ducts.
 47 Imaging Techniques for Partial Grafting 639

Normal biliary bifurcation of donor liver requires only

a single choledochocholedochostomy or hepaticojejunos-
tomy in the recipient. In donor livers with biliary trifur-
cation or aberrant right lobe duct drainage, two separate
biliary anastomoses are necessary to prevent postopera-
tive biliary leakage and long-term segmental atrophy of
the graft. Preoperative determination of donor biliary
anatomy is thus essential for surgical planning. Although
MRCP has traditionally been the most accurate noninva-
sive means for mapping biliary anatomy, more recently
CTC has demonstrated similar or better visualization of
the biliary system.1,27

COMPREHENSIVE MAGNETIC
RESONANCE IMAGING
Because of technical advancements, it is possible to
use MRI/MRA as the sole preoperative imaging tech-
nique, providing comprehensive depiction of the bili-
ary and vascular systems and assessment of the hepatic
parenchyma.28,29 This is desirable for potential liver
donors, the majority of whom are young and other-
wise healthy individuals who should be spared unnec-
essary radiation exposure (estimated to be around 15
FIGURE 47-11 n Three-dimensional volume-rendered computed to 20 mSv for comprehensive CT donor evaluation).
tomography cholangiogram demonstrates trifurcation of the A comprehensive MRI/MRA evaluation would include
biliary duct (arrow) with right anterior, right posterior, and left
main bile ducts. T1-weighted in-phase and opposed-phase images to
evaluate for steatosis, T2-weighted MR cholangiog-
raphy to assess biliary anatomy, and MRA before and
after intravenous administration of gadolinium con-
trast to visualize the hepatic and portal/hepatic venous
systems. The use of a hepatobiliary-specific contrast
agent such as gadoxetate disodium or gadobenate
dimeglumine can further improve visualization of bil-
iary anatomy (Fig. 47-14).

FIGURE 47-13 n Computed tomography cholangiogram in a

potential liver donor demonstrates a low-lying accessory duct
FIGURE 47-12 n Three-dimensional volume-rendered computed draining the right posterior inferior hepatic segment (white
tomography cholangiogram demonstrates aberrant drainage of arrow) into the main hepatic duct. There is an additional acces-
the right posterior bile duct (white arrow) into the left main duct sory duct draining the left lateral segment (gray arrow) into the
(gray arrow). right hepatic duct.
640 PART VI Split and Living Donor Transplantation

3. Lee MW, Lee JM, Lee JY, et al. Preoperative evaluation of the
hepatic vascular anatomy in living liver donors: Comparison of CT
angiography and MR angiography. J Magn Reson Imaging; 2006:24:5.
4. Fan ST, Lo CM, Liu CL, et al. Safety of donors in live donor
liver transplantation using right lobe grafts. Arch Surg. 2000;
135:3.
5. Yongjun C, Chenghong P, Baiyong S, et al. Safety evaluation of
donors when performing modified extended right lobe hepatec-
tomy in ALDLT. Hepatogastroenterology. 2010;57:99-100.
6. Selzner M, Kashfi A, Cattral MS, et al. A graft to body weight ratio
less than 0.8 does not exclude adult-to-adult right-lobe living
donor liver transplantation. Liver Transpl. 2009;15:12.
7. Schiano TD, Bodian C, Schwartz ME, et al. Accuracy and signifi-
cance of computed tomographic scan assessment of hepatic volume
in patients undergoing liver transplantation. Transplantation.
2000;69:4.
8. Deroose JP, Kazemier G, Zondervan P, et al. Hepatic steatosis is
not always a contraindication for cadaveric liver transplantation.
HPB. 2011;13:6.
9. Zamboni F, Franchello A, David E, et al. Effect of macrovescicular
steatosis and other donor and recipient characteristics on the out-
come of liver transplantation. Clin Transpl. 2001;15:1.
10. Ploeg RJ, D’Alessandro AM, Knechtle SJ, et al. Risk factors for
primary dysfunction after liver transplantation–a multivariate anal-
ysis. Transplantation. 1993;55:4.
11. Angele MK, Rentsch M, Hartl WH, et al. Effect of graft steatosis
on liver function and organ survival after liver transplantation. Am
J Surg. 2008;195:2.
12. Limanond P, Raman SS, Lassman C, et al. Macrovesicular hepatic
steatosis in living related liver donors: Correlation between CT
and histologic findings. Radiology. 2004;230:1.
FIGURE 47-14 n Three-dimensional volume-rendered gadoxetate 13. Qayyum A, Nystrom M, Noworolski SM, et al. MRI steatosis
disodium (Eovist)–enhanced magnetic resonance cholangiogra- grading: Development and initial validation of a color mapping
phy in a 19-year-old man demonstrates good opacification of system. Am J Roentgenol. 2012;198:3.
the biliary tree. The left bile duct (white arrow), right bile duct, 14. van Werven JR, Marsman HA, Nederveen AJ, et al. Assessment of
and common bile duct (gray arrow) are well visualized. hepatic steatosis in patients undergoing liver resection: comparison
of US, CT, T1-weighted dual-echo MR imaging, and point-
resolved 1H MR spectroscopy. Radiology. 2010;256:1.
Pearls and Pitfalls 15. Qayyum A, Chen DM, Breiman RS, et al. Evaluation of diffuse
liver steatosis by ultrasound, computed tomography, and magnetic
resonance imaging: which modality is best? Clin Imaging. 2009;
• Both computed tomography (CT) and magnetic reso- 33:2.
nance imaging (MRI) can be used to reliably diagnose 16. Kim H, Taksali SE, Dufour S, et al. Comparative MR study of
hepatic steatosis and eliminate potential living donors; hepatic fat quantification using single-voxel proton spectroscopy,
however, biopsy is necessary to definitively exclude two-point dixon and three-point IDEAL. Magn Reson Med.
steatosis. 2008;59:3.
• Hepatic arterial variations are common and can be 17. Cassidy FH, Yokoo T, Aganovic L, et al. Fatty liver disease: MR
accurately identified preoperatively with CT angiogra- imaging techniques for the detection and quantification of liver
phy; MR angiography can provide comparable results steatosis. Radiographics. 2009;29:1.
if radiation exposure is a concern. 18. Szczepaniak LS, Nurenberg P, Leonard D, et al. Magnetic reso-
nance spectroscopy to measure hepatic triglyceride content: preva-
• Biliary variations can be assessed by MR cholangio- lence of hepatic steatosis in the general population. Am J Physiol
pancreatography or CT cholangiography and must be Endocrinol Metab. 2005;288:2.
identified to reduce the chance of postoperative biliary 19. Hiatt JR, Gabbay J, Busuttil RW. Surgical anatomy of the hepatic
leak; the use of hepatobiliary-specific contrast agents arteries in 1000 cases. Ann Surg. 1994;220:1.
such as gadoxetate disodium may improve biliary anat- 20. Michels NA. Newer anatomy of the liver and its variant blood sup-
omy assessment on MRI. ply and collateral circulation. Am J Surg. 1966;112:3.
• Portal vein variations require dual anastomoses to the 21. Atri M, Bret P, Fraser-Hill M. Intrahepatic portal venous varia-
right and left portal vein in the recipient. tions: prevalence with US. Radiology. 1992;184:1.
• An accessory inferior right hepatic vein variant most 22. Kamel I, Kruskal J, Raptopoulos V. Imaging for right lobe living
donor liver transplantation. Semin Liver Dis. 2001;21:2.
often drains directly into the inferior vena cava and 23. Lee KK, Lee SK, Moon IS, et al. Surgical techniques according to
   should be preserved if it is greater than 5 mm. anatomic variations in living donor liver transplantation using the
right lobe. Transplant Proc. 2008;40:8.
24. Hwang S, Lee SG, Park KM, et al. Hepatic venous congestion in
REFERENCES living donor liver transplantation: preoperative quantitative pre-
diction and follow-up using computed tomography. Liver Transpl.
1. Sommer CM, Schwarzwaelder CB, Stiller W, et al. Dual-energy 2004;10:6.
CT-cholangiography in potential donors for living-related liver 25. Erbay N, Raptopoulos V, Pomfret EA, et al. Living donor liver
transplantation: improved biliary visualization by intravenous mor- transplantation in adults: Vascular variants important in surgical
phine co-medication. Eur J Radiol. 2012;81:9. planning for donors and recipients. Am J Roentgenol. 2003;
2. Coskun M, Kayahan EM, Ozbek O, et al. Imaging of hepatic arte- 181:1.
rial anatomy for depicting vascular variations in living related liver 26. Huang TL, Cheng YF, Chen CL, et al. Variants of the bile ducts:
transplant donor candidates with multidetector computed tomog- clinical application in the potential donor of living-related hepatic
raphy: comparison with conventional angiography. Transplant Proc. transplantation. Transplant Proc. 1996;28:3.
2005;37:2.
 47 Imaging Techniques for Partial Grafting 641

27. Yeh BM, Breiman RS, Taouli B, et al. Biliary tract depiction in liv- 29. Lee VS, Morgan GR, Teperman LW, et al. MR imaging as the
ing potential liver donors: Comparison of conventional MR, man- sole preoperative imaging modality for right hepatectomy: a pro-
gafodipir trisodium-enhanced excretory MR, and multi-detecto­ r spective study of living adult-to-adult liver donor candidates. Am J
row CT cholangiography - Initial experience. Radiology. 2004;230:3. Roentgenol. 2001;176:6.
28. An SK, Lee JM, Suh K-S, et al. Gadobenate dimeglumine-
enhanced liver MRI as the sole preoperative imaging technique:
a prospective study of living liver donors. Am J Roentgenol.
2006;187:5.
 CHAPTER 48

Living Donor Transplantation

in Children
Koichi Tanaka • Yukihiro Inomata

CHAPTER OUTLINE

HISTORY AND SIGNIFICANCE OF PEDIATRIC Recipient Surgery

LIVING DONOR LIVER TRANSPLANTATION Vascular Reconstruction
ETHICAL ISSUES AND INFORMED CONSENT Hepatic Vein
Portal Vein
INDICATIONS Hepatic Artery
DONOR EVALUATION Bile Duct Reconstruction
Disease Transmission and Donor Selection SURGICAL COMPLICATIONS AND TREATMENT OF
Significance of HLA Matching in Living Donor RECIPIENTS
Liver Transplantation
Early Complications (Within One Month)
Size Matching and Anatomy of the Donor
Late Complications
Liver
Repeat Living Donor Liver Transplantation in
TECHNICAL CONSIDERATIONS Pediatric Recipients
Donor Surgery
IMMUNOSUPPRESSION
Left Lateral Segmentectomy and Left
Tolerance
Lobectomy
ABO Incompatibility in Pediatric Living Donor
Monosegment Harvesting
Liver Transplantation

HISTORY AND SIGNIFICANCE OF innovation to overcome the shortage of size-matched

PEDIATRIC LIVING DONOR LIVER deceased liver donors. Before the development of LDLT,
TRANSPLANTATION reduction of an adult graft for use in a pediatric patient was
attempted. In this procedure a large part of the graft was
The first living donor liver transplantation (LDLT) in discarded and thus did not help adult patients, who
the world was performed in Brazil by Raia in December accounted for the majority of patients on the waiting list. As
1988, but the recipient did not survive long.1 The first the next step, an innovative technique of splitting an adult
successful LDLT was reported by Strong et al2 in 1990. graft was developed and has become increasingly sophisti-
The recipient was a Japanese boy who received a left lat- cated.7 Even with the development of these techniques,
eral segment from his mother. Unfortunately, chronic there was still a shortage of organs. Subsequently LDLT
rejection developed a year later, and the patient under- was started. Pediatric recipients were preferred for two rea-
went retransplantation with a liver from a deceased donor. sons: parents can be most easily selected as potential donors
He has been doing well since then. He has been doing with the fewest ethical problems, and donor safety can be
well since then and is now working as a public servant. In more easily preserved by leaving the larger right lobe of the
1989 Nagasue et al3 performed the first LDLT in Japan donor intact after harvesting the left side of the liver. The
on a boy with biliary atresia. In the United States, Broel- left lobe is usually sufficient for the metabolic demands of a
sch et al4 started an LDLT program in Chicago in 1989 pediatric recipient.
and reported the cumulative result of 20 cases in 1990. Split-liver transplantation from deceased donors, if
Encouraged by these results, Ozawa in Kyoto and Makuu- sufficiently available, can reduce the number of pediatric
chi in Matsumoto started LDLT programs in Japan.5,6 patients waiting for organ donation without decreasing
In the first experiences with LDLT the target subjects the persistently inadequate donor pool for adult patients.
were pediatric patients. LDLT was developed as a technical So theoretically this procedure should be the first choice

642
 48 Living Donor Transplantation in Children 643

for pediatric liver transplantation in countries in which

TABLE 48-1 R
 elation of Living Donor Liver
deceased donor livers can be retrieved easily, as reported
Transplantation Donors in Japan
by the Rogiers group.8 However, splitting of deceased
donor livers is sometimes limited because of their mar- Pediatric
ginal condition and the reluctance of centers or surgeons Adult ≥ 18 yr (%) Age < 18 yr (%)
to establish split-liver programs, although such programs Son 30.3 0
have started to expand.9 Alternatively, the development Wife 12.7 0
and clinical application of LDLT could successfully Daughter 12.4 0
reduce mortality on the waiting list, as reported by both Brother 10.5 0.4
Essen and Brussels.10 Multimodal procedures, including Husband 10.5 0
the splitting technique and LDLT, should henceforth be Sister 7.8 0.2
considered as means of enlarging the overall donor pool Mother 5.5 52.4
for not only pediatric patients but also all recipients. At Father 5.2 42.8
least in pediatric recipients, LDLT already has a solid Grandparents 0 2.7
foundation. In selected institutions an adult liver surgeon Others 5.1 1.5
in one hospital and a pediatric transplant surgeon in a (n = 3875) (n = 2224)
children’s hospital are both involved in LDLT for the
pediatric recipient.11 Such combined participation is one Data from the registry of the Japanese Liver Transplantation
means of respecting specialization on both sides. LDLT Society, 1989-2010.
can be electively done, and this is suitable for the treat-
ment of pediatric hepatic malignancies that need the mul-
timodal planned strategy. With recent technical the donor is usually one of the parents, a situation that
innovation, LDLT has been expanded to smaller or even affords the best matching of the donor and recipient
newborn babies with congenital metabolic diseases or ful- with the least ethical conflict. Preserving the life of their
minant hepatic failure. child may be very gratifying for parents. However, in
some instances, social pressure may oblige the parents to
become donors. During the informed consent process,
ETHICAL ISSUES AND INFORMED other means to avoid being a living donor should always
CONSENT be mentioned after all the risks and benefits of LDLT
have been explained to the family in complete detail. In
Even in donation for pediatric recipients, living liver rare cases, siblings or parents younger than 18 years may
donors have a potential of mortality and morbidity. In be included as donor candidates for pediatric LDLT. In
general, the balance between donor safety and hope for such cases, not only their emotional response to being a
the recipient’s survival should define the availability of living donor but also their competence to understand
LDLT. This balance is affected by the availability of the LDLT process and donor risk should be carefully
deceased donors, so this situation should be different in evaluated during the initial stages of the LDLT process.
each country.12 In the United States the annual number Grandparents may be also included among the donor
of LDLTs had a peak in 2001, more than 500, and has candidates, and in such cases extra risk to an elderly
been decreasing since then. This might be related to the donor should be included in the informed consent dis-
donor death in 2002 in an adult LDLT.13 In Japan the cussion after meticulous evaluation of the health of the
first and only mortality of a live liver donor occurred in donor candidate. In repeat LDLT after initial failed
2002, also in a case for an adult recipient.14 In Japan the LDLT, donor selection tends to be harder than in the
annual number of LDLTs had a peak of 566 in 2005 and initial one. When the donor is a more distant relative,
has also decreased since then. However, the number for such as an uncle or aunt, voluntary willingness should be
pediatric patients is quite stable, around 140 per year. At carefully ascertained. In general, donor candidates
least in emergency cases or for pediatric patients, LDLT should be interviewed independently in the absence of
will remain significant from now on. In Asian countries the recipient and other family members. If the parents
LDLT has been well accepted and has developed into are divorced, the parent living with the child is usually
the main liver transplantation technique performed selected as the donor; however, the noncustodial parent
because the concept of brain death is not well established may be included as a donor candidate if so desired.
in this region.15 In recent years, even in Asian countries During the informed consent process, it is essential
like Korea, the number of deceased donor liver trans- that the possibility of donor mortality be included. In a
plantations (DDLTs) is increasing.16 In Japan, an inno- survey of 3565 LDLTs in Japan, the incidence of compli-
vative law for organ donation became effective in 2010, cations after donor surgery was 8.4% overall, 9.4% for
and the number of DDLTs is now increasing.17 This right lobe donation, 8.7% for left lobe donation, and 3.5%
may change the balance of DDLT and LDLT in the for left lateral segment donation.18 According to the
near future. In Japan the relationship between the donor report of Lo19 in a review of Asian LDLTs in 2003, the
and the recipient is regulated by the principle of the incidence of complications for donors was 9.3% for left
Japanese Society of Transplantation that the donor and lateral segmentectomy and 7.5% for left lobectomy (Table
recipient should be relatives (Table 48-1). Official docu- 48-2). From the recent report from Kyoto University, the
ments identifying the donor and the donor’s relation- incidence of biliary complications in left-sided graft
ship to the patient are mandatory. In pediatric LDLT donors was significantly lower than that of right-sided
644 PART VI Split and Living Donor Transplantation

TABLE 48-2 C
 omplications of Donors After TABLE 48-3 C
 omplications of Donors After
Living Related Liver Transplantation Living Related Liver Transplantation
in Asian Centers at Kyoto University Hospital
Lateral Left Group RG Group LG
Segmentectomy Left Lobectomy (n = 500) (n = 762) P
Complication (n = 605) (n = 334)
Biliary Complications
Bile leakage 33 8 Bile leakage 53 (10.6%) 36 (4.7%) <0.05
Hyperbilirubinemia 2 0 Biliary stricture 8 (1.6) 2 (0.3) <0.05
Small bowel 5 1 Other Abdominal
obstruction Complications
Biliary stricture 1 0 Fluid collection 46 (9.2) 7 (0.9) <0.05
Pulmonary 0 1 Skin wound infection 26 (5.2) 36 (4.7) NS
embolism
Small bowel 13 (2.6) 15 (1.9) NS
Pancreatitis 1 0 obstruction
Bleeding duodenal 1 0 Intra-abdominal abscess 8 (1.6) 2 (0.3) <0.05
ulcer
Drug-induced 6 (1.2) 6 (0.8) NS
Gastric perforation 0 1 hepatotoxicity
Wound infection 9 10 Massive ascites 5 (1.0) 1 (0.1) <0.05
Gastric outlet 4 3 Hyperamylasemia (>300 4 (0.8) 1 (0.1) <0.05
obstruction IU/L)
Pneumonia 0 1 Hyperbilirubinemia 3 (0.6) — —
Total (%) 56 (9.3) 25 (7.5) Gastritis/intractable 2 (0.4) 8 (1.1) NS
ulcer
Modified from Lo CM. Complications and long-term outcome of
Portal venous 1 (0.2) — —
living liver donors: a survey of 1508 in five Asian centers.
thrombosis
Transplantation. 2003;S12-S15.
Liver failure 1 (0.2) — —
Others 2 (0.4) 4 (0.5) NS
Extra-abdominal
graft donors (Table 48-3).20 Unlike adult LDLT, in pedi- complications
atric LDLT, postdonation liver failure is considered Pleural effusion 22 (4.4) — —
unlikely in the donor, but events such as pulmonary Pulmonary embolism 6 (1.2) 5 (6.5) NS
embolism or serious infectious episode may nevertheless (including suspected
result in death of the donor.15 Bile leakage is commonly cases)
cared for conservatively or with simple drainage, but some Fever of unknown 3 (0.6) 8 (1.1) NS
may need relaparotomy. Adhesion of the gastric wall to origin
the cut surface of the liver also occurs more frequently Others 12 (2.4) 12 (1.6) NS
after left-sided hepatectomy than after right lobectomy. From Iida T, Ogura Y, Oike F, et al. Surgery-related morbidity in
Such adhesion causes gastric stasis (Fig. 48-1). With accu- living donors for liver transplantation. Transplantation.
mulation of LDLTs, various complications have been 2010;1276-1282.
experienced, such as pleural effusion, peptic ulcers, tem- Group RG, Right lobe graft donors; Group LG, left lobe or left lateral
porary numbness of extremities, palsy of vocal cord, ugly segment donors.
scar of the wound, and so on. Donor candidates should be
informed in advance about all the possible donor risks.
Even though the recipients are children, they have the However, in LDLT the organ is donated to a specified
right to select the treatment option according to their age recipient and not shared by other candidates. There-
and ability. Family members or physicians and coordina- fore the indication is not affected by the problem of
tors must explain the treatment before the procedure. organ allocation as it is in deceased donor transplanta-
During puberty or adolescence, LDLT is sometimes tion. Contraindications to deceased donor transplanta-
difficult for patients to accept. They may be distressed to tion are not necessarily the same for LDLT. For
live with the sacrifice being made by their parent or example, cases with malignant disease such as hepato-
relative. They may experience considerable anxiety about blastoma, which is large and invasive, may be consid-
the operation and the future if not completely informed. ered to have low priority or be excluded from listing in
Their anxiety should be relieved after a patient, thorough deceased donor transplantation. However, in LDLT
explanation. The goal that all family members can enjoy the operation might be done with full understanding of
and participate in the happy, healthy life of the patient the potential donor, recipient, and other relatives about
should be presented as the motivation for LDLT. the potential risk for recurrence of the original disease
and risk of the surgery itself.21 The advantage of LDLT
is that total hepatectomy and transplantation can be
INDICATIONS done on an elective basis. Chemotherapy followed by
LDLT and the following posttransplant chemotherapy
Indications for LDLT are basically not different from can be organized as one treatment strategy for advanced
those for deceased donor transplantation (Fig. 48-2). hepatoblastoma.
 48 Living Donor Transplantation in Children 645

A B
FIGURE 48-1 n Adhesion of the gastric wall to the cut surface of liver after left lateral segmentectomy in pediatric living related liver
transplantation. A, Gastric stasis as a result of outlet obstruction. B, Computed tomography shows the hairpin curve of the gastric
outlet at the adhesion site (arrow).

N=2148
immunodeficiency virus; electrocardiography; chest radi-
Metabolic Others
2% ography; and ultrasonography of the liver. After prelimi-
disease
9% nary examination the results are presented as a tool for
Fulminant selecting the final candidate.
hepatic failure The age of the donor should ideally be between 20 and
9% 60 years, although we include 60 to 70 years if no younger
donor is available. Younger candidates should be evalu-
Tumor 3% ated for their competence in making a voluntary decision.
Candidates older than 60 years are judged on an individ-
Cirrhosis 2% ual basis in terms of cardiopulmonary and neurological
Cholestatic function in addition to the routine workup.
(91%: biliary atresia) Postoperative pulmonary embolism is a genuine threat
75% to the donor. Smoking, routine use of birth control pills,
or serious obesity should be considered a possible risk
factor for this complication. The possibility of diet and
correction of the habit is one of the advantages of living
FIGURE 48-2 n Indications for pediatric living related liver trans-
donor transplantation. A body mass index greater than 30
plantations (not including retransplantation) in Japan. The most should be corrected, or an alternative donor should be
common indication is cholestatic disease, mainly biliary atresia. selected out of concern for the donor’s safety.
(Data from the registry of the Japanese Liver Transplantation Soci- ABO blood typing should be identical or compatible in
ety from 1989 to 2010.) general, but in pediatric recipients younger than 2 years,
ABO combination does not affect the outcome even under
the conventional immunosuppression (see later). The sec-
DONOR EVALUATION ond line of screening is endoscopy of the upper and lower
gastrointestinal tract, blood tests to check for tumor mark-
Donor evaluation in LDLT is necessary both for the ers (α-fetoprotein, carcinoembryonic antigen), respiratory
safety of the donor and recipient (Table 48-4). Suitable function tests, echocardiography, and an imaging study of
donors can be selected on the basis of two perspectives: the liver. The imaging study of the donor liver is impor-
(1) donors with normal liver function and normal anatomy tant to ensure safe surgical procedures in both the donor
with adequate size of the liver and (2) donors without any and recipient. For this purpose, three-dimensional (3-D)
systemic diseases, abnormalities, and high possibility of computed tomography (CT) angiography is a suitable
postoperative risks. In Japan, criteria for donor selection modality because it is less invasive and provides consider-
are determined in each institution with approval of the able information.22 Conventional catheter angiography is
institution’s review board (Table 48-5). As the initial not necessary because it is invasive for the donor. Mag-
phase, preliminary conditions such as age, relationship to netic resonance imaging may present the same informa-
the recipient, ABO blood matching, and history of any tion as enhanced CT does without serious risk for the
diseases can be identified. After full consent has been allergy to the contrast dye, but sometimes the images are
given, the medical tests start. If multiple candidates are not as clear as those obtained with CT.23 It is important to
available, conventional studies may be performed at the assess the potential volume of the graft in adult transplan-
initial screening for each if requested. Such studies tation because the graft is sometimes critically small.
include a blood count; coagulation profile; blood chem- When the right lobe is necessary for bigger recipients
istry studies for hepatic and renal function; serological from relatively smaller donors, residual volume after the
tests for hepatitis C and B virus, syphilis, and human graft harvesting should also be estimated. Thirty percent
646 PART VI Split and Living Donor Transplantation

TABLE 48-4 Donor Workup TABLE 48-5 F

 actors Involved in Donor Selection
for Living Donor Liver
Confirmation of voluntary willingness to donate after a full
explanation of the risks and benefits
Transplantation (Kumamoto
Confirmation of cooperative and supportive willingness of University)*
the donor candidate’s intimate relatives/spouse
Medical history Age: 20-70
No major current diseases or drug therapy Relation to the recipient: parents, siblings, offspring,
No history of malignancies (confirmation of “cure” if spouses, grandparents, uncles, and aunts
positive) ABO matching: compatible or identical (incompatible is not
No history of transmittable diseases (confirmation of a excluded)
nontransmittable state if positive) HLA matching: (a donor with homozygous haploidentical
Blood tests HLA to the recipient is excluded)
Complete blood count; biochemical studies, including Health of the donor
renal and hepatic function; coagulation profile (pro- History and present condition of any systemic diseases
thrombin time, activated partial thromboplastin time, Assessment of the present disease (consult a specialist)
levels of fibrinogen and antithrombin III, bleeding time) (Take care to asthma, diabetes mellitus, and hyper-
Serological tests for hepatitis A, B, and C; sexually tension)
transmitted diseases; human immunodeficiency virus; Obesity (body mass index > 30)
human T-lymphotrophic virus 1; cytomegalovirus; and Time after delivery of a child (should be longer than 1
Epstein-Barr virus month)
Tumor markers (α-fetoprotein, carcinoembryonic antigen, Blood chemistry (liver and kidney), complete blood count,
CA 19-9, CA 125) coagulation profile
ABO blood group, preformed irregular antibodies Electrocardiogram and ultrasonic cardiogram (UCG),
HLA typing chest and abdominal plain radiographs
Electrocardiogram Arterial blood gas analysis and ventilatory function
Chest and abdominal plain radiographs Neurological evaluation if older than 60 years (brain MRI)
Spirogram or arterial blood gas analysis Psychological status (evaluation by psychiatrist if
Abdominal ultrasonography of the hepatic parenchyma and indicated)
vasculature, evaluation of other abdominal organs Disease transmission
Abdominal computed tomography (assessment of hepatic Hepatitis B, C, HIV, HTLV1
parenchyma, three-dimensional reconstruction of blood, Malignancy
vessels, and estimation of graft volume) Tumor markers (carcinoembryonic antigen,
Needle biopsy of the liver if steatosis is reasonably α-fetoprotein, CA 19-9, CA 125)
suspected Endoscopy of the upper and lower gastrointestinal tract
if older than 40 years
HLA, Human leukocyte antigen. No residual tumor after the treatment of any previous
malignant disease
Metabolic diseases: loading test, liver biopsy for assess-
ment of target enzyme activity
of the whole liver is commonly used as the smallest limit Graft quality and volume
of the residual volume. Segmental volume can be calcu- Doppler and conventional ultrasound: fatty liver, space-
occupying lesion (SOL)
lated using commercially available simulation software.24 Three-dimensional computed tomography: fatty liver,
In pediatric cases the graft is usually selected among the architecture of vessels (veins, arteries)
whole left lobe and the whole or a part of the left lateral Three dimensional computed tomographic cholangiogra-
segment. Small-for-size problems are rare, but in small phy: branching pattern of the bile duct
infants, large-for-size problems are more important. In Needle biopsy of the liver (if steatosis or other pathology
is suspected on ultrasound, computed tomography, or
addition to the volume of the graft, the size of the poten- blood chemistry)
tial graft estimated on CT scan should be compared with More than 30% of the fatty infiltration should be excluded
the diameter of the peritoneal cavity of the recipient. and treated by diet
Preoperative 3-D bile duct imaging of the donor liver Computed tomographic volumetry
Expected graft volume > 0.7%, < 4% of the recipient’s
is also informative for both adult and pediatric cases, body weight
although there is a concern about hypersensitivity for the Residual liver after donation > 30% of the whole liver of
contrast medium.25 the donor
Fatty liver is a common contraindication to donation,
*Patients with values out of the range in each criterion are
with fatty infiltration of more than 25% to 35% being a evaluated on an individual basis.
criterion for exclusion.26 In LDLT the use of a fatty liver HIV, Human immunodeficiency virus; HLA, human leukocyte
graft up to the moderate level can be justified, even antigen; HTLV-1, human T-lymphotrophic virus 1; MRI, magnetic
though ischemia-reperfusion injury tends to be severe in resonance imaging.
such grafts.27 In our institution the averaged plain CT
value of the liver measured at multiple spots is compared
with that of the spleen. If the ratio is lower than 1, which
means that the liver has less density than the spleen does,
Disease Transmission and Donor Selection
fatty infiltration is more than 30%. However, an exact In pediatric LDLT, inherited diseases such as metabolic
diagnosis of the degree of fatty infiltration depends on disorders and Alagille syndrome are not as rare as the
preoperative liver biopsy. Accurate diagnosis of nonalco- indication. If a parent is selected as the donor, the poten-
holic steatohepatitis, which may be suspected from tial donor may have an inheritable genetic factor or a
hepatic profile and imaging studies, also depends on the subclinical manifestation of the disease. A genetic analy-
pathological findings by needle biopsy. sis, metabolic loading test, or measurement of the target
 48 Living Donor Transplantation in Children 647

enzyme in a liver specimen taken by needle biopsy may

TABLE 48-6 Donor Contraindications
be helpful as a tool for possible exclusion of such patient
from becoming a donor candidate.28 In case of Alagille Infectious diseases
syndrome, pathological diagnosis of paucity of the intra- Hepatitis B surface antigen, hepatitis C virus antibody,
hepatic bile ducts should be considered and investigated human immunodeficiency virus: positive
Active infection with any pathogen
in the potential donor. However, adults with subclinical Uncured malignancy
Alagille syndrome may have only mild elevation of biliary Major systemic or organ diseases inappropriate for
tract–related enzymes without any sign of cholestasis. hepatectomy
Magnetic resonance cholangiopancreatography or drip Liver abnormality or dysfunction
Steatosis greater than 30%
infusion cholangiography–CT should be done in poten- Rare variant of vascular anatomy that may make harvesting
tial donors suspected of having subclinical Alagille dangerous
syndrome.29 Subclinical phenotype of the inheritable diseases of the
Ruling out infectious diseases or malignancy is not spe- recipient
cific for determining acceptability for LDLT. Nonethe- Metabolic diseases
Alagille syndrome
less, if there is a patient with a disease such as tuberculosis One-way mismatch in HLA typing
or hepatitis in the family of the patient, the possibility of
latent or previous subclinical infection of the donor candi- HLA, Human leukocyte antigen.
dates is high. Careful examination of the donor candidates
is necessary in such a situation. Contraindications to
donor selection are summarized in Table 48-6. identified, and in such cases it is better to use an alter-
native donor.
Significance of HLA Matching in Living
Donor Liver Transplantation Size Matching and Anatomy of the Donor
As in the case of deceased donor transplantation, the
Liver
impact of human leukocyte antigen (HLA) matching on In most pediatric LDLT, graft options consist of the full
the outcome has been controversial in the LDLT set- left lobe, including the middle hepatic vein (segments II,
ting. In pediatric LDLT the donor is usually one of the III, and IV); the left lateral segment with a part of segment
parents, which means that the recipient has haploidenti- IV, but without the middle hepatic vein; the left lateral
cal HLA typing. Sugawara et al30 reported that zero segment (segments II and III); and the partial or reduced
HLA mismatching was associated with a low incidence left lateral segment (segment II or segment III, or reduced
of acute rejection in 58 pediatric LDLT cases. Part of both). Selection of the graft is based on the potential vol-
this advantage may be related to the better HLA match- ume of the graft in relation to the recipient’s body size.
ing in LDLT. However, a study of HLA matching in The relative size of the standard liver volume is used as
the series of pediatric LDLTs by Kasahara et al31 one of indices.35 We use the ratio of graft weight to recipi-
showed poor correlation of HLA matching and the inci- ent body weight: graft weight (g)/recipient’s body weight
dence of rejection. The zero-mismatch group had a ten- (g) × 100 (%).36 If this ratio is within 1% to 3%, the graft
dency toward a lower incidence of steroid-resistant size is considered adequate. Generally the left lobe is used
rejection and a lower level of tacrolimus maintenance 5 in a recipient with a body weight between 20 and 40 kg,
years after LDLT and a higher rate of withdrawal of whereas the left lateral segment or the left lateral segment
immunosuppression, although there was no significant plus a portion of segment IV is used for smaller recipients.
difference. By the analysis of the OPTN/UNOS Liver When a slightly larger graft than the left lobe is necessary,
Transplant Registry, HLA matching correlated with the left half of the caudate lobe can be added.37 By preop-
graft survival in autoimmune hepatitis, but not in chir- erative volumetry, the volume of the potential graft can be
rhosis.32 In one recent analysis of adult liver transplan- estimated in cubic centimeters. The specific gravity of the
tation, poorer HLA matching had the possibility of hepatic graft is considered to be 1. Therefore volume is
better outcome and of the special influence of the calculated in the same manner as weight. If the potential
HLA-A locus.33 Longer follow-up and further accumu- graft is 200 g and the recipient’s body weight is 10 kg, the
lation of experience is necessary to clarify the role of ratio is 2%. The smallest unit in conventional LDLT is
HLA matching in LDLT. the left lateral segment. If the ratio of graft weight to
A definite merit of pre-LDLT HLA matching is the recipient body weight is more than 4%, poor perfusion of
predictability of possible graft-versus-host disease the graft may cause unsatisfactory primary function. In
(GVHD). After liver transplantation, GVHD is gener- general the mother may be more suitable than the father
ally a rare complication. In LDLT from parent to off- in infantile cases because of her possibly smaller liver. Of
spring, the donor may have homozygous HLA typing course, after information is provided about the risks of the
and the recipient, heterozygous typing. In such a case large-for-size problem, the final decision should be made
involving a so-called donor-dominant one-way donor- in the family. If only a large donor liver is available, reduc-
recipient HLA matching at three loci, the incidence of tion of the left lateral segment is necessary. Monosegment
GVHD has been reported to be high in organ trans- transplantation using segment II or III or a part of both, as
plantation, including liver transplantation.34 Before discussed later in this chapter, is a solution in such a case.
LDLT the potential for matching a homozygous donor Regarding size matching, the size of the graft should be
with a heterozygous recipient in HLA typing should be compared with the size of the recipient’s peritoneal cavity
648 PART VI Split and Living Donor Transplantation

P2
P3 P3

P2
P2
P3

A B
FIGURE 48-3 n Variation of the portal vein to the left lateral segment. The portal vein to segment III (P3) and segment II (P2) is branch-
ing separately. If this lateral segment is taken as the graft, the graft will have two orifices in the portal stump. A, Three-dimensional
computed tomography. B, Ultrasonography.

on CT images. If the anteroposterior diameter of the

potential graft is greater than the anteroposterior diam-
eter of the recipient’s peritoneal cavity by 2 cm or more,
primary closure is expected to be difficult. In such a case,
skin closure or prosthesis closure can be used, but this
technique may cause more trouble than simple closure.
Because the left lobe is more commonly used than the
right lobe, the anatomy of the left lobe of the donor is an
important factor in LDLT in pediatric recipients. In left
lateral segmentectomy the hepatic vein from segments II
and III may become separated on entry into the inferior
vena cava (IVC). In left lobectomy the left and middle
hepatic veins may also separately drain into the IVC. Con-
sideration of such possibilities is necessary before LDLT.
Regarding the anatomy of the portal vein, P2 and P3 may
branch separately from the main portal trunk and form a
trifurcation with the right portal trunk (Fig. 48-3). A left-
sided gallbladder is frequently associated with this variation
of the portal vein.38 If available, an alternative donor should
be chosen. On evaluation of the donor artery, an aberrant
left hepatic artery arising from the left gastric artery is not
very rare. This artery is in the lesser omentum, and atten-
tion should be paid to preserving as long a vessel as possible
because a longer vessel can be more easily used as the recon-
struction vessel (Fig. 48-4). When left lobectomy is being FIGURE 48-4 n Aberrant hepatic artery supplying the left lateral
segment (long arrow) originating from the left gastric artery. If
considered, the size and distribution of the middle hepatic the main left hepatic artery (small arrow) is small, this aberrant
artery should be assessed. For evaluation of bile duct anat- artery may be large. For reconstruction in the recipient, this
omy, 3-D reconstruction CT is very useful. Preoperative artery should be kept long by transecting as indicated by the
assessment by such imaging facilitates better understanding double line.
of the intraoperative cholangiogram (Fig. 48-5).
caudate lobe is dissected from the left wall of the IVC.
After dissection of this area the hepatic porta is approached.
TECHNICAL CONSIDERATIONS The left hepatic artery is dissected proximally to the point
at which it branches from the common hepatic artery. If
Donor Surgery the middle hepatic artery is supplying the left lateral seg-
Left Lateral Segmentectomy and Left ment, it should also be dissected. The bifurcation of the
Lobectomy left hepatic duct is not necessarily identified in the left
lateral segmentectomy. Instead, the wall of the left hepatic
The abdomen is opened through an inverted T incision. duct is identified just on the surface of the left portal vein,
The horizontal incision can be very short in left lateral usually through the space between the middle and left
segmentectomy. In a thin donor, only the median incision hepatic arteries (Fig. 48-6). Small hemoclips are applied
can be enough. After transection of the falciform liga- here as markers for the transection site on the intraopera-
ment, intraoperative Doppler ultrasonography is per- tive cholangiogram. A 24-gauge intravenous catheter is
formed to confirm the anatomy of the hepatic and portal inserted directly into the common bile duct and used for
veins. The Arantius duct is transected just at the entrance the cholangiogram in left lateral segmentectomy. At the
to the left hepatic vein. The most cranial portion of the time of intraoperative cholangiography, the common bile
 48 Living Donor Transplantation in Children 649

FIGURE 48-5 n Three dimensional reconstruction of drip infusion FIGURE 48-7 n Parenchymal transection in left lateral segmentec-
cholangiography–computed tomography of the donor. The tomy. After transection of the left hepatic duct, the left portal
image can be rotated on the monitor, and the branching can be vein is encircled. If curved DeBakey forceps are inserted between
easily identified. the lateral segment and the caudate lobe and pulled up ven-
trally, a crest of parenchyma is fashioned. With this procedure
the direction of transection is clearly shown, and the operating
field is made shallow. The operator holds the forceps in the left
hand and uses the right hand to manipulate the Cavitron ultra-
sonic aspirator (CUSA).

route of the middle hepatic vein in left lobectomy. The

parenchymal transection is performed with the Cavitron
ultrasonic aspirator (CUSA) held by the surgeon and VIO
soft-coagulation system held by the first assistant.40 The
bile duct is sharply transected at the marked site in the
intraoperative cholangiography. The stump on the donor
side is closed with 6-0 absorbable running suture, whereas
FIGURE 48-6 n Identification of the left hepatic duct in left lateral the graft side is left open. Bleeding from the bile duct
segmentectomy. Between the left and middle hepatic arteries stump on the graft side is ceased with suturing, not with
on the ventral surface of the left portal vein, a wall of the left coagulation. After transection of the bile duct, the left
hepatic duct can be identified. Tracing the hepatic duct from the portal vein can easily be encircled. Once the portal vein is
bifurcation of the hepatic ducts is not necessary.
encircled, curved DeBakey forceps are inserted under the
left lateral segment along the fissure between the segment
duct on the duodenal side and the neck of the gallbladder and the caudate lobe. After the segment is pulled up with
are clamped with small bulldog clamps. In left lobectomy, the forceps, the transection line is easily identified and
cholangiography is performed through the cystic duct resembles a crest in a valley (Fig. 48-7). This is a kind of
because the gallbladder is resected. Because branches may hanging maneuver using the forceps.
overlap on the film, fluoroscopic images using a C-arm Once the parenchymal transection is completed, hepa-
may be more helpful for identification of each duct if the rin sodium (1000 U/body) is injected intravenously just
operating table is tilted while the operator is watching the before harvesting. Usually in situ perfusion of the graft is
x-ray images. The left portal vein is identified but can be possible in left lobe resection because the left portal trunk
encircled later after transection of the left bile duct. Some is long enough for insertion of the perfusion catheter.
institutions prefer the transection of bile duct later after First, the hepatic artery is transected. After clamping the
transection of the hepatic parenchyma because of better portal vein at the bifurcation, a perfusion catheter is then
visualization. In our institution, parenchymal transection inserted into the left portal vein before transecting the
is performed without clamping the hepatic pedicle. portal vein. Clamping of the left hepatic vein or the com-
Makuuchi’s group recommends a Pringle procedure for mon trunk of the middle and left hepatic veins is followed
donor hepatectomy.39 A line of transection is 0.5 to 1 cm by transection of the vein or veins, and portal perfusion of
to the right along the falciform ligament in left lateral the graft is started immediately. To facilitate easier recon-
segmentectomy and along the right side of the traced struction in the recipient, one orifice of the graft vein is
650 PART VI Split and Living Donor Transplantation

A B
FIGURE 48-8 n Reduced left lateral segment transplanted from the mother to her 3.5-kg 1-month-old boy. In this case the left lateral
segment was 200 g, and the transplanted graft was 140 g. A, Marking the reduction on the surface of the left lateral segment. B, After
reduction the graft weighs 140 g.

mandatory. To make a single orifice, transection of the which is the most common indication for pediatric
Arantius duct and the left phrenic vein is helpful for LDLT, one or more surgical interventions such as the
deeper clamping of the common trunk of the left and Kasai procedure have usually been performed
middle hepatic veins in left lobectomy.41 After it has been previously. In these cases, the bowel is firmly attached
confirmed that the color of the perfusate drained from the to the anterior margin and lower surface of the liver.
hepatic venous stump has lightened, the graft is removed Numerous collaterals are passing through these
from the peritoneal cavity and transferred to a basin filled adhesions. Meticulous adhesiolysis by electrocautery is
with preservation solution. Weight of the graft is mea- useful to shorten the duration of surgery and decrease
sured. In situations in which the cold preservation time blood loss. Possible burn of the bowel can be prevented
should be kept as short as possible, as in a donor with with intermittent flushing of water over the bowel. The
hepatic steatosis, the graft should remain vascularized in Roux-en-Y limb made in the Kasai operation should be
the body of the donor after parenchymal transection until kept as long and intact as possible. Hepatic arteries are
the recipient side is ready for implantation. transected as distally as possible to facilitate selection of
Recently, laparoscopic or laparoscopic-assisted (hybrid a vessel of appropriate diameter for reconstruction.
approach) left lateral segmentectomy has been reported Usually the wall of the hepatic artery is very fragile in
and is being expanded in donor surgery of LDLT.42,43 In small babies. To prevent intimal dissection of the
respect of the donor safety, the team should be well- artery, manipulation should be done gently. After
trained in preparation to perform such an advanced transection of the hepatic arteries, the portal vein is
technique. dissected and should be preserved untransected if
When a vein graft is expected to be necessary during possible until the last phase of the hepatectomy.
the recipient procedure, the ovarian or inferior mesen- However, in fact, pediatric patients usually tolerate the
teric vein can be harvested from the donor. total occlusion of the portal vein during the procedure
of hepatectomy until graft reperfusion, even in cases of
Monosegment Harvesting noncirrhotic diseases without preformed collateral
vessels. In LDLT, hepatectomy is performed with the
In small babies it is difficult to keep the graft-recipient IVC left intact. In patients without cirrhotic changes in
body weight ratio less than 4%. If the recipient has a large their livers, as in those with metabolic diseases, it is not
peritoneal cavity, which is common when ascites is mas- difficult to dissect the retrohepatic space while
sive, a large graft can be accommodated easily. However, preserving the IVC, even if the hepatic pedicle is not
from the perspective of graft perfusion, it is better to keep transected. This technique can reduce the clamping
the ratio less than 4%. When the ratio is larger than 4%, time of the portal vein as much as possible. In cases of
monosegmental transplantation can be performed. The cirrhosis, as in biliary atresia, transection of the hepatic
left lateral segment is cut down in situ before the hepatic hilum before dissection of the retrohepatic space makes
pedicle is transected in the body of the donor. Segment II hepatectomy easier. In such a case, cutting the portal
or III is used with reduction of the other tissue. To obtain vein in the early phase of the hepatectomy does not
the thinner graft for small babies, segment II is more suit- usually cause severe congestion of the bowel because of
able. In our institution a 2.6-kg newborn baby with the presence of so many preformed collateral vessels. In
hemochromatosis underwent LDLT from his father general, venovenous bypass or a temporary
using such a graft. Kasahara has applied a hyperreduced portosystemic shunt is not necessary in pediatric
graft for small babies.44 This hyper-reduced graft shows a LDLT, regardless of the indication. After transection
cuboidal shape with cutting edge (Fig. 48-8). of the short hepatic veins, a blunt dissector can easily be
passed through the avascular space just to the left of the
Recipient Surgery right hepatic vein to encircle the root of the right
hepatic vein. Transection of the right hepatic vein
Recipient surgery consists of total hepatectomy and followed by transection of the middle and left hepatic
reconstruction of vessels. In patients with biliary atresia, veins completes the hepatectomy.
 48 Living Donor Transplantation in Children 651

recipient’s hepatic venous stump is reported to be an easy

and safe method by Makuuchi and Sugawara.47 Sakamoto
from the Kyoto group pointed out the high incidence of
hepatic vein stenosis in cases with multiple orifices of
hepatic vein in the graft and smaller ratio of the graft to
the recipient body size.48 As the prophylaxis they recom-
mend a cuff insertion on the anterior side of the hepatic
vein anastomosis, although it is still controversial as to
whether such a cuff is really effective or not. To prevent
restriction of outflow secondary to torsion on the graft,
the vascular pedicle should be short. In patients with bili-
ary atresia, retrohepatic IVC may be incorporated into
the severely hypertropic caudate lobe. In patients with
situs inversus or polysplenia syndrome, the retrohepatic
IVC may be completely absent. In such cases, the hepatic
vein of the graft is anastomosed in an end-to-end fashion
FIGURE 48-9 n Hepatic venous anastomosis using the stump of
with complete clamping of the suprahepatic IVC, or even
the middle and left hepatic veins. The right edge of the middle the wall of right atrium (Fig. 48-10). Venovenous bypass
hepatic vein is incised to enlarge the orifice to a dimension in is also not usually necessary in these cases because of
keeping with the size of the graft hepatic vein. This technique good collaterals.
fixes the graft to the wall of the inferior vena cava itself and is
helpful in preventing rotation of the graft.
Portal Vein

Vascular Reconstruction In pediatric LDLT, portal vein reconstruction is one of

the crucial elements for success. In cases of biliary atresia
The two basic principles of vascular reconstruction are a the portal vein of the recipient is commonly sclerotic and
larger anastomosis and abundant flow. In pediatric hypoplastic. Propulsive front flow from the portal vein
LDLT, vascular reconstruction is started with the hepatic stump after hepatectomy is a minimum requirement
vein and then the portal vein. After completion of portal before putting in the graft. If it is not satisfactory, every
vein reconstruction, the graft is reperfused. Following procedure to enhance this portal flow should be done
the reperfusion, the hepatic artery is reconstructed with a before the implantation. These procedures include adhe-
surgical microscope or magnification loupe. Doppler sion lysis of the intestine from the abdominal wall, liga-
ultrasonography should be done after completion of vas- tion of the dominant collaterals, obliteration of the
cular reconstruction. retrosplenic small collateral venules, and so on. However,
the most important step is securing the good-sized flexi-
Hepatic Vein ble portal trunk. Augmentation of the portal vein is nec-
essary to secure abundant flow.49 Because of recent
In LDLT the retrohepatic IVC of the recipient is always advances in imaging technique, pretransplant evaluation
preserved, and the graft’s hepatic vein is anastomosed to of the hepatic vasculature, including the portal venous
the IVC in an end-to-side fashion. Typically the left system, is getting easier. The presence of hepatofugal
hepatic vein or the common trunk of the left and middle flow in the portal vein before transplantation indicates a
hepatic vein is anastomosed to the recipient side in left greater possibility that augmentation will be needed.
lateral segment or whole left lobe LDLT, respectively. Many methods have been used for such procedures using
When the hepatic vein has two orifices on the graft side, a venous graft from various origins. Usually the narrowed
either reconstruction to make one hole or creation of two segment of portal trunk distal to the confluence of the
separate anastomoses between the two orifices is selected. superior mesenteric and splenic veins is replaced by an
Anastomosis of a single hepatic vein is simple and safe. If interposition graft or augmented with a patch graft.
two separate anastomoses are necessary, stumps of the Another important point in reconstruction of the portal
middle hepatic vein and left hepatic vein or stumps of the vein is alignment of the axis of anastomosis. For this pur-
right hepatic vein and trunk of the middle/left hepatic pose we use curved forceps inserted into the graft’s portal
vein can be used on the recipient side. vein to determine the direction (Fig. 48-11). The axis of
When the trunk of the middle and left hepatic vein on the recipient’s side is oriented by placement of the clamp.
the recipient side is used for anastomosis, the orifice is The clamp is applied with transverse direction, and each
enlarged to a dimension adjusted for the size of the graft’s end of the graft portal vein in Figure 48-11 matches the
hepatic vein by incising the IVC wall on the right side of right and the left edge of the stump of the recipient’s por-
the common trunk (Fig. 48-9). This procedure fits the tal vein. The anastomosis is usually done with a two–stay
graft directly to the wall of the IVC and is helpful in pre- suture technique. If the calibers are very different, a four–
venting rotation of the graft around the axis made by the stay suture technique is recommended. When the diam-
hepatic venous pedicle.45 Triangular anastomosis is rec- eter is larger than 10 mm, creation of an anastomosis with
ommended by Emond et al for creation of a large anasto- running 6-0 monofilament suture is easy and fast. If the
mosis with good fixation of the graft to the IVC wall.46 diameter is smaller, partly or completely interrupted
End-to-end anastomosis after reconstruction of the suture is recommended.
652 PART VI Split and Living Donor Transplantation

A B
FIGURE 48-10 n End-to-end anastomosis of the hepatic vein in a patient with a hypoplastic retrohepatic inferior vena cava (IVC).
A, Before transection of the IVC. B, End-to-end anastomosis.

FIGURE 48-11 n To clarify the direction of the graft-side portal

vein, curved forceps are inserted while closed and then opened
while pulling out a little. This technique can be used to deter-
mine the horizontal direction of the graft portal vein, even if it is FIGURE 48-12 n Establishing an operative field for microsurgical
quite short. Each end of the graft portal vein is fixed to its coun- reconstruction of a hepatic artery in a small child undergoing
terpart of the recipient’s portal vein with the two–stay suture living related liver transplantation. Gentle, but secure, fixation
method. of the graft after reperfusion through the portal vein is neces-
sary for good field exposure.

In case of poor portal flow immediately after the reper-

fusion, every effort should be made to recover it, surgi- the graft is relatively large because the graft covers the
cally or interventionally.50 surgical field. Holding the graft with a malleable blade
fixed to the head arch is very useful for ensuring adequate
exposure of the surgical field (Fig. 48-12). Generally the
Hepatic Artery
diameter of the hepatic artery in a cirrhotic recipient is
Anatomy of hepatic arteries of the donor can also be eval- large enough, and its size is compatible with the arterial
uated preoperatively using 3-D CT and ultrasonography. size of a graft from an adult donor. However, in noncir-
During the LDLT the information about the anatomy of rhotic cases the size discrepancy is usually large. The
the hepatic artery in the donor side should be reported to branch patch technique and tapering can be used to adjust
the recipient side as soon as possible. Microsurgical tech- the size. End-to-side anastomosis should be avoided
nique is recommended for reconstruction of the hepatic because of the high incidence of HAT as a result of tur-
artery in pediatric LDLT. Such technique could reduce bulence. If the artery on the graft side bifurcates near the
the incidence of hepatic arterial thrombosis (HAT).51 In anastomosis, it may also cause turbulence after anastomo-
pediatric LDLT, establishing an adequate surgical field sis. In such cases the branching artery is transected, and
for reconstruction of the hepatic artery is difficult when the dominant artery is anastomosed first (Fig. 48-13). If
 48 Living Donor Transplantation in Children 653

TABLE 48-7 R
 ecipient Complications in Pediatric
Living Donor Liver Transplantation
Early
Hemorrhage (intra-abdominal and intestinal)
Vascular complications
Hepatic arterial thrombosis
Hepatic vein stenosis or torsion
Portal vein stenosis
Gastrointestinal complications
Bowel perforation
Anastomotic leakage
Poor perfusion of the graft (“large-for-size” problem)
Late
Vascular complications
Portal vein stenosis
Hepatic vein stenosis
Biliary complications
Biliary stricture at the anastomotic site

and use of a stent. In our institution, interrupted suture of

1-mm interval using 6-0 absorbable material, and the
knot outside, with 5F external stent tube is preferred.54 If
FIGURE 48-13 n Anastomosis of the artery in the case of bifurca- the bile duct of the recipient can be used in recipients
tion just distal to the stump on the graft side. The branch is tran-
sected, and the dominant artery is first anastomosed to the
with metabolic diseases or fulminant hepatic failure,
recipient side. Usually good backflow is obtained from the other duct-to-duct anastomosis is possible in pediatric and
stump, which indicates that a second anastomosis is not neces- adult cases, although there is still much controversy in
sary. the selection of duct-to-duct anastomosis or hepaticoje-
junostomy54,55 In infants the bile duct on the recipient
side is very fragile and thin. The blood supply to the
two or more arteries are present in the graft side, the stump of the recipient’s bile duct should be carefully pre-
most dominant one is anastomosed first. Then backflow served without dissecting the connective tissue around
from the others is checked. If backflow is good and pulsa- the common bile duct.
tile, the other artery or arteries can be safely ligated. If
backflow is not sufficient, additional anastomosis is nec-
essary. When multiple anastomoses are expected from SURGICAL COMPLICATIONS AND
the findings during the donor operation, at least two ori- TREATMENT OF RECIPIENTS
fices should be prepared during hepatectomy of the
recipient. The suture material is 8-0 or 9-0 nonabsorb- Early Complications (Within One Month)
able monofilament, and as little tension as possible is
placed on the anastomosis. If there is some tension in the Early surgical complications specific for pediatric LDLT
anastomosis, the gastroduodenal artery can be divided to are problems related to large-for-size grafts, small vessels
elongate the stump on the recipient side. As an alternative for reconstruction, and gastrointestinal tract injury
to the proper or common hepatic artery, the stump of the related to adhesion lysis, especially after a failed Kasai
splenic or gastroduodenal artery, left or right gastric procedure for biliary atresia (Table 48-7). Primary non-
artery, or dissected gastroepiploic artery can be used.52 In function is quite rare in LDLT. When the graft is rela-
cases requiring an interposition graft, a segment of autol- tively large, high pressure on the graft after closure of the
ogous inferior mesentery artery or radial artery can be abdominal wall may cause serious graft injury. Skin clo-
harvested and used. Venous graft can be used as the last sure with ventral hernia is performed or artificial mesh is
option, although there is some concern about the possi- applied in these cases. Artificial mesh or a prosthesis is
bility of thrombosis, torsion, or aneurysmal dilatation.53 not strongly recommended because it may add a source of
Except in cases with a high possibility of HAT, like a very postoperative infection. Skin closure may be safer. Trial
fine artery or complicated anastomosis, routine antico- closure and monitoring of flow by Doppler ultrasonogra-
agulant therapy is not necessary. phy may be helpful in judging between the primary and
secondary abdominal closure.
After the routine use of microsurgical techniques was
Bile Duct Reconstruction introduced, the incidence of HAT was 2.4% (8/332) in a
In biliary atresia the bile duct of the graft is anastomosed large series of LDLT.56 In a recent report the most dan-
to the previously existing or newly made Roux-en-Y limb. gerous arterial injury is intimal dissection on the graft or
Regarding bile duct reconstruction, there are still many the recipient side (or on both).57 If intimal dehiscence
controversial issues, such as the suture material, use of an occurs on the recipient side, the artery must be traced
inside or outside knot, continuous or interrupted sutures, proximally to obtain an intact wall and good forward
654 PART VI Split and Living Donor Transplantation

flow for safe construction of an anastomosis. The inci-

dence of HAT in a large series of pediatric LDLT is
reported as 7.1%.57 The basic principle in treating HAT
in LDLT in Japan, where the second graft can rarely be
expected, is reanastomosis to salvage the original graft.
Early detection of HAT is essential for successful re-
reconstruction. Doppler ultrasonography is performed
at least three times a day during the first 7 days and two
times daily during the subsequent 7 days. CT angiogra-
phy is also effective for disclosing HAT. If the signal is
detectable but shows poor flow, anticoagulant therapy is
given, and administration of systemic urokinase (60,000
IU/body/6 hr as a continuous intravenous infusion) is
mandatory. Emergency angiography and arterial infu-
sion of a thrombolytic agent such as urokinase may be
implemented. Complete disappearance of the arterial
signal within the first 10 days necessitates urgent reanas-
tomosis, even though there are no signs of hepatic necro-
sis on imaging studies or biochemical analysis.
Angiography before repeat surgery is skipped to save
time. At the revision, quick disruption of the anastomo-
sis should be performed to stop progression of the
thrombosis. Good backflow from the graft-side artery
after irrigation with a fine soft catheter (24 or 28 gauge) FIGURE 48-14 n Diversion of the Roux-en-Y limb in the event of
is an encouraging sign for possible success of the reanas- anastomotic dehiscence of the hepaticojejunostomy. The stoma
can be taken down after healing of the leakage.
tomosis. When no arterial signal is detected on Doppler
ultrasonography 10 days after LDLT and no signs of
hepatic necrosis are apparent, radiological intervention Late Complications
can be performed. In such cases—and even in cases in
which the reanastomosis was not successful—the graft Late complications after pediatric LDLT include hepatic
may survive by portal perfusion and later rearterializa- vein stenosis, portal vein stenosis, and biliary stricture
tion by spontaneously formed collaterals.58 The route of (see Table 48-7). These complications are not specific for
this arterialization is through the diaphragmatic artery pediatric LDLT and are relatively common, as in
or the mesenteric artery of the Roux-en-Y limb. Even in deceased donor partial-liver transplantation. Torsion or
these “spontaneously recovered” cases, intrahepatic or compression of the hepatic venous anastomosis by the
extrahepatic biliary stricture may subsequently occur in enlarging liver may cause hepatic vein stenosis after sev-
several months. eral months or a few years. The symptoms of hepatic vein
Hepatic venous obstruction (outflow block) with early stenosis are ascites, a low albumin level, and a decreased
onset will cause severe congestion of the graft. In pediat- platelet count. Doppler ultrasonography shows a dilated
ric cases, graft disposition by graft growing might be one hepatic vein with low flow velocity inside the liver and jet
cause. Fixation of the graft may be effective in a larger flow at the confluence with the IVC. In catheter angiog-
recipient with a relatively small graft. Early thrombosis of raphy, imaging with contrast dye enhancement and pres-
the portal vein may also cause a serious or fatal outcome. sure study through the anastomotic site can confirm the
Surgical thrombectomy is necessary. This complication diagnosis. The catheter is inserted via the transhepatic
should be avoided by making a wide anastomosis with route (normograde) or the IVC route (retrograde). Bal-
good flow. Preformed collaterals should be obstructed loon dilation has been highly successful. Repeated dila-
during the transplant operation to secure good front flow tion may be necessary, and placement of an expandable
of the portal vein. metallic stent is required in these cases. For possible
Biliary complications are more common after LDLT retransplantation in patients with hepatic fibrosis second-
than after whole-liver transplantation. Such complica- ary to graft congestion despite conservative procedures,
tions are not specific for pediatric LDLT, and stenosis is the location of the stent should be chosen cautiously and
not so common in the early period. Bile leakage from in a manner that does not interfere with any reoperation
the hepaticojejunostomy in the immediate postoperative if such becomes necessary.59,60
period may be fatal as a result of peritonitis and sepsis. Portal stenosis is a late complication after pediatric
Diversion of the limb to prevent reflux of amylase-rich LDLT. Portal vein thrombosis is usually associated with
bowel contents is recommended in cases with much dis- stenosis. Reconstruction using the venous conduit is
charge of enteric fluid (Fig. 48-14). Intestinal perfora- reported to be associated with a higher incidence of steno-
tion is another significant cause of death, especially in sis, although there is no definite evidence.59 Symptoms are
cases of failed Kasai biliary atresia. Fasting and drainage liver dysfunction and those of portal hypertension—
are not usually sufficient to control the peritonitis. ascites and thrombocytopenia. Steatosis can be seen asso-
Temporary exteriorization of the perforation site may ciated with portal stenosis.61 Doppler ultrasonography
be necessary. can be used to diagnose stenosis by detection of narrowing
 48 Living Donor Transplantation in Children 655

TABLE 48-8 R
 epeat Living Donor Liver
Transplantation, Kyoto University
Hospital, 1990-2002
Causes of 28 Repeat LDLTs After 547 LDLTs for
­Patients Younger than 18 Years
PV Cause No. of Patients
Chronic rejection 10
Chronic cholangitis 6
Vascular complication 7
Others 5

FIGURE 48-15 n Poststenotic dilatation of the portal vein (arrow- Interval From the First LDLT to the Repeat LDLT
head) and stenosis of the portal vein anastomosis (arrow). The Interval No. of Patients
patient is a 25-year-old man 12 years after left lobe living related <1 wk 1
liver transplantation for biliary atresia. The spleen is quite huge 8-31 days 2
with prominent hypersplenism.
1-12 mo 13
>1 yr 12

of the lumen, poststenotic dilatation, and a jet flow with LDLT, Living donor liver transplantation.
damping of the flow velocity (Fig. 48-15). Three-dimen-
sional CT can be used as the diagnostic tool, although
direct portography is usually needed in case of interven- the possibility of re-LDLT when the availability of a
tional radiology. For direct portography, the percutane- deceased donor is not expected may place great pressure
ous transhepatic route or intraoperative portography via on the family. However, if they are not told all of the
laparotomy can be chosen. Balloon dilation is the first line options, the recipient may progress along the worst
of the treatment. If it is not successful, surgical thrombec- course before the family recognizes the necessity for
tomy plus re-reconstruction can be tried, although it is retransplantation. The possibility of re-LDLT should be
not easy and promising. With good fortune, development included as one of the general issues in the informed
of spontaneous collaterals into the liver may sometimes consent in the initial LDLT. If the recipient is a child,
secure enough perfusion. Even though portal flow is not the range of selection of a second donor has to be wider
detected in the liver, initially the patient may not have any than for adults. Parents, grandparents younger than
symptoms. However, in many cases, symptoms of a porto- 70 years, and uncles or aunts can be included as candi-
systemic shunt or portal hypertension become prominent dates. In Japan retransplantation after pediatric LDLT is
later. In such cases with difficult re-reconstruction, increasing and has had satisfactory results, although
retransplantation is indicated. Hepatopulmonary syn- results are worse than those for the initial procedures.63
drome or portopulmonary hypertension should be In the experience of Kyoto, 6.3% of 600 pediatric
watched in the follow-up of these patients. patients have undergone retransplantation.64 The most
Late-onset biliary stenosis can be detected with inter- common indication for re-LDLT is chronic rejection
mittent liver dysfunction and cholangitis. Because the (Table 48-8).65 Recurrence of the original disease is rare
original anastomosis is mainly a hepaticojejunostomy, after pediatric LDLT. However, in the Kyoto experi-
intervention through endoscopic retrograde cholangio- ence, young children undergoing LDLT for fulminant
pancreatography is not possible. Percutaneous transhe- hepatic failure have a higher incidence of further massive
patic cholangiodrainage under ultrasound guidance is hepatic necrosis requiring re-LDLT, although it is dif-
possible if the intrahepatic bile duct has some size. Dou- ficult to differentiate from severe rejection.66 Primary
ble-balloon intestinal fiberscope may be useful in cases of sclerosing cholangitis also has a high possibility of recur-
hepaticojejunostomy.62 Balloon dilation is commonly rence and graft failure after LDLT. According to the
used. If not effective after repeated trials of dilation, report by Egawa et al,67 the recurrence rate in 31patients
stenting will be necessary. Revision after long-term fol- younger than 18 years old in Japan was 31%. Naturally
low-up is not very difficult. If conservative treatment is re-LDLT presents greater technical difficulty than the
not effective, it is better to proceed to reanastomosis than initial procedure does. The overall survival rate after re-
to take much time; otherwise, irreversible cirrhosis might LDLT in Kyoto is less than 40%. Early retransplanta-
require retransplantation. tion is performed if the recipient’s condition is poor, and
the result is worse than when it is done after a long
Repeat Living Donor Liver Transplantation period.65
in Pediatric Recipients
In the initial experience with LDLT, there was hesitancy
about performing repeat LDLT (re-LDLT) after failure
IMMUNOSUPPRESSION
of LDLT. It is generally difficult to find another proper Tolerance
donor because the selection range is limited within the
close family. Of course, if a deceased donor is available, it is After liver transplantation, complete weaning from immu-
reasonable to list the patient as an urgent case. Discussing nosuppression has been reported to be possible in select
656 PART VI Split and Living Donor Transplantation

100
Twice a day (b.i.d.) 3-6 month follow-up
at each step 0~2 (n = 204)
Once a day 80

Patient survival (%)

Once per 2 days
Twice a week 60
Once a week 18~ 3-17 (n = 89)
40 (n = 347)
Twice a month
Once a month 20
Completely off P<.0001
0
FIGURE 48-16 n Protocol for weaning from tacrolimus immuno­
suppression.
0 5 10 15 20
Year
FIGURE 48-17 n Patient survival after ABO-incompatible living
donor liver transplantation according to the age of the patient.
The survival rate of patients younger than 2 years old is signifi-
TABLE 48-9 C
 riteria for Protocol for Weaning cantly better than that of older patients. (Data from the registry of
From Immunosuppression (Kyoto the Japanese Liver Society from 1989 to 2010.)
University)
Longer than 2 years after liver transplantation the application of rituximab (anti-CD20 monoclonal anti-
Normal liver function body).75 This monoclonal antibody will suppress the B-cell
No episode of rejection during the previous year activity and then cause suppression of humoral immunity.
Evidence of medical compliance
Cooperative local physician for follow-up There are still many regimens for ABO-incompatible adult
LDLT, and the dose and timing of rituximab has not yet
been well fixed. However, in many institutions the drug is
given once, 2 or 3 weeks before the LDLT. The dose for
cases.68 In pediatric LDLT it has been noticed that immu- adult patients is usually 375 mg/m2 of body surface area.
nosuppression could be reduced or stopped because of One institution in Japan prefers the dose of 200 mg/m2 of
complications or noncompliance. After confirmation of the body surface area in pediatric recipients.
possibility of complete withdrawal in such incidental cases, Again, in ABO-incompatible LDLT for recipients
protocols for weaning were developed.69 During the proto- younger than 2 years, no special regimen is necessary.
col trial, 25% of the post-LDLT pediatric recipients
enrolled in the study could be completely weaned off immu-
nosuppressants for a median of more than 21.9 months.70 Pearls and Pitfalls
The protocol for weaning adopted by Kyoto University is
shown in Figure 48-16, and the criteria for application of • Obtain informed consent detailing the risk to the donor,
including mortality, before performance of living donor
this protocol are listed in Table 48-9. However, in recent liver transplantation (LDLT).
reports, there has been an accumulation of patients who • Minimal handling of the vascular pedicle and the graft
have sinusoidal fibrosis with normal biochemical data on itself is necessary in both the donor and recipient opera-
routine follow-up.71 More meticulous consideration about tions.
the possibility of complete withdrawal of immunosuppres- • A flat and straight line should be used for transection of
sion should be done using the information provided by hepatic parenchyma in the donor operation.
biopsy results.72 However, promising results of basic • The Arantius duct should be completely transected at
research on the establishment of clinical operational toler- its confluence with the left hepatic vein when harvesting
ance have also been reported.73 the left lobe from the donor.
• The bowel should be cooled by flushing of water during
enterolysis by electrocautery.
ABO Incompatibility in Pediatric Living • Good flow through the portal vein should be confirmed
Donor Liver Transplantation before the graft is inserted.
• In any vascular reconstruction a stoma as large as pos-
ABO-incompatible matching cannot be avoided in countries sible with flow as abundant as possible is strongly recom-
in which LDLT is the main method of liver transplantation. mended.
The outcome after LDLT depends on the age of the recipi- • Interrupted suture is recommended in patients with a
ent. The survival rate of patients younger than 2 years old is small portal vein.
significantly better than that of older patients. (Fig. 48-17). • A microsurgical technique of hepatic arterial reconstruc-
Therefore in recipients younger than 2 years the immuno- tion should be used.
suppression regimen after ABO-incompatible matching can • Reconstruction of the dominant artery may be sufficient
without reconstructing other arteries in patients with
be similar to that after compatible matching. In adults, multiple arterial supply to the graft.
including older pediatric patients, there have been many tri- • If possible, a duct-to-duct anastomosis is safe and also
als to manage ABO-incompatible liver transplantation, useful in pediatric LDLT.
mostly from living donors.74 A recent advance in this field is
Continued
 48 Living Donor Transplantation in Children 657

10. Otte JB. History of pediatric liver transplantation. Where are we

Pearls and Pitfalls—Cont’d coming from? Where do we stand? Pediatr Transplant. 2002;6:
378-387.
• Blood flow should be confirmed by Doppler ultrasonog- 11. Revillon Y, Michel JL, Lacaille F, et al. Living-related liver
raphy before closure of the abdomen and before exiting transplantation in children: The “Parisian” strategy to safely
­
the operating room. increase organ availability. J Pediatr Surg. 1999;34:851-853.
• Application of a hyperreduced graft enables LDLT for 12. Vagefi PA, Ascher NL, Friese CE, et al. Use of living donor liver
newborn babies. transplantation varies availability of deceased donor liver trans-
• A regular (bimonthly) checkup of the grafted liver by plantation. Liver Transpl. 2012;18:160-165.
13. MillerFlorman CS, Kim-Schluger L, et al. Fulminant and fatal gas
Doppler ultrasonography should be performed in the
gangrene of the stomach in a healthy live liver donor. Liver Transpl.
posttransplant outpatient clinic for early detection of 2004;10:1315-1319.
vascular and biliary anastomotic stenosis. 14. Akabayashi A, Slingsby BT, Fujita M, et al. The first donor death
• Lifelong follow-up is necessary, especially for pediatric after living-related liver transplantation in Japan. Transplantation.
LDLT. 2004;77:634.
• Ignorance of the subclinical phenotype in a donor can- 15.  de Villa VH, Lo CM, Chen CL. Ethics and rationale of
didate with inheritable diseases such as metabolic disor- living-donor liver transplantation in Asia. Transplantation.
­
ders, Alagille syndrome, or Caroli’s disease is a pitfall. 2003;75:S2-S5.
• In HLA matching, avoid a graft from a homozygous 16. Min SI, Kim SY, Park YJ, et al. Trends in deceased organ donation
and utilization in Korea: 2000-2009. J Korean Med. Sci.
­donor to a heterozygous recipient.
2010;25:1122-1127.
• Physical injury in the bowel of the recipient must be 17. Egawa H, Tanabe K, Fukushima H, et al. Current status of organ
­prevented. transplantation in Japan. Am J Transpl. 2011;12:523-530.
• A graft larger than 4% of the recipient’s body weight 18. Hashikura Y, Ichida T, Umeshita K, et al. Donor complications
may result in poor perfusion of the graft and cause associated with living donor liver transplantation in Japan.
­unsatisfactory primary function. ­Transplantation. 2009;88:110-114.
• Hesitation regarding portal vein augmentation ­before 19. Lo CM. Complications and long-term outcome of living liver
insertion of the graft in recipients with sclerotic or donors: A survey of 1508 in five Asian centers. Transplantation.
thrombotic changes in the portal vein should be avoided. 2003;75:S12-S15.
20. Iida T, Ogura Y, Oike F, et al. Surgery-related morbidity in living
• End-to-side anastomosis of the artery may result in a
donors for liver transplantation. Transplantation. 2010;89:1276-1282.
higher incidence of hepatic artery thrombosis. 21. Miyamura T, Yoshida R, Yagi T, et al. Successful treatment of
• In patients in whom hepatic artery thrombosis occurs unresectable advanced hepatoblastoma: living liver transplantation
within 10 days of the operation, waiting until an increase after surgical removal of lung metastasis. Pediatr Transplant.
in transaminase levels occurs will make saving the graft 2011;1:E87-E91.
hopeless. 22. Uchida K, Taniguchi M, Shimamura T, et al. Three-dimensional
•  Bilioenteric dehiscence or intestinal perforation after computed tomography scan analysis of hepatic vasculatures in the
transplantation requires a more aggressive surgical in- donor liver for living donor liver transplantation. Liver Transpl.
tervention than simple drainage and fasting. 2010;16:1062-1106.
23. Cheng YF, Chen CL, Huang TL, et al. Single imaging modality
• Weaning from immunosuppression should be guided by
evaluation of living donors in liver transplantation: Magnetic
the pathological findings, even though biochemical data ­resonance imaging. Transplantation. 2001;72:1527-1533.
are stable. 24. Mochizuki K, Takatsuki M, Soyama A, et al. The usefulness of a
high-speed 3D-image analysis system in pediatric living donor
liver transplantation. Ann Transplant. 2012;17:31-34.
25. Hashimoto M, Itoh K, Takeda K, et al. Evaluation of biliary
­abnormalities with 64-channel multidetector CT. Radiographics.
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37. Miyagawa S, Hashikura Y, Miwa S, et al. Concomitant caudate transplantation. Abdom Imaging. 2002;27:546-548.
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 CHAPTER 49

Living Donor Transplantation:

Evaluation and Selection in
Adults
James F. Trotter • Igal Kam

CHAPTER OUTLINE

RECIPIENT SELECTION DONOR SELECTION

Liver transplantation is the treatment of choice for evaluation is identical to that for any other patient. That
selected patients with end-stage liver disease. However, is, the potential recipient must complete a comprehensive
many patients are unable to receive a transplant because of evaluation to ensure that he or she is suitable for trans-
the shortage of deceased donor (DD) livers. In fact, plantation. Once listed for DD transplantation, selected
approximately 2000 patients either die or are removed patients may be considered for LDLT. To identify the
from the transplant list as too sick to transplant each year.1 most appropriate patients for LDLT, the benefits and
To increase the availability of donor organs, living donor risks of the procedure must be considered. The primary
liver transplantation (LDLT) was developed along with benefit of LDLT is an expedited and elective transplant.
other innovations including extended criteria donation Therefore the transplant may be performed before the
and donation after cardiac death. After the first LDLT in candidate deteriorates to the point that the outcome of
the late 1980s, the volume of cases was relatively stagnant the surgery is jeopardized. Consequently, patients likely
until the late 1990s. Then with the apparent success of the to reap the greatest benefit from LDLT are those with a
right hepatic lobe LDLT and the growing shortage of significant risk for death or deterioration before the
DD livers, the number of cases increased from 25 adults in anticipated deceased donor liver transplantation (DDLT).
1998 to over 400 by 2001, or approximately 10% of all However, the benefit of an expedited transplant must be
liver transplants in the United States (Fig. 49-1). Thereaf- balanced with the inherent risk for death or complica-
ter, however, the number of cases dropped by two thirds, tions from the surgery itself. Therefore the selection of
and by a decade later in 2011 fewer than 200 adult-to- the most appropriate candidates for LDLT is made by
adult LDLTs were performed in the United States, balancing the risks and benefits of remaining on the list
accounting for only 3.2% of adult liver transplants. The for a DD transplant versus that for an LDLT. For patients
reasons for this decline are complex and related to a com- with severe decompensation, a high MELD score, and a
bination of factors, including increased volume of DD short anticipated waiting time, there may not be any
liver transplants, better prioritization of recipients with apparent benefit of LDLT. In such cases the DDLT may
the Model for End-Stage Liver Disease (MELD) score, occur as soon as an LDLT, and such patients may not
and increased concern over donor safety. Despite its lim- tolerate the slightly higher complication rate of LDLT.2
ited application, LDLT offers the unique advantages of an However, for patients with a low MELD score and life-
expedited and elective transplant that can often be per- threatening complications of liver disease such as ascites,
formed before clinical deterioration (or death) of the can- encephalopathy, variceal bleeding, and hepatocellular
didate, thereby increasing the success of the operation. carcinoma (HCC), LDLT may be considered as a treat-
The best selection process pairs recipients with the great- ment option. In fact, a study by the Adult-to-Adult Liv-
est likelihood of benefit with donors who are able to safely ing Donor Liver Transplantation (A2ALL) Study Group
undergo the operation with minimal or no complications. sponsored by the National Institutes of Health analyzed
the potential survival benefit of LDLT.3 This study com-
pared survival for patients undergoing LDLT with con-
RECIPIENT SELECTION trols, defined as patients considered for LDLT without a
suitable donor and therefore remained on the DD trans-
Most centers use a staged approach to recipient selection plant list. LDLT recipients had a nearly two-thirds
and evaluation (Table 49-1). The initial step is to con- reduction in mortality with LDLT compared to control
sider the recipient for DD transplant. At this point the patients (who remained listed for DDLT) with an

659
660 PART VI Split and Living Donor Transplantation

450
400
350
300
250
200
150
100
50
0
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
FIGURE 49-1 n Adult living donor liver transplantation by year.

adjusted mortality hazard ratio of 0.35 (P < .05). The

TABLE 49-1 P
 hases of Recipient and Donor
median MELD score in this entire cohort was only 15,
Evaluation
demonstrating that MELD score is not a useful indicator
Phase 1
for selecting patients who may benefit from LDLT. In
summary, any patient listed for liver transplantation who
Recipient has developed life-threatening complications of liver dis-
Listed for cadaveric transplant with defined medical ease, regardless of MELD score, may be considered med-
urgency for transplantation
Absence of significant contraindication
ically eligible for LDLT. In addition, any patient with a
MELD score of approximately 18 or higher (associated
Donor with a 10% 90-day mortality) may also be considered for
Age ≥18 and ≤55 the procedure.
Identical or compatible blood type with the recipient
Absence of significant medical or psychiatric problems and The selection of LDLT recipients based solely on
previous abdominal surgery quality of life requires careful consideration. For DDLT
Demonstrable, significant, long-term relationship with recipients, quality-of-life issues are rarely considered as
recipient an indication for transplant. Currently DDLT candidates
Normal liver function test results, serum electrolyte levels,
complete blood count with differential cell count; negative
are prioritized for transplant based on patient survival (as
hepatitis B surface antigen, hepatitis B core antibody, and described by the MELD score), and quality-of-life issues
hepatitis C antibody have been almost completely discounted. However, for
Phase 2
selected patients, LDLT may be an effective treatment
Complete medical history and physical examination of for symptoms affecting their quality of life, independent
potential donor of any survival benefit. These would include patients
Laboratory studies: whose MELD score remains low despite symptoms such
Serum ferritin, iron, transferrin, ceruloplasmin as recurrent cholangitis, cachexia, symptomatic polycys-
α1-Antitrypsin level and phenotype
Rapid plasmin reagin
tic liver disease. Because the LDLT includes a risk for
Cytomegalovirus antibody (IgG), Epstein-Barr virus death associated with the operation, the most direct
antibody (IgG) means of determining if a patient’s symptoms are suffi-
Antinuclear antibody ciently severe to warrant the risk of LDLT is to ask the
Human immunodeficiency virus antibody patient: “Are you willing to accept the risk for death to
Toxicology/substance abuse screen
Urinalysis potentially alleviate your current symptoms?” The donor
Blood oxygen saturation should also be apprised of the transplant indication in
Chest radiograph such cases.
Electrocardiogram The proportion of listed patients meeting these crite-
Surgical evaluation of donor
Anesthesia preoperative evaluation
ria for LDLT has been calculated based on the experi-
Computed tomography or magnetic resonance imaging of ence at an active LDLT center.4 About one third of
the liver, biliary system, and hepatic vasculature patients listed for DD transplant are sufficiently ill to be
Phase 3
considered for the procedure (Fig. 49-2). However, not
Other tests or consultations to clarify problems uncovered
all of these patients are considered surgically suitable for
during phase 2: the procedure. Of the one third of potential LDLT can-
Endoscopic retrograde cholangiopancreatography didates deemed sufficiently ill to undergo LDLT,
Hepatic angiogram approximately half will be considered surgically suitable
Liver biopsy for the operation.4 Surgical considerations for selecting
Echocardiogram
Stress echocardiogram appropriate LDLT recipients must account for unique
aspects of this procedure. Specifically, LDLT recipients
 49 Living Donor Transplantation: Evaluation and Selection in Adults 661

100 potential recipients initially evaluated for LDLT

50 recipients suitable for LDLT 50 rejected for recipient issues

25 unable to find donor 25 with donor for evaluation

15 with unacceptable donor 10 with suitable donor

10 donor/recipient
pairs able to undergo LDLT
FIGURE 49-2 n Outcomes of 100 potential living donor liver transplantation (LDLT) recipients. (Modified from Trotter JF, Wachs M,
Trouillot T, et al. Evaluation of 100 patients for living donor liver transplantation. Liver Transpl. 2000;6:290-295.)

experience a slightly higher complication rate and receive California–San Francisco) are based in states within the
a smaller graft compared to DDLT. The A2ALL study lowest decile for obesity.6 Small LDLT candidates may
reported a significantly higher rate of complications, be particularly well suited for the operation. Women
including more complications leading to retransplanta- have a 19% higher waiting list mortality rate (P < .001)
tion or death (Clavien grade 4) after LDLT versus compared to men, and this difference is explained in part
DDLT (15.9% versus 9.3%, P = .023).2 In addition, by their shorter stature.7 The likely explanation is the
LDLT recipients have significantly higher posttrans- inability to find a sufficiently small DD graft for these
plant hospitalization rates, primarily related to biliary petite patients. Consequently, small patients tend to wait
complications, which are about twice as common with longer and have higher waiting list mortality rates.
LDLT.5 In general, problem(s) that would jeopardize the However, graft size restrictions are never a problem for
success of the operation are considered as strong relative small adult LDLT recipients, making them particularly
contraindications for the procedure. These include com- well suited for this operation.
plex mesenteric venous thrombosis, multiple medical One recent development is the use of LDLT in
comorbidities, simultaneous renal transplantation, retrans- patients with HCC, which accounted for 15% of patients
plantation, and others. These problems may be poorly in the A2ALL study cohort.8 This group of patients
tolerated by the LDLT recipient, smaller graft size, and would seem likely to benefit from LDLT because they
higher rate of complications after LDLT compared to have an obvious need for an expedited transplant and
DDLT. typically have a better physiological status than other
Body size, both large and small, is another important patients. The A2ALL study examined the outcome of
consideration in selecting LDLT recipients. Large body HCC patients from the time of donor evaluation com-
size is a particular problem in the United States, where pared to controls (defined as HCC patients who were
obesity rates continue to climb. LDLT candidates weigh- considered for LDLT but remained on the DDLT list
ing more than 100 kg may have more difficulty identify- because they did not have a suitable donor). These inves-
ing a suitable donor. The average weight of the liver is tigators found no difference in survival for LDLT versus
approximately 1.5 kg, or 2% of the body weight of an DDLT patients with HCC.9 Similar results have been
average person (70 kg). Although estimates vary on the replicated by two other groups in Canada and France.10-12
minimally acceptable weight of a donor organ, the esti- For advocates of LDLT these data provide a basis for its
mated lower limit of acceptability is 0.8% graft weight– continued application; the outcomes for LDLT recipi-
to–body weight ratio (GWBWR), and the average weight ents are as good as DDLT. In fact, for selected HCC
of a right hepatic lobe is about 1 kg. Thus for a 100-kg patients, LDLT could be their best option. Small patients
recipient, an average donor of 70 kg would be able to (who have inherent difficulty in securing a size-appropriate
yield a 1-kg graft (1% GWBWR), which approaches the deceased donor) in high-MELD regions (with long waiting
margins of acceptability. For larger recipients (whose times for HCC patients) may benefit from the predictably
graft size requirements are even higher), most potential shorter waiting times associated with LDLT. However,
donors are simply too small to yield an adequately sized there is a more critical analysis of the study’s conclusion:
graft. In addition, larger donors may be too obese to be from the time of decision to pursue LDLT, there is no
considered for the donor operation. These considerations survival benefit over remaining listed for and undergoing
of donor and recipient size are likely one explanation for a DDLT.13 Part of the reason for this negative finding is
the disproportionate rates of LDLT across the United the high priority awarded to DDLT candidates with
States. Three of the busiest LDLT centers (the Univer- HCC under MELD-based liver allocation. For patients
sity of Colorado, Lahey Clinic, and the University of listed at “low MELD” centers where HCC patients may
662 PART VI Split and Living Donor Transplantation

be transplanted in less than 90 days, a DDLT can often personal medical benefit. The actual risk for death is dif-
be performed before an LDLT can even be arranged. ficult to determine because of the low number of donor
Another plausible explanation is that LDLT patients are deaths, as well as difficulties in identifying donor deaths
“fast-tracked” to transplant and predictably have shorter and their attribution to the operation. However, most
waiting times compared to DDLT. Compared to LDLT, analyses place the risk at about 1/500.25,26 Of note, the
the longer waiting times associated with DDLT may number of documented donor deaths by suicide and drug
allow patients with aggressive tumor biological charac- overdose (n = 4) rivals the total number of early periop-
teristics sufficient time for tumor progression and removal erative deaths by other means (n = 5).27 This underscores
from the list. Therefore one would predict a higher HCC the psychological impact of donation and the importance
recurrence rate after LDLT, although this has not been of a careful psychosocial donor evaluation.28 The risk for
demonstrated in any of the studies mentioned. The find- donor complications is estimated at approximately 40%,
ings of these studies should cause transplant physicians to with only 1% to 2% resulting in chronic problems.29
carefully consider the decision to perform an LDLT for Because of this inherent risk in the donor operation, the
HCC patients. consideration of donor candidates may be different from
There are several reports of successful LDLT in acute that for other live donor operations (namely, kidney), in
liver failure (ALF).14-21 Patients with ALF are clinically which the operative risks are smaller. Most centers there-
very unstable and typically have a short window for trans- fore evaluate only donor candidates with a significant
plantation (a few hours to days) from the time of listing long-term relationship with the recipient who would rea-
until death. In this setting LDLT offers a potential sonably incur such a risk. There are rare individuals,
important advantage in that the surgery can be performed deemed “good Samaritan” or altruistic donors, with no
within hours following the identification of a suitable emotional ties to the recipient, who willingly undergo the
donor. However, there are potential problems with donor operation. There are in fact reports of such donors
LDLT in this setting. Most important, the donor has a who have successfully donated for LDLT.30,31 However,
limited time to undergo evaluation and may not have suf- most centers do not consider such individuals for dona-
ficient time to adequately consider his or her decision to tion out of concern for ulterior motivations (financial),
donate. The donor must make the decision while his or mental illness, or inability to understand the risks of the
her family member suffers a critical illness that is rapidly operation.
progressive. In addition, the transplant team is under The donor evaluation is performed in a staged manner
pressure to perform a comprehensive, careful donor eval- to disqualify inappropriate donors as early in the process
uation over a very short time interval. Because of the con- as possible, thereby minimizing unnecessary and invasive
cerns regarding LDLT in the setting of ALF, some testing. The process is started at most centers with the
centers have elected to exclude ALF as an indication for potential donor contacting the transplant center to initi-
LDLT.22,23 The A2ALL group published their findings ate the donor evaluation. The precise means of donor
in a subset of patients with ALF, which accounted for evaluation varies from center to center. One way to initi-
only 1% of patients considered for LDLT.24 The out- ate the process is for potential donors to contact the cen-
comes in both the donors and recipients in this small ter to relate basic information, including age, height,
cohort were not different than those for patients with weight, prior surgeries, medical problems, medications,
chronic liver disease. The median time from listing to marital/family status, blood type (if known), and reason
transplantation was only 2.5 days. Although LDLT is for donating. Many poor donor candidates may be dis-
rarely performed for ALF, it may be an acceptable option qualified following review of this preliminary data. At
in selected patients. The utility of LDLT in fulminant most centers donor candidates must be between the ages
liver failure depends in part on the availability of cadav- of 18 and 55, although older donors have successfully
eric organs. In the United States, where cadaveric organs donated. Exclusion criteria for donor candidates based on
are scarce but usually available for status 1 patients, the their medical and surgical history varies by center. Major
overall impact of LDLT will likely be minimal. Between abdominal operations are contraindications for donation.
July 2010 and June 2012 only 5% of LDLTs were done Candidates with lesser abdominal operations (appendec-
for ALF. However, in Asia, where virtually all liver trans- tomy, ovarian cystectomy) are generally considered suit-
plantation is performed with live donors, LDLT will able. Any medical problem that might jeopardize the
likely remain the only viable treatment option for these health or success of the donor operation is exclusionary.
critically ill patients. Such problems include diabetes, significant cardiac his-
tory, recent history of noncutaneous malignancy, and
others. Mild and controlled hypertension is a relative
DONOR SELECTION contraindication. Body size, especially as it relates to obe-
sity, is an important consideration. The donor must be
The primary purpose of the donor evaluation is to ensure, approximately 70% of the weight of the recipient to yield
as much as possible, that the donor may safely undergo a sufficiently large graft (see earlier discussion). However,
the operation. In addition, the potential donor may learn obesity is a common problem in donor candidates, and
about the risks and benefits of the operation so that he or most are rejected because of comorbidities (hypertension,
she can make an informed decision regarding donation. diabetes) that could increase the perioperative risk for the
The most obvious consideration in selecting appropriate donor. In addition, obese donors are more likely to yield
donors for LDLT is the risk for death and complications a steatotic graft, which would be considered unsuitable
after the donor operation, which offers the donor no for transplant at most centers. There are no national
 49 Living Donor Transplantation: Evaluation and Selection in Adults 663

criteria for a body mass index (BMI) cutoff for donor can- data to support this. In fact, successful LDLT has been
didates, but the average donor BMI in the A2ALL study reported with grafts with higher rates of steatosis. For
was 26 kg/m2, and only 15% had a BMI greater than donor candidates with greater than 10% steatosis, inten-
30 kg/m2. Similar to DDLT, the donor and recipient sive dietary treatment to reduce hepatic steatosis has
must have the same or compatible blood type. Some been reported to be successful.33,34 Remarkably, hepatic
potential LDLT recipients do not have any potential steatosis resolves in the recipient of a steatotic graft
donors for evaluation. Special consideration is given to within just 2 weeks.35,36
selecting donors who are parents with dependent chil- Anatomical criteria are important in evaluating the
dren, especially for mothers (or single mothers) with donor. From a surgical standpoint, parenchymal, biliary,
small children. Although such individuals may success- and vascular anomalies that could complicate or preclude
fully donate, special attention should be given to an alter- successful donor hepatectomy must be identified during
native caregiver(s) for the children during the period of the donor and recipient evaluation. Although many
postoperative recuperation. For this reason, unencum- donors undergoing evaluation do not have conventional
bered donors may be more suitable for donation. In our biliary, venous, and arterial anatomy, most anatomical
experience about half of potential LDLT recipients are abnormalities do not preclude successful hepatectomy by
able to identify an acceptable donor to undergo evalua- an experienced surgical team. The decision to proceed
tion. Of the remaining half, the most common reasons with the hepatectomy in a donor with anatomical anoma-
that a donor candidate is not available include estrange- lies is based on the judgment and experience of the sur-
ment from family, no children or siblings meeting age geon. In all cases the safety of the donor should be
criteria, and obvious medical problems in the donor considered as the paramount concern.
candidate.4 Common parenchymal abnormalities found during
Once the best potential donor has been identified from routine imaging of the potential donor include hepatic
the available pool, most centers proceed with a staged cysts, hemangiomata, and other benign hepatic tumors.
workup. In most cases the evaluation is done at the trans- Donors with single, small (<1 cm) benign lesions may
plant center, but some of the initial testing (blood type, successfully undergo donor hepatectomy. However, as
basic laboratory tests) may be performed in the donor’s the lesion(s) increase in size and number, the safety of the
local community, especially for donors that reside far donor hepatectomy and quality of the donor graft may be
from the center. Table 49-1 outlines the phases used by compromised, and the donor may be judged unsuitable
the University of Colorado. The initial phase of donor for donation. The size of the right hepatic graft can be
evaluation includes determination of serum electrolyte estimated with abdominal imaging. As noted earlier, spe-
levels, blood count with differential, liver function tests, cific formulas exist to estimate whether the right lobe is
and hepatitis serological tests. Persons positive for hepa- large enough for the recipient.37,38 In general a GWBWR
titis C antibody or hepatitis B surface antigen are not greater than 0.8% is desirable. In practice, however, we
acceptable donors. However, donors with hepatitis B rarely use this calculation in the determination of a
core antibody may successfully donate after careful potential donor’s suitability for LDLT, because other
evaluation. recipient factors are of equal importance. The degree of
If results of the initial blood work are acceptable, then portal hypertension and severity of illness in the recipi-
the donor candidate proceeds to more intensive evalua- ent are critical factors in determining if a right hepatic
tion, which includes a complete medical history and lobe is sufficiently large for a given recipient. Recipients
physical, psychosocial, and surgical evaluation, as well as with severe portal hypertension or clinical decompensa-
comprehensive serological testing, chest radiograph, tion will require larger grafts than patients who are less
electrocardiogram, and magnetic resonance imaging of sick, who may do well with a small right hepatic lobe
the liver, biliary system, and hepatic vasculature. Alterna- graft. The donor surgeon must also consider the size of
tively, many centers rely on high-resolution computed the remnant (left) hepatic lobe. Donors with a diminutive
tomography (CT) and CT angiography. For specific left hepatic lobe may have insufficient hepatic mass fol-
donors, other tests may be required, including a cardiac lowing donor right hepatectomy. However, the exact size
stress test or specialty consultations as indicated. of remnant liver mass that is required by the donor fol-
There are several specific aspects of the donor evalu- lowing hepatectomy is unknown. To our knowledge,
ation that require special consideration. The role of liver there are no data that provide a rational basis for estimat-
biopsy varies from center to center; that is, some centers ing the required size of the remnant hepatic mass. How-
require all candidates to undergo a biopsy, and others do ever, we estimate that the donor requires more than
not. In the United States the most common reason to 0.4% (remnant hepatic mass ÷ body mass × 100%) to
perform a liver biopsy on a donor candidate is to rule out ensure adequate hepatic function following right donor
hepatic steatosis, which is more common in heavier hepatectomy. Therefore the average 70-kg donor would
donors. Rinella et al32 found that 76% of potential require a left hepatic lobe size of 280 g or larger. In our
donors with a BMI greater than 28 kg/m2 had hepatic experience a small fraction of potential donors (approxi-
steatosis, whereas none of those with a BMI below mately 2%) undergoing evaluation have a diminutive left
25 kg/m2 had steatosis. Steatosis may be identified with hepatic lobe that would preclude safety of the donor
hepatic ultrasonography or cross-sectional imaging, right hepatectomy.
although liver biopsy is clearly a more sensitive test. The Although abnormalities of the biliary tract are common,
generally accepted cutoff for excessive histological ste- they almost never preclude the donor from donation.39-41
atosis for a live donor is 10%, although there are few However, biliary leaks are a common complication
664 PART VI Split and Living Donor Transplantation

following donor hepatectomy. The most important issue artery in 13%. Marcos et al43 reported that 59% of 95
in preventing biliary complications in the donor is to right lobe donors had conventional anatomy. The two
clearly identify the biliary anatomy. Preoperative imaging most common variants were a replaced right hepatic
with magnetic resonance cholangiopancreatography or artery (14%) and “unique aberrant anatomy” (11%).
CT-cholangiogram is very useful; however, we perform Patients with multiple arteries supplying the right hepatic
an intraoperative cholangiography on all of our donors artery or crossing arteries from the left hepatic artery to
and believe that this is the best diagnostic modality for the right hepatic artery may be rejected for donation. In
defining the donor biliary anatomy. With the current our experience many of these patients will also have con-
state of cross-sectional imaging in defining the biliary comitant anatomical variations in the portal venous and
anatomy, preoperative endoscopic retrograde cholangio- biliary anatomy, which increase the complexity of the
pancreatography are rarely needed. Proper definition of surgery and increase the risk for complications in the
the biliary anatomy prevents excessive hilar dissection recipient.
and transection of critical donor biliary ducts, which may Other situations that may arise are consideration of
lead to increased complications in the donor. In addition, the asymptomatic donor candidates with a positive anti-
careful preoperative definition of the biliary anatomy nuclear antibody. There are no strict criteria for evaluat-
identifies anatomical variations in the donor that are ing such candidates, but most centers would consider
quite frequent, as reported by Nakamura et al.41 In 120 such donors with one or more of the following features:
right hepatic lobe living donors, 73 patients (61%) had a (a) low titers, (b) the donor/recipient with no autoim-
single duct orifice and single anastomosis and the remaining mune disease, and (c) normal liver biopsy results. In
39% had two or three duct orifices. Biliary complications recipients with genetic liver disease (most commonly α1-
in the recipient were higher in patients with two ducts antitrypsin deficiency, hemochromatosis, Wilson’s dis-
who had one anastomosis with ductoplasty compared to ease, and porphyria), related donor candidates should be
either a double anastomosis or single anastomosis without screened for the same disease. Carriers of such genetic
ductoplasty. In the A2ALL cohort, donors with three or diseases may be considered for donation in almost all
more bile ducts had a significantly higher risk for biliary cases.44,45
complications in the recipients (odds ratio [OR] = 2.72, In addition to the medical criteria, several psychosocial
P = .035).2 aspects cannot be overemphasized. A social worker famil-
Abnormalities in the donor portal vein are uncom- iar with LDLT should evaluate all potential donors, and
mon and rarely exclude donor candidates from dona- psychiatric examination may be required for a few
tion. Nakamura et al41 reported that only one donor (of patients. In recent years, governmental regulations have
120 LDLTs) was rejected based on preoperative assess- mandated the participation of a donor advocate or donor
ment of portal venous anatomy. In their series 92% of advocate team. Specifically, the transplant center must
donors had conventional portal venous anatomy, and identify either an independent living donor advocate or
the remaining 8% had one of four types of variants. advocate team to ensure protection of the rights of living
Common abnormalities in the portal venous system donors and prospective living donors.46,47 The role of the
include trifurcation in the donor portal vein and anoma- donor advocate or advocate team is to act independently
lous branches from the right portal vein, both of which of the transplant team to advise and promote the interests
result in two portal vein orifices in the right hepatic of the donor to ensure that the donor is informed and free
graft.39,41,42 The hepatic venous anatomy is well defined of coercion to donate. The donor advocate must have
with CT angiography or magnetic resonance angiogra- knowledge of living donation, as well as the pressures on
phy. The approach to hepatic venous reconstruction the donor to donate, but be independent from the influ-
varies widely from center to center. Most experienced ence of the transplant team. Financial considerations are
LDLT surgeons have learned that adequate venous also important. In our experience almost all recipient
drainage requires inclusion of the middle hepatic vein insurance plans will cover the medical costs for the donor
branches from segments V and VIII with the right lobe evaluation, but not costs such as travel expenses, lodging,
graft. During the donor hepatectomy, accessory hepatic and lost wages. These out-of-pocket expenses and use of
veins smaller than 1 cm are ligated, whereas large veins medical resources grow steadily as the evaluation pro-
are preserved with the donor graft. The donor right ceeds. Therefore it is important to disqualify inappropri-
hepatic vein is anastomosed to the recipient right hepatic ate donors at the earliest point possible. The mean
vein, whose orifice is extended down the anterior sur- estimated noncovered cost of LDLT donors was $3,660 a
face of the vena cava to match the right hepatic vein decade ago.48
orifice on the donor graft. In almost all cases there is The likelihood of accepting a donor candidate follow-
only one right hepatic vein. In only 1% to 2% of cases ing completion of the evaluation is 40%.49 The donor
two right hepatic veins may be present, whereas 30% to characteristics significantly associated with acceptance
40% of donors have significant accessory hepatic veins are younger age, lower BMI, and biological or spousal
(>5 mm).39,41 The only indication for the middle hepatic relationship to the recipient (P < .05). Recipient charac-
vein reconstruction is a right hepatic vein smaller than teristics significantly associated with donor acceptance
1 cm in diameter. were younger age, lower MELD score, and shorter time
Variations in the hepatic artery are not uncommon but from listing to first donor evaluation. The two most com-
are rarely the reason for donor rejection. Nakamura et al41 mon reasons that donor candidates were rejected were
found conventional anatomy in 87% of cases. The right medical contraindications (17%) and anatomical contra-
hepatic artery originated from the superior mesenteric indications (11%).
 49 Living Donor Transplantation: Evaluation and Selection in Adults 665

15. Liu CL, Fan ST, Lo CM, et al. Right-lobe live donor liver trans-
Pearls and Pitfalls plantation improves survival of patients with acute liver failure. Br
J Surg. 2002;89:317-322.
• The number of living donor liver transplantations 16. Nishizaki T, Hiroshige S, Ikegami T, et al. Living-donor liver
(LDLTs) has decreased over the past decade in the transplantation for fulminant hepatic failure in adult patients with
West and now accounts for fewer than 5% of adult a left-lobe graft. Surgery. 2002;131:S182-S189.
liver transplants. 17. Uemoto S, Inomata Y, Sakurai T, et al. Living donor liver trans-
• In properly selected candidates the decision to under- plantation for fulminant hepatic failure. Transplantation. 2000;70:
go an LDLT is associated with a significant improve- 152-157.
18. Marcos A, Ham JM, Fisher RA, et al. Emergency adult to adult liv-
ment in survival compared to remaining on the list for
ing donor liver transplantation for fulminant hepatic failure. Trans-
a deceased donor liver transplantation. plantation. 2000;69:2202-2205.
• Patients considered for an LDLT must be carefully 19. Miwa S, Hashikura Y, Mita A, et al. Living-related liver transplan-
evaluated to ensure that their medical comorbidities tation for patients with fulminant and subfulminant hepatic failure.
do not jeopardize the success of the operation. Hepatology. 1999;30:1521-1526.
• Because several recent studies show no survival benefit 20. Lo CM, Fan ST, Liu CL, et al. Applicability of living donor liver
of LDLT for patients with HCC, these patients should transplantation to high-urgency patients. Transplantation. 1999;67:
be carefully considered for LDLT. 73-77.
• Approximately 60% of donor candidates evaluated as liv- 21. Liu CL, Fan ST, Lo CM, et al. Living-donor liver transplantation
for high-urgency situations. Transplantation. 2003;75:S33-S36.
ing donors in the West are found unsuitable for donation.
22. Marino IR, Doyle HR. Living donor in urgent cases: ethical haz-
• The complication rate of living liver donors is approxi- ard. Liver Transpl. 2002;8:859-860.
mately 40%, with only 1% to 2% leading to some form 23. Abouna GJ. Emergency adult to adult living donor liver transplan-
of chronic debilitation. tation for fulminant hepatic failure–is it justifiable? Transplantation.
• The rate of living liver donor death is estimated at 2001;71:1498-1500.
0.17%, which is approximately threefold higher than 24. Campsen J, Blei AT, Emond JC, et al. Outcomes of living donor liver
   the rate for living kidney donors. transplantation for acute liver failure: the adult-to-adult living donor
liver transplantation cohort study. Liver Transpl. 2008;14:1273-1280.
25. Trotter JF, Adam R, Lo CM, et al. Documented deaths of hepatic
lobe donors for living donor liver transplantation. Liver Transpl.
2006;12:1485-1488.
26. Muzaale AD, Dagher NN, Montgomery RA, et al. Estimates of
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transplantation. Ann Surg. 2010;251:542-549. 31. Neuberger J. Making an offer you can’t refuse? A challenge of
6. http://www.cdc.gov/obesity/data/adult.html#Prevalence (accessed altruistic donation. Transpl Int. 2011;24:1159-1161.
August 1, 2012) 32. Rinella ME, Alonso E, Rao S, et al. Body mass index as a predictor
7. Lai JC, Terrault NA, Vittinghoff E, et al. Height contributes to the of hepatic steatosis in living liver donors. Liver Transpl. 2001;7:
gender difference in wait-list mortality under the MELD-based 409-414.
liver allocation system. Am J Transplant. 2010;10:2658-2664. 33. Nakamuta M, Morizono S, Soejima Y, et al. Short-term intensive
8. Berg CL, Merion RM, Shearon TH, et al. Liver transplant recipi- treatment for donors with hepatic steatosis in living-donor liver
ent survival benefit with living donation in the model for endstage transplantation. Transplantation. 2005;80:608-612.
liver disease allocation era. Hepatology. 2011;54:1313-1321. 34. Oshita A, Tashiro H, Amano H, et al. Safety and feasibility of diet-
9. Kulik LM, Fisher RA, Rodrigo DR, et al. Outcomes of living and treated donors with steatotic livers at the initial consultation for
deceased donor liver transplant recipients with hepatocellular car- living-donor liver transplantation. Transplantation. 2012;93:
cinoma: results of the A2ALL cohort. Am J Transpl. 2012;12: 1024-1030.
2997-3007. 35. Moon D, Lee S, Hwang S, et al. Resolution of severe graft steatosis
10. Sandhu L, Sandroussi C, Guba M, et al. Living donor liver trans- following dual-graft living donor liver transplantation. Liver
plantation versus deceased donor liver transplantation for hepato- Transpl. 2006;12:1156-1160.
cellular carcinoma: comparable survival and recurrence. Liver 36. Cho JY, Suh KS, Kwon CH, et al. The hepatic regeneration power
Transpl. 2012;18:315-322. of mild steatotic grafts is not impaired in living-donor liver trans-
11. Bhangui P, Vibert E, Majno P, et al. Intention-to-treat analysis of plantation. Liver Transpl. 2005;11:210-217.
liver transplantation for hepatocellular carcinoma: living versus 37. Urata K, Kawasaki S, Matsunami H, et al. Calculation of child and
deceased donor transplantation. Hepatology. 2011 May;53(5): adult standard liver volume for liver transplantation. Hepatology.
1570-1579. doi:10.1002/hep.24231. 1995;21:1317-1321.
12. Liang W, Wu L, Ling X, et al. Living donor versus deceased donor 38. Heinemann A, Wischhusen F, Puschel K, et al. Standard liver vol-
liver transplantation for hepatocellular carcinoma: A meta-analysis. ume in the Caucasian population. Liver Transpl Surg. 1999;5:
Liver Transpl. 2012;18:1226-1230. 366-368.
13. Trotter JF. Living donor liver transplantation for hepatocellular 39. Marcos A, Ham JM, Fisher RA, et al. Surgical management of ana-
carcinoma: through the looking glass. Am J Transpl. 2012;12: tomical variations of the right lobe in living donor liver transplan-
2873-2874. tation. Ann Surg. 2000;231:824-831.
14. Park SJ, Lim YS, Hwang S, et al. Emergency adult-to-adult living- 40. Cheng YF, Huang TL, Chen CL, et al. Variations of the intrahe-
donor liver transplantation for acute liver failure in a hepatitis B patic bile ducts: application in living related liver transplantation and
virus endemic area. Hepatology. 2010;51:903-911. splitting liver transplantation. Clin Transplant. 1997;11:337-340.
666 PART VI Split and Living Donor Transplantation

41. Nakamura T, Tanaka K, Kiuchi T, et al. Anatomical variations and 46. Sites AK, Freeman JR, Harper MR, et al. A multidisciplinary pro-
surgical strategies in right lobe living donor liver transplantation: gram to educate and advocate for living donors. Prog Transplant.
lessons from 120 cases. Transplantation. 2002;73:1896-1903. 2008;18:284-289.
42. Lee SG, Hwang S, Kim KH, et al. Approach to anatomic variations of 47. Rudow DL. The living donor advocate: a team approach to edu-
the graft portal vein in right lobe living-donor liver transplantation. cate, evaluate, and manage donors across the continuum. Prog
Transplantation. 2003;75:S28-S32. Transplant. 2009;19:64-70.
43. Marcos A, Killackey M, Orloff MS, et al. Hepatic arterial recon- 48. Trotter JF, Mackenzie S, Wachs M, et al. Comprehensive cost
struction in 95 adult right lobe living donor liver transplants: evo- comparison of adult-adult right hepatic lobe living-donor liver
lution of anastomotic technique. Liver Transpl. 2003;9:570-574. transplantation with cadaveric transplantation. Transplantation.
44. Morioka D, Takada Y, Kasahara M, et al. Living donor liver trans- 2003;75:473-476.
plantation for noncirrhotic inheritable metabolic liver diseases: 49. Trotter JF, Wisniewski KA, Terrault NA, et al. Outcomes of
impact of the use of heterozygous donors. Transplantation. donor evaluation in adult-to-adult living donor liver transplan-
2005;80:623-628. tation. Hepatology. 2007;46:1476-1484.
45. Sokal EM. Liver transplantation for inborn errors of liver metabo-
lism. J Inherit Metab Dis. 2006;29:426-430.
 CHAPTER 50

Adult Living Donor Right

Hepatectomy and Recipient
Operation
Chung-Mau Lo • See-Ching Chan

CHAPTER OUTLINE

PREOPERATIVE EVALUATION Hepatic Venoplasty

Recipient Evaluation Portal Venoplasty
Donor Evaluation RECIPIENT OPERATION
DONOR OPERATION Recipient Hepatectomy
Donor Right Hepatectomy Implantation of Liver Graft
Exposure Hepatic Vein Anastomosis
Operative Cholangiogram Portal Vein Anastomosis
Isolation of Major Vessels Hepatic Artery Anastomosis
Parenchymal Transection Management of Small-for-Size Grafts
Middle Hepatic Vein Controversy Biliary Reconstruction
Graft Delivery Postoperative Care and Common
Liver Graft Back-Table Procedure Complications
CONCLUSION

Living donor liver transplantation (LDLT) has emerged while the risks borne by the donors are shown to be
to relieve the global shortage of deceased donor liver acceptable. The application of this procedure has
grafts. After the first success in a child was reported by expanded tremendously, and it has become the main
Strong et al1 of Brisbane in 1990, significant advance- workload in centers active in adult LDLT.6,7 LDLT
ments in various fields have been achieved that allow dra- accounted for nearly 90% of the liver transplants per-
matic growth and a wider application of this lifesaving formed in Asia excluding mainland China, and nearly
operation. Among these, the advent of adult right liver 90% of the adult LDLTs were right liver LDLT.8
LDLT, which overcomes the restriction of donor-­ Adult right liver LDLT is one of the most complicated
recipient size matching and evades small-for-size syn- and technically demanding procedures, and there are
drome,2 has had the most significant impact. numerous technical variations that have been described
Incidentally, the first right liver LDLT was anecdot- in both the donor and the recipient operations. In this
ally reported to have been performed in Kyoto not for an chapter the standard techniques as adopted in our center
adult but for a 9-year-old recipient avoid an anatomical will be presented, focusing on the tips and tricks and with
anomaly of the donor’s left hepatic arteries.3 The first reference to other important variations.
adult right liver LDLT was performed in Hong Kong on
May 9, 1996, in an adult with fulminant Wilson’s disease
who had a body weight of 90 kg. The donor was his elder PREOPERATIVE EVALUATION
brother, who weighed 74 kg.4 When the first series of
seven patients from Hong Kong was reported in 1997,2 A description of adult right liver LDLT is not complete
there was a cautionary note as to the future role of this without a few brief remarks on the evaluation of a right
operation. Indeed, in the initial phase, ethical controversy liver donor and recipient.
regarding the safety of the donor posed a major obstacle
toward a wider application of the procedure. Nonethe-
less, improved understanding of the anatomy of the liver
Recipient Evaluation
and advances in surgical techniques have dramatically The potential recipient evaluation for LDLT should not be
improved the outcome of both donors and recipients.5 different from that for deceased donor liver transplantation.
Recipients now can have excellent long-term survival The indications and contraindications for transplantation

667
668 PART VI Split and Living Donor Transplantation

are generally the same. Candidates for LDLT should also higher in sicker patients with more severe portal hyper-
be candidates for deceased donor liver transplant. Some tension and for liver grafts from older donors.25 For the
centers, however, have adopted extended criteria for safety of the donor, a remnant left liver of 30% or more
LDLT, especially in patients with hepatocellular carcinoma of the total liver volume is required.26 The presence of
because a graft from a living donor is a dedicated gift and is fatty change has to be factored into the liver graft and
not subject to any allocation system that mandates a strict remnant size estimation. In general, a fatty change of
set of criteria to justify organ use. Transplant centers need over 20% as verified by liver biopsy would prohibit a safe
to balance the donor risks versus the recipient benefit and right liver donation.
decide on a limit beyond which a transplant becomes futile.9 The anatomy of the liver and its vasculature must be
The recipient’s coping ability and attitude toward LDLT as studied in detail using three-phase contrast-enhanced
a treatment option is carefully assessed by the surgeon and computed tomography or magnetic resonance imaging.
then by the clinical psychologist. Anatomical variants in the hepatic artery and portal vein
Retransplantation, Budd-Chiari syndrome, and portal need to be identified. Appreciation of the hepatic venous
vein thrombosis, especially with extension into the superior drainage, especially that of segment IVb/V/VIII and sizable
mesenteric vein, had been regarded as contraindications (>5 mm) inferior right hepatic veins (RHVs), is of utmost
for LDLT because of the more difficult challenge in importance. At our center, all right liver grafts include
vascular reconstruction for right liver LDLT. With better the middle hepatic vein (MHV), which allows optimal
technique and experience, however, these technical hurdles venous drainage. Preoperative biliary imaging is not
can be overcome and hence are not considered as absolute performed.
contraindications.
Although LDLT is not the preferred procedure for a
high-urgency situation in Europe and the United DONOR OPERATION
States,10,11 it was the impetus for development of adult
right liver LDLT in Hong Kong and other parts of Asia. Donor Right Hepatectomy
All seven recipients in our first reported series were high- Exposure
urgency patients in the intensive care unit.2 Right liver
LDLT not only shortens the waiting time but allows Access is gained through a short right subcostal incision
excellent timing for the transplantation of these critically of only the right rectus muscle with upper midline exten-
ill patients. The transplant rate and survival rate are both sion. The two curved blades of the Bookwalter retractor
improved.12 A high-urgency patient is a prime indication pull the rib cage laterally and anteriorly to open up the
for right liver LDLT in Asia. aperture made by the costal margins. The ligamentum
teres is ligated and divided, and the falciform ligament is
taken down. Following careful laparotomy for unex-
Donor Evaluation pected intra-abdominal pathological conditions, intra­
The evaluation of a potential living liver donor should operative ultrasonography is performed to study the
proceed in a stepwise fashion13 to ensure that the volun- anatomy, especially that of the junction of the MHV and
teer remains psychologically and physically healthy in the left hepatic vein with the inferior vena cava (IVC). The
long-term after the organ donation. Only healthy indi- relation of the segment IVb vein to the MHV, already
viduals 18 to 60 years of age are eligible. ABO incompati­ known from computed tomography, is ascertained. This
bility is no longer an absolute contraindication for also registers the flow characteristics of the hepatic arteries,
LDLT.14 After careful planning and workup, donor portal veins, and hepatic veins bilaterally for reference
interchange can also convert two pairs of ABO-­ throughout the operation.
incompatible LDLTs into two compatible ones.15
Donation of the right liver represents removing two Operative Cholangiogram
thirds of the liver in contrast to keeping two thirds as in a
donor left hepatectomy. The former has an estimated A good-quality operative cholangiogram using a C-arm
donor mortality of 0.5% and the latter 0.1%.16 Hence a fluoroscope is mandatory. The Calot triangle is dissected
right liver graft is generally chosen only if the left liver to isolate the cystic duct and cystic artery. After cannulation
volume as estimated by volumetry using computed of the cystic duct with a balloon catheter, the gallbladder
tomography is too small for the needs of the recipient. is excised. Minimal sharp dissection of the hilar plate just
Previous studies have indicated that graft survival will be enough to identify the junction of the right hepatic duct
compromised if the graft volume–to–standard liver volume with the common hepatic duct is done. The planned site
ratio is less than 40%17-19 or the graft weight–to–­recipient of right hepatic duct division is then marked with a large
body weight ratio is less than 0.8%.20,21 The mode of fail- metal clip externally to correlate with the findings of an
ure for small-for-size grafts is often manifested as small- operative cholangiogram. The balloon of the catheter is
for-size syndrome and is characterized by coagulopathy, inflated, and the biliary tract is outlined by real-time
cholestasis, ascites, sepsis, encephalopathy, and eventu- operative cholangiogram under fluoroscopy.27 Swinging
17
ally graft failure. With maturation of surgical tech- the C-arm of the fluoroscope laterally to the right (a right
niques, the minimum graft volume–to–standard liver anterior-oblique view) allows a true “anterior-posterior”
volume ratio can be lowered from 40%22 to 35%,23 and display of the right and left duct, and the parallax tech-
perhaps even lower,24 without compromising outcome. nique clarifies the location of the right anterior and pos-
Nonetheless, the graft size requirement may become terior sectoral ducts (Fig. 50-1, A). The liver capsule just
 50 Adult Living Donor Right Hepatectomy and Recipient Operation 669

Left hepatic ducts

Left hepatic ducts

Right hepatic ducts

Common bile duct
Right hepatic ducts
Common bile duct

A B
FIGURE 50-1 n Intraoperative cholangiogram with radiopaque marker for precise transection of right hepatic duct. A, Right anterior
oblique view intraoperative cholangiogram showing a very short right hepatic duct (arrow). B, A large metal clip (arrow) as radio-
marker correlating the cholangiogram with the planned site of right hepatic duct transection.

superior of the planned site of right hepatic duct transec- MHV, for the hanging maneuver to facilitate the liver
tion is marked by diathermy. transection. Temporary right liver inflow control with
atraumatic vascular clamps is performed, and the line of
Isolation of Major Vessels transection, the Cantlie line, is marked with electrocau-
tery. The line of demarcation is usually poorly defined
Hilar dissection is then continued to isolate the right between segments VIII and IVb at the cephalic end and is
hepatic artery and the right portal vein. The right hepatic guided by extrahepatic identification of the RHV and
artery dissection should be limited to the right side of the MHV. The transection line should be directed toward
common hepatic duct, and the branch to segment IV the root of the MHV. The line on the inferior surface of
should be preserved. If any branches to segment IV need the liver is just to the left of the gallbladder fossa and is
to be sacrificed, the artery is temporarily clamped and a extended to join the planned point of division of the right
Doppler study is performed to ascertain that there are hepatic duct as marked earlier.
good collaterals from the left hepatic artery. The right
hepatic artery and hilar plate should be completely sepa-
Parenchymal Transection
rated, but the space between the right hepatic artery and
the right hepatic duct should not be disrupted in order to Liver parenchymal transection is performed using a Cavi-
preserve the blood supply of the latter. To isolate ade- tron Ultrasonic Surgical Aspirator (CUSA) with a fine
quate length of the right portal vein, a number of branches precision tip (1.14 mm in diameter) at a frequency of
to the caudate lobe need to be ligated and then divided. 32 kHz, which is set at amplitude of 60% to 70% with
The right triangular and coronary ligaments are then irrigation with normal saline at approximately 4 to 6 mL/
taken down to mobilize the right liver. Excessive rotation min. Suction is set to a low to moderate level just enough
and compression of the right liver results in ischemic liver to provide a clear operative field. Electrocautery incorpo-
injury and should be avoided. Intermittent rotation may rated into the CUSA allows coagulation of vessels less
be required. The right liver is freed from the right adre- than 1 mm in diameter. The CUSA disrupts the liver
nal, which may be adherent, and bleeding is controlled by parenchyma and allows visualization of the vessels and
the argon beam coagulator and plication with sutures. biliary radicles that are controlled with electrocautery,
Short hepatic veins on the right side of the midline of the metallic clips, ligatures, or sutures. Other liver transec-
IVC are individually isolated and divided between liga- tion techniques that allow precise liver transection
tures. Inferior RHV(s) larger than 5 mm are preserved for include the use of crushing clamps or a water jet. Power-
reconstruction in the recipient. These are particularly ful hemostatic devices that allow rapid liver transection
crucial when the right liver graft is relatively small. The by coagulation without visualizing the vessels and biliary
IVC ligament contains vessels and should be suture radicles along or next to the transection plane are not
ligated after division. The RHV is then encircled with a desirable. A low central venous pressure is a key element
vessel loop. A nylon tape is placed posterior to the cau- in reducing blood loss, especially from hepatic veins, and
date lobe, passing between the roots of the RHV and can only be attained with good rapport with the
670 PART VI Split and Living Donor Transplantation

anesthetist. The Pringle maneuver is generally not advis- inclusion of MHV and routine or selective reconstruction
able or necessary. of segments V and VIII venous branches based on graft
A segment IVa vein is commonly encountered after size, liver remnant size, and venous anatomy, have been
parenchymal transection for 4 to 5 cm. After this vein is proposed.33,34 We consider a right liver graft without
divided and followed, the main trunk of the MHV is MHV drainage for segments V and VIII a marginal graft.
exposed on its left side, which serves as an important
landmark for the plane of the transection within the liver
parenchyma (Fig. 50-2).26 Transection continues with
Graft Delivery
division of branches entering the left side of the middle Graft delivery starts with applying a clamp onto the prox-
hepatic vein until the junction with the left hepatic vein is imal right hepatic artery. The right hepatic artery is then
reached. Any sizable segment IVb branch joining the root divided with scissors. The right portal vein is then divided
of the MHV should be preserved for draining the liver between vascular clamps applied at a right angle to the
remnant in the donor.28 course of the main portal vein. The MHV, RHV, and if
At the liver hilum the right hepatic duct is dissected present the inferior RHV are controlled with vascular
and encircled with minimal use of the CUSA. Excessive staplers (TA 30; Tyco Healthcare, Norwalk, CT) before
dissection that denudes the right hepatic duct from its its division by scissors. The right liver graft is then deliv-
blood supply should be avoided. The line of division is ered and immediately put into ice sludge on the back
verified with the help of another operative cholangio- table. The right portal vein stump is sutured in a trans-
gram with radiopaque marker (see Fig. 50-1, B), and the verse manner with 6-0 polypropylene (Prolene) sutures,
right hepatic duct(s) is divided sharply and precisely with continuous, back-and-forth. Patency of the remnant left
scissors, tangential to the transection plane that is often hepatic duct is confirmed with intraoperative cholangio-
quite horizontal. The right hepatic duct stump of the gram, and leakage from the hepatic duct stump or liver
donor is repaired by 6-0 polydioxanone continuous remnant transection surface is checked by gentle injec-
suture. Liver parenchyma dorsal to the MHV and the tion of diluted methylene blue into the cystic duct can-
caudate lobe is further transected until the IVC is exposed. nula. The cannula is then removed, and the cystic duct
The nylon tape placed between the RHV and MHV pre- stump is ligated.
viously serves the hanging maneuver, lifting up the cau- The remnant left liver is maintained in the anatomical
date lobe to facilitate the liver transection. position by reconstitution of the falciform ligament.
Patency of the vessels is verified with intraoperative Dop-
Middle Hepatic Vein Controversy pler ultrasonography. The greater omentum is allowed to
ascend into the right subphrenic space to cover the tran-
The importance of the MHV in venous drainage of seg- section surface, and the abdomen is closed without any
ments V and VIII of a right liver graft is well recognized.29 catheter drainage.35
We regularly include the MHV in a right liver graft, and
the safety and necessity of including the MHV have been
validated.30-32 Preservation of the segment IVb hepatic
Liver Graft Back-Table Procedure
vein in the liver remnant is desirable and is tailored to the To shorten the cold ischemic time, the right liver graft is
surgical anatomy of the individual right liver donor.28 not delivered until the recipient is almost ready for graft
Other centers, however, are reluctant to include the implantation. The graft once delivered is flushed via the
MHV in the right liver graft for fear of compromising right portal vein with three times the graft volume of cold
donor safety. Different strategies, including selective histidine-tryptophan-ketoglutarate (HTK) solution
(Dr. Franz Köhler Chemie GmbH, Alsbach-Hähnlein,
Germany) while immersed in an ice-sludge basin on the
back table.36 The color of the graft must be inspected,
and areas that are not completely clear of blood should
receive more attention. Retrograde flushing via the
hepatic vein is helpful. If there are two separate right por-
tal vein openings, flushing should be done by cannulating
both simultaneously. The right hepatic artery is also
flushed with HTK solution under gravity through a fine-
in

bore angiocatheter. The right anterior and posterior sec-

ve
ic

toral ducts are also flushed with cold HTK solution to

pat

remove the bile. The graft is then weighed and trans-

he
le

ferred to another basin containing cold HTK solution.

idd
M

Hepatic Venoplasty
Inclusion of the MHV could only be justified if the recon-
struction could be simplified and venous outflow capacity
maximized. This is achieved by converting the RHV and
FIGURE 50-2 n Donor right hepatectomy with the middle hepatic MHV to a single triangular cuff by venoplasty.37 Exploit-
vein exposed. ing the resilient liver parenchyma between the MHV and
 50 Adult Living Donor Right Hepatectomy and Recipient Operation 671

RHV and the elasticity of the right and middle hepatic expedite the portal vein anastomosis in the recipient
veins, the single cuff is kept widely open.38 This will operation because size matching and orientation will be
match the triangular venotomy made on the recipient perfect.
IVC. Even though the MHV and the RHV are often at a
distance of up to 2 cm, they can be drawn together for
fashioning of a single venous cuff (Fig. 50-3).38 RECIPIENT OPERATION
Portal Venoplasty Recipient Hepatectomy
There is a 10% to 35% chance of portal vein anomaly in As a result of the shorter vessels and bile duct in a living
a right liver graft39-41 (Fig. 50-4, A), and techniques have donor right liver graft, the recipient hepatectomy is dif-
been devised to tackle such anomalies, including the use ferent from that for a deceased donor liver transplant in
of autologous vein (e.g., the great saphenous vein) or many ways. A generous bilateral subcostal incision with
cryopreserved cadaveric vein grafts. However, autolo- upward midline extension is essential for adequate expo-
gous vein procurement prolongs the donor operation sure. Meticulous hilar dissection is necessary to preserve
time and may cause donor morbidity. The long-term the portal triads in preparation for the reconstruction. A
results of the use of cryopreserved vein grafts are also good length of each of the right, middle, and left hepatic
suboptimal. Dual portal vein venoplasty is the preferred arteries is dissected and isolated. A suitable-size micro-
technique. It uses a portion (approximately 1 cm long) of vascular clamp is used to control the proximal end of each
the main portal vein of the recipient as an “interpositional artery before the distal end is ligated and divided. Dissec-
graft”(see Fig. 50-4, B), which is to be anastomosed to the tion of the common hepatic duct should start high up at
graft portal veins after venoplasty.42 The technique can the hilum, and excessive skeletonization should be
avoided in order to preserve its blood supply.43 The com-
mon hepatic duct is severed by sharp dissection, and
bleeding from the 3 and 9 o’clock feeding arteries on the
distal stump is controlled by plication using fine sutures.
Diathermy coagulation on the bile duct should be
avoided. Although enough length for the subsequent
duct-to-duct anastomosis is necessary, an excessively long
recipient bile duct is prone to ischemic stricture forma-
tion. The main, right, and left portal veins are isolated.
Middle hepatic vein The main portal vein is controlled with a Blalock 18-mm
pulmonary vascular clamp, and the right and left portal
veins are divided close to the liver hilum.
In contrast to a deceased donor whole graft liver trans-
plant, the recipient inferior vena cava needs to be pre-
served in a living donor right liver transplant. Hence it is
necessary to mobilize the caudate lobe from the IVC and
Right hepatic vein
to divide all the short hepatic veins. This can be more
easily done after the portal vein is divided and the liver
retracted upward and cephalad. The RHV and the com-
FIGURE 50-3 n Venoplasty of the middle and right hepatic veins mon trunk of the middle and left hepatic veins are iso-
to form a single cuff. lated and divided by an Endo GIA vascular stapler

Interpositional
portal vein graft
Right posterior from recipient
portal vein Right posterior
portal vein

Right hepatic
artery Right anterior
portal vein
Right anterior
portal vein

A B
FIGURE 50-4 n Dual portal vein venoplasty using recipient portal vein as interpositional graft. A, Dual right portal vein in donor
­operation. B, Completed venoplasty with interpositional graft on the back table.
672 PART VI Split and Living Donor Transplantation

(ATW 35; Ethicon Endo-Surgery, Inc., Cincinnati, OH), Portal Vein Anastomosis
thus allowing delivery of the native liver.
To ensure an optimal hepatic vein anastomosis, cir- HTK solution with a low potassium content allows graft
cumferential isolation and cross-clamping of the IVC is reperfusion without prior flushing.44 After the hepatic
necessary. Several lumbar veins and the phrenic veins on vein anastomosis is completed, the portal vein stump of
both sides have to be divided and ligated before the ret- the liver graft is inspected for correct orientation and is
rohepatic IVC is fully mobilized. The presence of an occluded by a bulldog vascular clamp. The clamps on the
inferior hepatic vein of over 5 mm in the graft calls for IVC are released, and systemic venous return can be
the need to isolate the IVC more inferiorly. After hemo- restored before portal vein anastomosis.36 Earlier resto-
stasis of the retroperitoneum, the IVC is occluded with a ration of blood flow through the IVC has an advantage of
Rummel tourniquet and nylon tape at the infrahepatic better hemodynamic stability without the need for veno-
region and an Ulrich Swiss clamp in the suprahepatic venous bypass. The latter has been shown in our series to
region. The RHV stump is reopened, and the lumen of be associated with worse outcomes, related to hypother-
the retrohepatic IVC is flushed with heparinized normal mia and bleeding diathesis.45 Gradual rewarming of the
saline. The longitudinal orifice of the RHV is enlarged graft will take place while the portal vein anastomosis is
by incising transversely across the anterior wall of the completed. This will also prevent significant hypother-
IVC to fashion a triangular venotomy opening that mia during reperfusion. Before portal vein anastomosis,
matches in size and shape the hepatic vein venoplasty cuff the length of the recipient portal vein is shortened if nec-
in the graft. essary to avoid excessive length and redundancy. The
anastomosis is performed with 6-0 polypropylene run-
ning sutures with a growth factor of about two thirds of
Implantation of Liver Graft the diameter of the portal vein.46
Hepatic Vein Anastomosis
Hepatic Artery Anastomosis
Graft implantation starts with anastomosis of the
hepatic vein cuff of the graft with the recipient caval The selection of the recipient hepatic artery for arterial
opening performed in a triangular fashion using reconstruction is based on length, caliber, and orienta-
5-0 polypropylene. Running sutures are applied, start- tion. Patients who have undergone transarterial oily che-
ing with the base of the triangle (the posterior wall of moembolization for hepatocellular carcinoma may have
the RHV) (Fig. 50-5) and continuing forward along the sustained damage to the hepatic artery. The gastroduo-
two sides to join at the apex. A stay suture applied to the denal artery may be used as an alternative for arterial
apex helps in the alignment of these two walls during inflow. The Kyoto group initiated hepatic artery anasto-
the suturing. The procedure can be facilitated by tilting mosis in LDLT under high magnification with an oper-
the graft upward and downward for better exposure and ating microscope,47 which has now been adopted as a
alignment of the caudal and cephalic sides, respectively. standard technique in most centers. Our 10-year experi-
The continuous suture is tied with a small growth factor ence of hepatic artery anastomosis with the operating
of 3 to 4 mm to allow opening up of the anastomosis on microscope by a team of dedicated microvascular sur-
release of the cross-clamps on the IVC. Right inferior geons showed a complication rate of only 2%.48 Multiple
hepatic veins of significant size (>5 mm) that have been interrupted stitches with 9-0 nylon monofilament sutures
preserved in the liver graft are anastomosed directly to are used. Adequate lengths of both the recipient and graft
the IVC. hepatic arteries are necessary to allow rotating the vessels
for placement of sutures on the posterior wall.
Doppler ultrasonography is performed immediately
after the arterial anastomosis and after closure of the
abdominal wound to ensure patency of all the vascular
anastomoses. Triphasic Doppler pulsatility of the hepatic
veins testifies to good outflow capacity of the graft. A low
pulsatility index and good diastolic flow indicate satisfac-
tory arterial anastomosis. Measurement of portal venous
blood flow volume is important not only in assessing the
patency of the portal vein anastomosis but in the preven-
tion and management of small-for-size syndrome.

Right liver graft Management of Small-for-Size Grafts

including middle
hepatic vein
Inferior vena cava Even right liver grafts from living donors are frequently
small-for-size for adult recipients, and small-for-size syn-
drome may develop. In our experience, most right liver
graft donations are from a woman to a man (Table 50-1).
Hence over 80% of right liver grafts are below 60% of
FIGURE 50-5 n Suturing of the posterior wall of the hepatic vein the recipient’s standard liver volume, and nearly 20%
to the inferior vena cava. are below 40%. To prevent small-for-size syndrome,
 50 Adult Living Donor Right Hepatectomy and Recipient Operation 673

it is necessary to perform routine portal flowmetry and caudal shifting is simple. The cranial part of the RHV is
manometry for any graft with graft volume–to–standard closed and the opening is extended caudally so that the
liver volume ratio under 50%.49,50 Portal flow is mea- triangular venotomy in the IVC is shifted to a more cau-
sured by Doppler ultrasonography or a laser flowmeter, dal part of the IVC. This technique brings the graft cau-
and manometry is performed by cannulation of the infe- dally for as much as 2 to 3 cm and allows tension-free
rior mesenteric vein or a branch of the superior mesen- anastomoses at the liver hilum without the use of interpo-
teric vein. With optimal venous outflow reconstruction sitional conduits.
(as in right lobe grafts containing the MHV), a right liver
graft can tolerate very high portal flow in excess of 250
Biliary Reconstruction
mL/100 g/min without elevation of the portal pressure.
If the portal pressure exceeds 20 mm Hg, portal inflow Biliary reconstruction in right liver LDLT can be per-
modulation can be done by splenic artery ligation.51 formed using duct-to-duct anastomosis or hepaticojeju-
It is important to note that portal flowmetry and nostomy. Duct-to-duct anastomosis is currently the
manometry is mandatory in the diagnosis and manage- preferred technique except in cases in which the recipient
ment of small-for-size syndrome because in the presence bile duct is not healthy, such as in patients with sclerosing
of spontaneous portasystemic shunt, even a small liver cholangitis. The advantages include a shorter operation
graft may suffer portal hypoperfusion.52 If a portal hemo- time and avoidance of contamination of the operation
dynamic study shows a low portal flow and portal pres- field by bowel contents from an enterotomy before anas-
sure, it may be necessary to ligate the shunt to augment tomosis with the Roux loop. The sphincter of Oddi as a
the flow and the pressure, which are essential for graft defense against enteric reflux and ascending infection is
regeneration. preserved. The risk for internal herniation is also
Our current safety limit for minimum graft vol- reduced.55 In case of bile leakage from the anastomosis,
ume–to–standard liver volume ratio is 35%. Occasionally contamination to the peritoneal cavity is less catastrophic.
a graft that is less than 35% of the standard liver volume It also allows access to the biliary anastomosis by endo-
can be safely used, and 5.8% of the right liver grafts in scopic means.
our center are below 35% of the standard liver volume of Duct-to-duct anastomosis is performed between the
the recipients. Further lowering of the safety limit of the graft right hepatic duct and the recipient common
graft volume–to–standard liver volume ratio will allow hepatic duct. One pitfall to avoid in biliary reconstruc-
more frequent use of smaller left liver grafts, thereby tion is preserving a common hepatic duct in the recipient
reducing donor risks while not jeopardizing recipient that is too long, with an ischemic end that may end up
outcomes.53 developing ischemic anastomotic stricture or even bile
Another major problem posed by a small-for-size graft leakage. Before anastomosis, bleeding from both ends of
is the gap between the graft hilar structures and the recip- the bile duct is stopped by plication using fine sutures
ient hepatoduodenal ligament that may result in inade- rather than diathermy. The anastomosis is performed
quate length for tension-free hepatic artery, portal vein, using 6-0 absorbable sutures, with continuous sutures
or duct-to-duct biliary anastomoses. In such a case the for the posterior wall and interrupted ones for the ante-
use of the caudal-shifting technique for the hepatic vein rior wall. A short segment of fine-bore cannula is tempo-
anastomosis should be considered.54 The concept of rarily placed across the anastomosis to guide the
placement of sutures on the anterior wall. The catheter
is removed before the sutures are tied. In the case of
TABLE 50-1 G
 ender Match and Graft Size in 452 more than one right hepatic duct in the graft that are
Living Donor Right Liver Transplants close together, the adjacent ductal orifices are approxi-
at Queen Mary Hospital mated to form a single cuff, and a single duct-to-duct
anastomosis is performed incorporating the hilar plate.56
Donor-Recipient gender match Ductoplasty is associated with a higher incidence of
M to F 54 stricture and is not advisable.
F to M 219 Abdominal drains are placed only selectively in our
M to M or F to F 179 patients after right liver transplant because drains have
Recipient body weight (kg)* 66 (40-116) been shown to be associated with a higher wound infec-
Donor body weight (kg)* 56.5 (37-108.5) tion rate after liver resection in patients with cirrhotic liv-
Graft weight (g)* 600 (320-1140) ers.57 Conventionally, abdominal drains placed in the
Graft weight–to–recipient body weight 0.91 proximity of the liver transection surface serve to detect
ratio (%)* (0.49-2.60) and contain bile leakage. By meticulous liver transection
Graft volume–to–recipient standard 49.3 (28.4-111) with ligation and clipping of vasculobiliary channels in
liver volume ratio (%)* the donor and refined techniques in biliary anastomosis,
Graft volume–to–recipient standard bile leakage has largely been avoided.
liver volume
<40% 83
40%-60% 298 Postoperative Care and Common
>60% 71 Complications
*Value shown as median (range). The care of a recipient after right liver LDLT differs
F, Female; M, male. from that after deceased donor liver transplantation in
674 PART VI Split and Living Donor Transplantation

two ways. First, a right liver graft is frequently small-for- accumulation of experience. Although a single technique
size. Intravenous fluid replacement should be cautious for of right liver LDLT with inclusion of the MHV is
a small-for-size graft to avoid venous congestion, and the described in this chapter, there are numerous variations
initial dosage of tacrolimus will have to be reduced. Sec- based on patient factors and the skill and experience of
ond, to ensure early detection of vascular complications, surgeons and centers. To justify LDLT, donor volun-
percutaneous ultrasound/Doppler studies are performed tarism, acceptable donor morbidity, and predictably good
daily to verify satisfactory vessel patency and pulsatility. recipient long-term outcome are the least that should be
expected.58 Given the reality of a limited choice of living
donors, the graft size could hardly be improved for a
CONCLUSION recipient, and the full potential of a partial liver graft has
to be used. Each gram of the liver graft is a valuable gift
Right liver LDLT is a complicated and technically from the donor to the recipient, and by including the
demanding operation. For the best recipient outcome, MHV coupled with a venoplasty to the RHV, the maxi-
every step in the donor and recipient operation must be mal functional liver parenchyma of a right liver graft is
perfect, and this can only be achieved after adequate transplanted to the recipient.

Pearls and Pitfalls

• Right liver living donor liver transplantation (LDLT) Ultrasonic Surgical Aspirator, which allows visualization
overcomes the restriction imposed by donor-recipient size of the vascular and biliary radicles along or next to the
matching and is the main workload in centers active in transection plane. Transection by a powerful hemostatic
adult LDLT. device is not desirable.
• Adult right liver LDLT is a complicated and technically • The middle hepatic vein serves as an important land-
demanding procedure. mark for the plane of the transection within the liver
• Donor hepatectomy: parenchyma.
• It is safe and important to include the middle hepatic vein • Recipient operation:
in a right liver graft to optimize its venous drainage and • Hepatic venoplasty on the back table that converts the
function. right hepatic vein and middle hepatic vein to a single
• Dissection of the right hepatic artery should be limited to triangular cuff facilitates the hepatic vein anastomosis in
the right side of the common hepatic duct. the recipient.
• A good-quality right anterior-oblique view operative • Hepatic artery anastomosis should be done by microvas-
cholangiogram using a C-arm fluoroscope is mandatory. cular surgeons using an operating microscope.
A radiopaque marker on the planned site of right hepatic • Duct-to-duct anastomosis is the preferred technique for
duct division is correlated with the findings of the chol- bile duct reconstruction.
angiogram. • Measurement of portal flow and pressure is mandatory
• Liver parenchymal transection should be performed in the diagnosis and management of small-for-size
precisely with techniques such as using the Cavitron    syndrome.

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862–853. 17. Emond JC, Renz JF, Ferrell LD, et al. Functional analysis of grafts
8. de Villa V, Lo CM. Liver transplantation for hepatocellular carci- from living donors. Implications for the treatment of older recipients.
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9. Merion RM. When is a patient too well and when is a patient too 18. Urata K, Kawasaki S, Matsunami H, et al. Calculation of child and
sick for a liver transplant? Liver Transpl. 2004;10(10 Suppl 2): adult standard liver volume for liver transplantation. Hepatology.
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19. Kiuchi T, Kasahara M, Uryuhara K, et al. Impact of graft size 39. Marcos A, Orloff M, Mieles L, et al. Reconstruction of double
mismatching on graft prognosis in liver transplantation from living hepatic arterial and portal venous branches for right-lobe living
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living donor liver transplantation. Transplantation. 1999;68(8): ficial femoral vein as a venous graft for portal vein reconstruction
1112–1116. in right lobe living donor liver transplantation. Transplant Proc.
21. Sugawara Y, Makuuchi M, Takayama T, et al. Small-for-size grafts 2009;41(1):195–197.
in living-related liver transplantation. J Am Coll Surg. 2001;192(4): 41. Xu MQ, Yan LN, Li B, et al. Surgical procedures for management
510–513. of right portal venous branching in right lobe living donor liver
22. Lo CM, Fan ST, Chan JK. Minimum graft volume for successful transplantation. Transplant Proc. 2008;40(5):1529–1533.
adult-to-adult living donor liver transplantation for fulminant 42. Chan AC, Lo CM, Chok KS, et al. Life made easy: simplifying recon-
hepatic failure. Transplantation. 1996;62(5):696–698. struction for dual portal veins in adult right lobe live donor liver
23. Fan ST, Lo CM, Liu CL, et al. Determinants of hospital mortality transplantation. Hepatobiliary Pancreat Dis Int. 2010;9(5):547–549.
of adult recipients of right lobe live donor liver transplantation. 43. Vellar ID. Preliminary study of the anatomy of the venous drainage
Ann Surg. 2003;238(6):864–869. discussion 869–870. of the intrahepatic and extrahepatic bile ducts and its relevance to
24. Chan SC, Lo CM, Ng KK, et al. Alleviating the burden of small- the practice of hepatobiliary surgery. ANZ J Surg. 2001;71(7):
for-size graft in right liver living donor liver transplantation 418–422.
through accumulation of experience. Am J Transplant. 2010;10(4): 44. Testa G, Malago M, Nadalin S, et al. Histidine-tryptophan-­
859–867. ketoglutarate versus University of Wisconsin solution in living
25. Ben-Haim M, Emre S, Fishbein TM, et al. Critical graft size in donor liver transplantation: results of a prospective study. Liver
adult-to-adult living donor liver transplantation: impact of the Transpl. 2003;9(8):822–826.
recipient's disease. Liver Transpl. 2001;7(11):948–953. 45. Fan ST, Yong BH, Lo CM, et al. Right lobe living donor liver
26. Fan ST, Lo CM, Liu CL, et al. Safety of donors in live donor liver transplantation with or without venovenous bypass. Br J Surg.
transplantation using right lobe grafts. Arch Surg. 2000;135(3): 2003;90(1):48–56.
336–340. 46. Starzl TE, Iwatsuki S, Shaw Jr BW. A growth factor in fine vascular
27. Fan ST, Lo CM, Liu CL. Technical refinement in adult-to-adult anastomoses. Surg Gynecol Obstet. 1984;159(2):164–165.
living donor liver transplantation using right lobe graft. Ann Surg. 47. Mori K, Nagata I, Yamagata S, et al. The introduction of microvas-
2000;231(1):126–131. cular surgery to hepatic artery reconstruction in living-donor liver
28. Chan SC, Lo CM, Liu CL, et al. Tailoring donor hepatectomy per transplantation—its surgical advantages compared with conventional
segment 4 venous drainage in right lobe live donor liver transplan- procedures. Transplantation. 1992;54(2):263–268.
tation. Liver Transpl. 2004;10(6):755–762. 48. Wei WI, Lam LK, Ng RW, et al. Microvascular reconstruction of
29. Lee S, Park K, Hwang S, et al. Congestion of right liver graft in the hepatic artery in live donor liver transplantation: experience
living donor liver transplantation. Transplantation. across a decade. Arch Surg. 2004;139(3):304–307.
2001;71(6):812–814. 49. Chan SC, Lo CM, Ng KK, et al. Portal inflow and pressure
30. Fan ST, Lo CM, Liu CL, et al. Safety and necessity of including changes in right liver living donor liver transplantation including
the middle hepatic vein in the right lobe graft in adult-to- the middle hepatic vein. Liver Transpl. 2011;17(2):115–121.
adult live donor liver transplantation. Ann Surg. 2003;238(1): 50. Man K, Fan ST, Lo CM, et al. Graft injury in relation to graft size
137–148. in right lobe live donor liver transplantation: a study of hepatic
31. Scatton O, Belghiti J, Dondero F, et al. Harvesting the middle sinusoidal injury in correlation with portal hemodynamics and
hepatic vein with a right hepatectomy does not increase the risk for intragraft gene expression. Ann Surg. 2003;237(2):256–264.
the donor. Liver Transpl. 2004;10(1):71–76. 51. Chan SC, Lo CM, Chok K, et al. Modulation of graft vascular
32. Cattral MS, Molinari M, Vollmer Jr CM, et al. Living-donor right inflow guided by flowmetry and manometry in liver transplantation.
hepatectomy with or without inclusion of middle hepatic vein: Hepatobiliary Pancreat Dis Int. 2011;10(6):649–656.
comparison of morbidity and outcome in 56 patients. Am J Trans- 52. Chan SC, Lo CM, Chik BH, et al. Flowmetry-based portal inflow
plant. 2004;4(5):751–757. manipulation for a small-for-size liver graft in a recipient with
33. Sugawara Y, Makuuchi M, Akamatsu N, et al. Refinement of spontaneous splenorenal shunt. Clin Transplant. 2010;24(3):
venous reconstruction using cryopreserved veins in right liver 410–414.
grafts. Liver Transpl. 2004;10(4):541–547. 53. Chan SC, Fan ST, Chok KS, et al. Increasing the recipient benefit/
34. Malago M, Molmenti EP, Paul A, et al. Hepatic venous outflow donor risk ratio by lowering the graft size requirement for living
reconstruction in right live donor liver transplantation. Liver donor liver transplantation. Liver Transpl. 2012;18(9):1078–1082.
Transpl. 2005;11(3):364–365. 54. Fan ST. Caudal shifting of hepatic vein anastomosis in right liver
35. Liu CL, Fan ST, Lo CM, et al. Safety of donor right hepatectomy living donor liver transplantation. Hepatobiliary Pancreat Dis Int.
without abdominal drainage: a prospective evaluation in 100 con- 2008;7(6):654–657.
secutive liver donors. Liver Transpl. 2005;11(3):314–319. 55. Liu CL, Lo CM, Chan SC, et al. Internal hernia of the small bowel
36. Chan SC, Liu CL, Lo CM, et al. Applicability of histidine-trypto- after right-lobe live donor liver transplantation. Clin Transplant.
phan-ketoglutarate solution in right lobe adult-to-adult live donor 2004;18(2):211–213.
liver transplantation. Liver Transpl. 2004;10(11):1415–1421. 56. Fan ST, Lo CM, Liu CL, et al. Biliary reconstruction and compli-
37. Lo CM, Fan ST, Liu CL, et al. Hepatic venoplasty in living-donor cations of right lobe live donor liver transplantation. Ann Surg.
liver transplantation using right lobe graft with middle hepatic 2002;236(5):676–683.
vein. Transplantation. 2003;75(3):358–360. 57. Liu CL, Fan ST, Lo CM, et al. Abdominal drainage after hepatic
38. Chan SC, Lo CM, Liu CL, et al. Versatility and viability of hepatic resection is contraindicated in patients with chronic liver diseases.
venoplasty in live donor liver transplantation using the right lobe Ann Surg. 2004;239(2):194–201.
with the middle hepatic vein. Hepatobiliary Pancreat Dis Int. 58. Abecassis M, Adams M, Adams P, et al. Consensus statement on
2005;4(4):618–621. the live organ donor. JAMA. 2000;284(22):2919–2926.
 CHAPTER 51

Adult Living Donor Left

Hepatectomy and Recipient
Operation
Masatoshi Makuuchi • Keiji Sano • Yasuhiko Sugawara

CHAPTER OUTLINE

DONOR AND GRAFT SELECTION Graft Removal

Back-Table Management (Fig. 51-7)
ANATOMY
Closure
Portal Venous Anatomy
Postoperative Management
Hepatic Arterial Anatomy
Biliary Anatomy RECIPIENT OPERATION
Hepatic Venous Anatomy Laparotomy (Fig. 51-10)
Hilar Dissection (Fig. 51-11) and Hepatectomy
DONOR OPERATION
Anhepatic Phase
Preoperative Preparation and Anesthesia
Outflow Reconstruction
Incision
Portal Vein Reconstruction
Hilar Dissection
Hepatic Arterial Reconstruction
Bile Duct Transection
Biliary Reconstruction (Fig. 51-15)
Mobilization
Postoperative Management
Parenchymal Transection

In 1993 the first successful adult-to-adult living donor Japan, right liver donation has resulted in one donor
liver transplantation was performed using a left liver death and one out of the two cases of severe aftereffects
graft.1 Until then, liver transplantations from living during the past 18 years of living donor living transplan-
donors had been performed only for pediatric recipients. tation experience.9,12
Because of the overwhelming shortage of liver grafts
from deceased donors to meet the demand, the number
of adult living donor liver transplantation has increased DONOR AND GRAFT SELECTION
dramatically throughout the world.2 Recipients’ poor
prognosis in adult living donor liver transplantation due Donor safety is paramount in living donor liver trans-
to small-for-size graft3 was soon ameliorated with the use plantation. In 2008 at Istanbul the Transplantation Soci-
of a right liver graft, which was first transplanted to a ety issued a declaration stating that “the provision of care
9-year-old child.4 Right liver graft harvested together for living donors before, during, and after surgery—as
with the middle hepatic vein (MHV) was also adopted described in the reports of the international forums orga-
successfully for an adult recipient for the first time in nized by the Transplantation Society in Amsterdam and
1996.5 Soon right liver graft without MHV became to be Vancouver—is no less essential than taking care of the
preferred for an adult recipient worldwide.6,7 transplant recipient,” and that “a positive outcome for a
However, the morbidity rate in donor hepatectomy recipient can never justify harm to a live donor.” All
was reported to be significantly higher in right hepatecto- countries require “a legal and professional framework to
mies than in left hepatectomies.8-10 The 10 early donor govern organ donation and transplantation activities, as
deaths reported involved five right liver donations, of well as a transparent regulatory oversight system that
which three were from the United States10-12; this tem- ensures donor and recipient safety and the enforcement
pered great enthusiasm for living donor liver transplanta- of standards.” Furthermore, the declaration addresses the
tion in the United States.11 Although the difference in the importance of the informed consent process.13
incidence rate of complications between right hepatec- One of the most important factors in donor evaluation is
tomy and left hepatectomy has now become small in to determine whether the donor candidate is medically and

676
 51 Adult Living Donor Left Hepatectomy and Recipient Operation 677

psychologically suitable for donation. It is also extremely Yes

important to confirm donor understanding of the risks and L  C  40% of recipient’s SLV L  C graft
benefits concomitant to the procedure and that he or she is No
making an autonomous and noncoerced decision.
Yes
Upon confirming the donor’s health suitability and RL  70% of donor’s TLV RL graft
resolve to become a donor, another complex but also
extremely important procedure of choosing the appropri- No
ate donor resection for the specific recipient awaits. An Yes
intricate balance of protecting the donor by performing RLS  40% of recipient’s SLV RLS graft
the smallest resection possible and at the same time pro-
No
viding the recipient with adequate liver mass and best Do not qualify as donor
chance for survival has to be sought. The smallest resec-
FIGURE 51-1 n Algorithm for graft type selection. The left liver (L),
tion that would provide adequate functional mass for the left liver plus caudate lobe (L + C), or right lateral sector (RLS)
recipient can only be called appropriate. graft is used when the volume of the graft exceeds 40% of recip-
Volume data of liver segments are usually obtained by ient’s standard liver volume (SLV). When the volume of the RLS
hand tracing the computed tomography (CT) images of is larger than L + C, the RLS graft should be used. RL, Right liver;
each slice14 and calculating the liver volume by integrat- TLV, total liver volume. (From Kokudo N, Sugawara Y, Imamura H,
et al. Tailoring the type of donor hepatectomy for adult living donor
ing those planar dimensions. This technique is gradually liver transplantation. Am J Transplant. 2005;5:1694-1703.)
being replaced by a region-growing method using three-
dimensional CT.15-17
Our graft selection criteria from the viewpoint of graft Portal Venous Anatomy
and remnant liver volume are as follows (Fig. 51-1):
1. The functional graft size should be at or more than The extrahepatic portal vein generally has a constant
40% ≥35% for low-risk recipients, ≥30% for nor- anatomy, with its bifurcation lying to the right and a lon-
mal liver recipients with metabolic diseases18) of the ger extrahepatic left portal vein. The transverse portion
recipient’s standard liver volume.19 of the left portal vein runs along the right end of the
2. The resection percentage should be under 70% lesser omentum to the ligamentum venosum, whereas the
(under 65% for right hepatectomy with the MHV umbilical portion runs up into the umbilical fissure.26 It is
graft). therefore much easier to gain sufficient extrahepatic left
3. When a non–right liver graft meets the first two portal length than right portal length. The vast majority
criteria, a right liver graft should, in general, not be of donors (more than 90%) have standard anatomy27;
selected. however, about 10% of donors have a trifurcation in the
4. A right lateral sector graft should be selected when portal venous anatomy in which the right lateral portal
the estimated graft volume is larger than the vol- vein branches off independently from the main portal
ume of a left liver with caudate lobe graft and when vein. The right paramedian and left portal veins form a
the right lateral sector graft size satisfies the trunk and then diverge. The donor operation is especially
criterion.20 technically demanding because the length of the left por-
5. Left liver with caudate lobe grafting is the standard tal vein is short and is situated deeply behind segment IV.
grafting procedure for the left liver. Intrahepatic left portal venous anomalies rarely preclude
A left liver graft may be a safer alternative to a right liver left lobe donation. The so-called double portal vein is not
graft for donors, and they are now used for properly a contraindication for donation but does require proper
selected cases in several centers.18,21,22 The caudate lobe identification and extrameticulous dissection in a donor
was added to the left liver graft in an effort to increase the left hepatectomy, and because the extrahepatic portion of
volume of the left liver graft in 1998.23 In 2000 a fully the left portal vein is shorter, technically advanced recon-
functioning caudate lobe was obtained by reconstructing struction is required in the recipient.28
the major drainage vein of the caudate lobe.24 Although
the size of an average caudate lobe is relatively small and Hepatic Arterial Anatomy
the increase in the size of the graft may remain only mini-
mal, particular attention must be paid to the venous Hepatic arterial anatomy is the most complicated variable
drainage of the caudate lobe.24,25 anatomical factor. One in four individuals have their left
hepatic artery arising from the left gastric artery.27,29,30 In
such cases thicker and longer arterial branches can be
ANATOMY obtained with ligation and division of the gastric branches
from the left gastric artery and arterial dissection at the
To best ensure donor safety, it is imperative that surgeons root of the left gastric artery at graft removal31 (Fig. 51-2,
have a thorough understanding of common hilar anat- A). In 7% the left hepatic artery alone branches out from
omy, as well as the individual anatomy of a specific donor. the common hepatic artery because of the replaced right
Accurate recognition of anatomy will also assist in select- hepatic artery.27 In such cases a wider orifice can be
ing the most appropriate donor in cases where multiple obtained by removing the left hepatic artery with bifurca-
candidates exist. The significance of hepatic anatomical tion of the common hepatic artery and the gastroduode-
variations and how they surgically affect the left liver liv- nal artery (see Fig. 51-2, B), which can be used to create a
ing donor transplantation is briefly reviewed. branch patch.32 In more than half of individuals, the
678 PART VI Split and Living Donor Transplantation

Gastric Br.
MHA

LHA
LGA

RHA LHA
LGA
CHA

SA
GDA CHA GDA
SA
RRHA
A B
FIGURE 51-2 n Advantageous arterial anatomy of the donor in left liver living donor liver transplantation. A, The left hepatic artery
(LHA) arising from the left gastric artery (LGA). In such cases thicker and longer arterial branches may be obtained by ligating and
dividing the gastric branches from LGA and dissecting the artery at the root of LGA. B, There is only the LHA branch from the common
hepatic artery (CHA) due to the replaced right hepatic artery (RRHA). In such cases the LHA may be removed together with bifurcation
of both the common hepatic artery (CHA) and the gastroduodenal artery (GDA), and a wider orifice can be obtained with branch patch
reconstruction. Br, Branch; MHA, middle hepatic artery; RHA, right hepatic artery; SA, splenic artery.

arterial supply to segment IV, often referred to as the Treatment of the MHV is a technical dilemma in adult
middle hepatic artery, originates independently of other living donor liver transplantation using left liver graft.37
arterial branches of the left liver.27,33 However, in most A considerably large congested area remains in the graft
cases reconstruction of one of the thickest branches is or donor’s remnant liver after left hepatectomy with
enough to arterialize the whole left liver graft.29,34 MHV. The area drained by the MHV varies among
patients, and the MHV was found to be the major drain-
ing vein of the right liver in 24% of the cases studied by
Biliary Anatomy Couinaud.38 Lee et al reported necrosis of the right liver
Biliary anatomy is another variable anatomical factor to graft without the MHV after liver transplantation. Two
be kept in mind. Intraoperative cholangiography is of the five patients had severe congestion, and one died
invaluable as a means of defining a “road map” of the bili- due to sepsis 20 days after transplantation.39 However,
ary anatomy and for identifying the exact site of the divi- because the MHV functions also as the drainage vein for
sions. Although magnetic resonance imaging now permits segment VI,40 if the left hemiliver was removed without
highly advanced imaging of the biliary tree for living the trunk of the MHV, graft function was compromised.
donors,35 intraoperative cholangiography remains the We therefore, proposed a criterion for MHV reconstruc-
gold standard. Just a few millimeters can change the tion in left liver grafts.37 When a thick tributary of the
number of bile duct orifices to be identified. Even more MHV draining the right liver is confirmed in donor oper-
important, a millimeter in the wrong direction could have ation, left liver grafts should be harvested without the
a lifelong crippling consequence for the donor. The right MHV trunk.41 The hepatic venous congestion in seg-
posterior hepatic duct may drain into the left hepatic duct ment IV can be investigated intraoperatively by Doppler
in 12% of individuals, a common variation important to ultrasonography after graft reperfusion. If the portal flow
remember especially in left liver donation.27 Although in segment IV is hepatofugal and the graft volume with
consequential variations of the bile ducts may be com- hepatopetal portal flow is calculated to be insufficient for
mon, they rarely necessitate any special surgical modifi- the recipient’s metabolic demand, the MHV branches
cation. Recognition of a correlation between anatomical should be reconstructed.37,41-43
variants of the biliary tree and portal vein helps to predict The caudate vein is another topic for left liver graft
the existence of variation in the bile duct before cholangi- with complete revascularization.24,25 Under preoperative
ography.27 In patients with a trifurcation pattern portal enhanced CT and intraoperative ultrasonography
vein, one out of three are found to have their right poste- (IOUS), two thirds of individuals are found to have the
rior hepatic duct draining into the left hepatic duct. caudate vein located on the ventral 60 degrees of the infe-
rior vena cava (IVC).44,45
Hepatic Venous Anatomy
It is important to assess the anatomical relationship of the
hepatic veins as they enter the vena cava. This relation-
DONOR OPERATION
ship can have important implications when identifying Preoperative Preparation and Anesthesia
the correct transection point in donors and graft outflow
reconstruction in recipients. Most commonly the right All donors in elective transplantation are recommended
hepatic vein (RHV) enters the vena cava separately from to have autologous blood available preoperatively.
the left and the MHVs, which then join together as a In the days before the surgery, kanamycin and lactu-
common trunk.36 lose are administered for chemical bowel preparation,
 51 Adult Living Donor Left Hepatectomy and Recipient Operation 679

purgative medicine is used for mechanical bowel prepara- artery are ligated and divided. The dissection around the
tion, and an enema is prescribed on the morning of the bile duct should be minimal to avoid postoperative bile
operation. Before the induction of general anesthesia, an duct stricture due to devascularization.
epidural catheter is placed for perioperative pain control.
After the induction of general endotracheal anesthesia, an
internal jugular central venous catheter is inserted to
Bile Duct Transection
measure the central venous pressure. Before laparotomy, Bile duct transection, including hilar plate dissection,
prophylactic antibiotics, a first-generation cephem anti- may be carried out at this time or after parenchymal
biotic, is administered. It is also administered every 6 transection. Intraoperative cholangiography using fluo-
hours during operation. roscopy helps to visualize biliary anatomy at anteropos-
Intravenous fluid infusion should be rationed at terior view and right anterior oblique angle. The right
approximately 4.5 to 5 mL/kg per hour to keep the cen- anterior oblique view is advantageous in identifying the
tral venous pressure low. bile ducts from the right lateral sector or from the Spi-
gelian lobe, which may join the left hepatic duct. After
the arterial and portal branches of the left liver are
Incision exposed, the root of the left hepatic duct is carefully
Inverted-T incision is selected in all cases to obtain best isolated from the connective tissues on the caudate
operative field. Midline incision should be placed from lobe, identified, and taped under fluoroscopy so as not
just beneath the mammary line to just above two fingers' to injure the confluence of the biliary branch from the
width from the navel. Transverse incision starts from the right liver (Fig. 51-3). After ligating the to-be-remnant
left side of the rectus muscle and extends toward the right side, fluoroscopy should be repeated to determine the
ninth intercostal space and enters the thoracic cavity. to-be-preserved safe margin of the stump to avoid com-
Right thoracotomy is unnecessary in left-side hepatec- promising the donor’s hepatic duct confluence. An extra
tomy. An alternative incision would be the Chevron inci- transfixing suture is added to the remnant side, and the
sion with Mercedes-Benz modification (with additional left bile duct is sharply transected. The remainder of
upper abdominal midline incision). The ligamentum the hilar plate is also sharply transected after ligating
teres and the falciform ligament are divided at the ante- only the remnant side. The stump of the hilar plate of
rior abdominal wall side for use in properly fixing the the graft side should be carefully inspected to search for
graft to the recipient. Dissection around the coronary the pinhole stump of the biliary branch from the spige-
ligament enables exposure of the root of the common lian lobe. Completion cholangiography is performed to
trunk of the LHV and the MHV. ensure that there is no narrowing in the donor’s rem-
Meticulous inspection and palpation of the liver and nant bile duct and that there is no bile leakage from the
IOUS confirm the final indication for the donor hepatec- remnant side of the liver.
tomy. If the liver is impermissibly steatotic, which was
not expected preoperatively, or unknown tumorous
lesions are found, surgical biopsy or needle biopsy should
Mobilization
be carried out for pathological diagnosis. Portal and After hilar dissection the gastrohepatic ligament is care-
hepatic venous anatomy is also surveyed under IOUS to fully divided so as not to injure the aberrant or accessory
check especially for the caudate portal branch that may left hepatic artery originating from the left gastric artery.
have originated from the main trunk of the portal vein,44 The left coronary ligament is attached approximately 1
tributaries of the MHV,37,41-43 or the principal caudate cm to the ventral surface from the cranial edge of the left
vein, which also drains the left side of the caudate lobe lobe, and insertion of gauze beneath the left lobe prevents
(spigelian lobe).43,44 the abdominal esophagus and stomach from being injured
during dissection of the ligament with electrocautery.
The left triangular ligament is divided after ligation.
Hilar Dissection Attention should also be directed not to tear off the
One percent lidocaine (Xylocaine) is injected subserosally omentum attached to the spleen.
around the left hepatic artery to prevent arterial spasm After the mobilization of the left lobe, dissection
during dissection. Cholecystectomy is commenced, and a around the common root of the left hepatic vein (LHV)
catheter for intraoperative cholangiography is inserted and MHV progresses more intensively. The diaphrag-
from the cystic duct stump. The left and middle hepatic matic ligament covering the anterior aspect of the IVC is
arteries and the root of the right hepatic artery are dis- carefully dissected from the right side of the MHV venous
sected free, and the left portal vein and its main trunk root to the left (Fig. 51-4). Dissection of the right side is
posterior to them are also exposed and encircled. The extended a couple of centimeters downward, followed by
caudate portal vein branch to the spigelian lobe has to be dissection between the caudal portion of the caudate lobe
preserved, but the branch feeding the paracaval portion and the infrahepatic IVC. A Kelly clamp with a longer
should be ligated and divided. The determination jaw is inserted blindly from the infrahepatic to suprahe-
between these two portal branches can be done by IOUS. patic IVC with maximal care. A hanging tape is passed
When an aberrant left hepatic artery exists, it should also through an avascular thin route on the midline of the
be dissected and encircled to prepare for arterial anasto- anterior surface of the IVC.46 If the procedure seems to
mosis in the recipient. To obtain a long arterial graft with be difficult, the use of IOUS is helpful to securing the
a wide orifice, the gastric branches from the left gastric blind dissection.44 Dissection of the left side of the venous
680 PART VI Split and Living Donor Transplantation

root is extended upward by ligating and dividing the left minimizing tidal volume, rationing intravenous fluids,
inferior phrenic veins, followed by the mobilization of and modest intraoperative blood salvage are useful.50,51
the cranial portion of the spigelian lobe from the IVC. For this purpose the transection point should be elevated
Next, the peritoneum is incised along the caudal and lat- by lifting up the ligamentum teres, or a hanging tape
eral border of the spigelian lobe. After the left hepatoca- should be inserted in front of the IVC. To use the hang-
val ligament (Makuuchi's ligament)47 is ligated and ing tape for the lift-up, a tape-repositioning technique
divided at the bottom, the spigelian lobe is mobilized should be adopted.52 The thin hepatic parenchyma on
from the lateral side of the IVC to the medial side of the
IVC (Fig. 51-5). When the lobe is cranially dissected
from the IVC, the root of the LHV and MHV is exposed
and taped together with the ligamentum venosum. With
this method, ligation and division of the ligamentum
venosum, which forms the right border of the lesser RIPV LIPV
omentum and attaches the root of the LHV, is unneces-
sary. Finally, the caudate vein, which drains the spigelian
lobe, is exposed and taped.44 Mobilization is complete if
the hanging tape is observable from the left side of the

LH
RH

V
IVC. Mobilization of the caudate lobe is difficult if it is

V
MH
done after transaction of the liver.

Parenchymal Transection FIGURE 51-4 n Dissection of the diaphragmatic ligament around

the common root of the left hepatic vein (LHV) and the middle
Demarcation of the left liver can become observable by hepatic vein (MHV). Fibrous tissue covering the anterior aspect
selectively clamping the arterial and portal branches of of the vena cava is cautiously dissected from the right side of
the left liver, and the Rex line is marked by electrocautery the MHV root to the left. Dissection of the right side is extended
a couple of centimeters downward, followed by dissection
as the transection line. Parenchymal transection is per- between the caudal portion of the caudate lobe and the infrahe-
formed under intermittent Pringle’s maneuver (inflow patic vena cava before carrying out Belghiti’s hanging maneu-
occlusion).48,49 Inflow occlusion is safe for donors and ver. Dissection of the left side of the venous root is extended
also for grafts in living donors’ hepatectomy.48,49 A com- upward by ligating and dividing the left inferior phrenic veins
(LIPVs). RHV, Right hepatic vein; RIPV, right inferior phrenic
bination of ultrasonic surgical dissector, clamp-crushing vein.
technique, and electrocautery are adopted in parenchy-
mal transection. Small vessels remaining on the transection
plane are meticulously ligated at both sides with fine strings
and are divided. To reduce bleeding during hepatic tran-
section, maintaining low central venous pressure (CVP) by

R. Lig.
LH
V

Makuuchi Lig.
FIGURE 51-5 n Mobilization of the spigelian lobe from the vena
FIGURE 51-3 n Minimal dissection around the root of the left cava. Left Makuuchi ligament (Lig.) is ligated and divided, and
hepatic duct before biliary transection using fluoroscopy. The the root of the left hepatic vein (LHV) and middle hepatic vein is
arrow indicate cutting point of the left hepatic duct. The double- exposed and taped together with the ligamentum venosum
headed arrow shows the division line of the connective tissue in without ligating or dividing the ligamentum venosum. C, Cau-
front of the caudate lobe. date lobe.
 51 Adult Living Donor Left Hepatectomy and Recipient Operation 681

the lower edge of the caudate lobe is divided in the usual side of the LHV is cut longitudinally, and rectangular-
manner. A curved Kelly clamp is inserted between the shaped vein patches are attached (Fig. 51-8).59
liver parenchyma and the arterial branch and portal When the left caudate lobe is harvested with the left
branch of the left liver (if the bile duct transection has not liver and the short hepatic vein is not planned to be anas-
yet been performed, between the liver parenchyma and tomosed directly to the recipient (Fig. 51-9, A),24 veno-
upper edge of the hilar plate) and passed caudally toward plasty of the short hepatic vein and LHV and MHV can
the posterior surface of the vessels (or the already dis- be included in the back-table management. When the
sected hilar plate). This procedure is similar to that for short hepatic vein, LHV, and MHV are located close to
anatomical liver resection as reported by Couinaud53 or each other,60 the posterior wall of the graft common trunk
by Takasaki et al.54,55 of the middle-left hepatic veins is sutured to the cranial
The parenchymal transection is performed along the end of the hepatic venous branch of the caudate lobe with
right side of the MHV without exposing its main trunk to intermittent sutures (see Fig. 51-9, B). When a long vein
prevent intravenous thrombus formation when an ultra- graft is available, one side of the conduit vein graft is cut
sonic surgical aspirator is used.56 Segment V and VIII longitudinally to widen the orifice, which will be anasto-
venous tributaries draining into the MHV are ligated and mosed to the orifice of the short hepatic vein. The other
divided. The tape-repositioning technique is especially side of a conduit vein graft is first cut longitudinally and
effective in obtaining lower traction without dividing the then horizontally. The opened edge is sutured to the pos-
hilar vessels, and the caudate lobe is completely sus- terior cuff of the LHV and MHV because the lumen of a
pended away from the IVC.52 conduit vein graft cannot be narrowed61 (see Fig. 51-9, C).
Upon accomplishing the parenchymal transection, After the venoplasty, the graft is weighed, submerged
hemostasis is achieved and the absence of bile leakage in preservative solution, and carefully brought to the
should be confirmed. Fibrin glue is spread onto the tran- recipient operating room.
section surface of the graft.
Closure
Graft Removal The stump of the hepatic vein is oversewn with continu-
Before the graft removal, a marking suture using thin ous suture. Hemostasis is achieved and absence of bile
monofilament string is placed at the midpoint of the leakage is confirmed by injecting saline from the catheter
anterior aspect of the graft-side left portal branch. with the balloon at the tip and the side hole only at the
With the direction from the recipient surgical team, proximal side to fill the biliary tree.62 The catheter is
graft removal is commenced, dividing the caudate vein. removed after the balloon is deflated, and the cystic duct
For wider anastomosis, the IVC wall near its orifice is stump is ligated. Fibrin glue is spread onto the transection
divided and clamped tangentially to the IVC wall like
the Carrel patch (Fig. 51-6).57 The root of the left por-
tal vein is clamped and divided with care to avoid com-
promising the donor’s main portal vein. If the portal
branch to the spigelian lobe originates from the main
portal trunk, it is independently ligated and divided for
reconstruction.58 Next, the arterial branches of the left
liver are doubly ligated at their roots and are divided.
As soon as the arterial feeding is stemmed, the IVC
wall around the orifice of the LHV and MHV is
clamped tangentially above the left phrenic vein and is
subsequently divided in the same manner as the cau-
SII & III
date vein resection, and the graft is removed from the
donor.

Back-Table Management (Fig. 51-7)

Before the graft is removed, another surgical team pre-
pares the back table with the appropriate-sized cannulas, V. trunk
instruments, solutions, ice, etc. When removed, the graft C
will be immediately brought to the back table and
immersed in chilled normal saline solution. An appropri-
ate-sized tube is carefully inserted into the orifice of the
portal vein, and cold normal saline solution is flushed
through the tube. The flushing is continued until the
effluent from the hepatic veins is clear. The preservation
solution is replaced with cold normal saline solution.
FIGURE 51-6 n Vena cava wall near the orifice of the vein is
Securing a wide orifice for outflow reconstruction might divided by tangentially clamping the vena cava wall and obtain-
be the most important strategy for preventing hepatic ing a Carrel patch to secure a wider and firmer orifice. C, Cau-
venous stricture. The right side of the MHV and the cranial date lobe; SII & III, segments II and III; V, venous.
682 PART VI Split and Living Donor Transplantation

LHV  MHV

PV

BD
Short hepatic
vein HA

A B
FIGURE 51-7 n Ventral (A) and visceral (B) surfaces of the resected left liver. BD, Bile duct; HA, hepatic artery; LHV, left hepatic vein;
MHV, middle hepatic vein; PV, portal vein.
MH

V V
LH LH
MH

MH
LH
V

V
P
P

V V
LH LH
M

M
HV

HV

FIGURE 51-8 n Right side of the middle hepatic vein (MHV) and left side of superficial left hepatic vein (LHV) is cut longitudinally, and
a rectangular vein patch (P) is attached for venoplasty.

surface of the remnant liver. Finger bougie of the pylorus prothrombin time, should be carried out. The nasogas-
is used to prevent delayed gastric emptying that is caused tric tube should remain in place until bowel function
by displacement of the stomach with the absent lateral returns. Acid-blocking agents are administered until
segment.63 IOUS is employed to confirm patent arterial, hepatic function is restored and oral diet is resumed. Pro-
portal, and venous flow in the remnant liver. An arterial phylactic antibiotics are administered preoperatively and
clamp test is also carried out to confirm the discolored are continued for 3 days after the operation. Incentive
venoocclusive area is similar to what had been expected spirometry is recommended to prevent atelectasis. Lower
preoperatively.42 A closed suction drain is placed along- extremity sequential compression devices should remain
side the cut surface of the liver, and another drain is added in place until patients are ambulatory.
in the Winslow’s pouch for better drainage. Finally, the
donor operation is completed by closing the wound layer
to layer. RECIPIENT OPERATION
Postoperative Management Laparotomy (Fig. 51-10)
Donors should be monitored closely during the immedi- The recipient is brought to the operation room simulta-
ate postoperative course. Frequent laboratory evalua- neously with the donor. When the recipient has underly-
tions, including liver function tests, creatinine levels, and ing hepatocellular carcinoma, especially if treated with
 51 Adult Living Donor Left Hepatectomy and Recipient Operation 683

IVC
A
LHV  MHV

Caudate lobe
B

C
FIGURE 51-9 n Venoplasty of the short hepatic vein A, The short hepatic vein can be anastomosed directly to the recipient inferior vena
cava (IVC). B, When the short hepatic vein, left hepatic vein (LHV), and middle hepatic vein (MHV) are located close to each other, the
posterior wall of the graft common trunk of the middle-left hepatic veins is sutured to the anterior wall of the hepatic venous branch
of the caudate lobe. C, When a long vein graft is available, one side of the conduit vein graft is cut longitudinally to widen the orifice,
which will be anastomosed to the orifice of the short hepatic vein. P, Vein patch.

FIGURE 51-10 n Laparotomy for the left liver recipient.

local therapy, he or she should be explored before the Hilar Dissection (Fig. 51-11) and
donor procedure. Existence of disseminated lesions in the Hepatectomy
abdominal cavity should be checked for with midline
incision, and the porta hepatis is palpated to check for There are some important considerations in hepatec-
metastatic lymph nodes in patients with advanced-stage tomy for the recipient of a partial liver graft that are not
carcinoma. Ultrasound examination to check for vascular necessary in cases of a whole liver graft. The main tech-
invasion is also mandatory. Once extrahepatic disease is nical principle is to maintain the length and integrity of
excluded, the procedure can proceed and the midline all hilar structures to preserve implantation options.
incision is extended to the right side, extending to the Left and right hepatic arteries should be dissected as
ninth intercostal space. At this time the donor surgeons long as possible. When accessory and replaced hepatic
are notified to begin their operation. arteries are present, they should be preserved as long as
684 PART VI Split and Living Donor Transplantation

UP

MHA
LHA
PV
CBD

RHA

UP

UP

PV

FIGURE 51-11 n Hilar dissection in the left liver recipient. The length and integrity of all hilar structures should be maintained. CBD,
Common bile duct; LHA, left hepatic artery; MHA, middle hepatic artery; PV, portal vein; RHA, right hepatic artery; UP, umbilical
portion.

possible. The left and right portal veins should be iso- in selected cases without preoperative portovenous shunts
lated as long as possible. The whole left portal vein (e.g., splenorenal shunts), which include patients indi-
(including the umbilical portion) can be resected, a part cated for acute liver failure. The most commonly con-
of which can be used as a venous patch for outflow structed venoportal shunt is an end-to-side anastomosis
reconstruction at the bench procedure, which would between the right portal branch and the vena cava.65
facilitate the dissection of the left bile duct as peripher- However, portosystemic shunt can be avoided, even in
ally as possible. such cases, if anhepatic phase duration can be minimized
Left and right bile ducts should be preserved. Preser- by adjusting the timing of the graft removal and inflow
vation of the entire hilar plate is useful for maximizing ligation in recipient operation.
the options in bile duct reconstruction. Caval preserva-
tion is imperative. All short hepatic veins are divided and
ligated. Three hepatic veins should be preserved as long
Outflow Reconstruction
as possible. The caval drainage is one of the most important technical
All ligaments between the liver and the abdominal cav- aspects of partial graft implantation. Alignment of the
ity are carefully divided. The IVC is dissected from the hepatic venous anastomosis is important because the out-
retroperitoneum from the diaphragm to the confluence flow can be easily blocked by torsion. Generally the con-
of the right suprarenal vein. All short hepatic veins are fluence of the LHV and MHV of the graft is anastomosed
identified, ligated, and divided. Dissection of all the to the LHV and MHV of the recipient end to end66 (Fig.
phrenic veins is mandatory to clamp the suprahepatic 51-12, A). When necessary,59 the common orifice of the
vena cava in outflow reconstruction.64 LHV and MHV of the recipient can be extended to the
right and joined with the orifice of the RHV (see Fig.
51-12, B). If the RHV cuff is short, the RHV is closed
Anhepatic Phase with a running suture at its root, and a venous patch is
In most cases it is unnecessary to construct portosystemic used as follows: After the LHV and MHV are joined, the
shunts. Venoportal shunts, however, may be considered IVC is cross-clamped above and below the hepatic veins.
 51 Adult Living Donor Left Hepatectomy and Recipient Operation 685

Stump
of RHV
LHV

MHV

RHV

C
FIGURE 51-12 n Venoplasty of the recipient’s hepatic veins. A, The left hepatic vein (LHV) and middle hepatic vein (MHV) of the recipi-
ent are joined. B, The common orifice of the left and middle hepatic veins of the recipient can be extended to the right and stitched
up with the orifice of the right hepatic vein (RHV). C, If the RHV cuff is short, the RHV is closed with a running suture at its root, and a
venous patch (P) used.

The right side of the MHV is then cut toward the closed left portal branches (Fig. 51-13). It is better for the left
RHV, making a horizontal cavotomy. The patch graft is liver graft portal vein anastomosis to be a little long and
then sutured to the cavotomy site (see Fig. 51-12, C). redundant. When it is too short, there can be signifi-
When the left caudate lobe is included with the left cant problems when the graft is regenerated and
liver, venous drainage of the caudate lobe should be con- rotated.
sidered because the regeneration of the congested cau- An isolated caudate portal vein originating from the
date lobe will be impaired.25 When venoplasty is left-side wall of the portal branches of the caudate lobe is
performed on the short hepatic vein using a vein con- sometimes observed.58,67 It is advisable to undertake a
duit61 (see Fig. 51-9, C), the created single wide orifice of reconstruction that ensures full graft function of the cau-
the hepatic veins of the liver graft is anastomosed with the date lobe.
recipient hepatic veins and IVC. In recipients with portal vein thrombosis, endovenec-
tomy68 or mesenteric interposition grafts are necessary,
similar to whole-organ deceased donor liver transplanta-
Portal Vein Reconstruction tion. The patency of mesenteric interposition grafts,
Left liver cases almost always require a single portal however, is not always satisfactory.69
reconstruction between the graft left portal vein and
recipient left portal branch or portal vein trunk. Align-
ment is critical, and the anterior wall of the graft and
Hepatic Arterial Reconstruction
recipient left portal branches are marked with 6-0 The technical aspects of arterial reconstruction are
Prolene. The first stitch is started with the adjustment important and critical for successful liver transplantation.
of the marked anterior walls of the graft and recipient The donor vessel is thin (2 to 5 mm in diameter) and
686 PART VI Split and Living Donor Transplantation

A A
A
B A
B A
A B B
C
B B B

A C
A
B
C
B
B C

FIGURE 51-13 n Portal vein anastomosis. Arrows indicate the center of the anterior wall of the portal vein.

FIGURE 51-14 n Arterial anastomosis. The recipient and graft arteries are clamped by single microclamps. The first suture is placed at
the center of the posterior wall. The posterior stitch is tied, pulling toward the back for good intima adaptation. Subsequent sutures
are placed on either side adjacent to the previous suture. The sutures of the anterior wall can be performed with common single-
needle microsutures. Arrows indicate the process of the procedure.

short. The anastomosis is generally performed in an arterial stumps. Multiple arterial reconstructions are not
interrupted fashion with 8-0, 9-0, and 10-0 nylon sutures always necessary for arterial communication. Intrahepatic
under an operating microscope70 and sometimes a surgi- arterial communication is confirmed twice before the
cal loupe. recipient operation. First, the patency of the left hepatic
In detail, the recipient and graft arteries are clamped artery is checked by Doppler ultrasonography after tem-
with single microclamps to temporarily halt blood-flow porarily clamping the middle hepatic artery in the donor
(Fig. 51-14). The first suture is placed using monofila- operation, and backflow is confirmed from the stump of
ment sutures at the most dorsal point in the artery to be the middle hepatic artery by gently injecting cold normal
visualized. Each stitch is always placed from the inner saline from the stump of the left hepatic artery after the
side of the arterial wall to the outer side. The posterior graft is harvested and placed in the basin. If pulsating flow
stitch is tied by pulling toward the back. Subsequent is observed from the remnant stump (suggesting intra-
sutures are advanced anteriorly on either side adjacent to graft communication between the left and middle hepatic
the previous suture. A nylon microsuture with double arteries) or middle hepatic arterial flow is confirmed by
needles (W10V43-9N, Keisei Medical Industrial, Tokyo, intraoperative Doppler ultrasonography after the recon-
Japan) is useful when it is difficult to turn the graft artery struction of the dominant artery, reconstruction of the
over.71 The recipient left, middle, or right hepatic artery remaining stump is unnecessary.34,72,73
is suitable for reconstruction. Other arteries, which will
not be used as inflow arteries, should be saved for the
revision operation.
Biliary Reconstruction (Fig. 51-15)
Because of the highly variable arterial supply to seg- Biliary reconstruction is considered the Achilles’ heel of
ment IV, left liver grafts are more likely to have multiple whole-liver transplantation from deceased donors. This
 51 Adult Living Donor Left Hepatectomy and Recipient Operation 687

PV LHA

LBD Hilar plate

Stent
tubes
B1

FIGURE 51-15 n Stent tubes are introduced from the orifice opposite to the hilar plate where the tube will be fixed to the plate. The
anastomosis is begun at the posterior wall, and the needle is inserted into the bile duct in the graft from outside to inside, then the
orifice of the hilar plate from inside to outside. The knots are always outside of the bile duct. B1, Bile duct of the caudate lobe; LBD,
left hepatic duct; LHA, left hepatic artery, PV, portal vein.

is even more true for partial liver grafts, which often have that all ducts are identified in the liver grafts. Minute
multiple and small ducts (usually 2 to 5 mm in diame- ducts can be oversewn and remain unreconstructed.
ter).74 The reconstruction is technically more demanding Biliary tree anastomosis should be fashioned tension-
than choledochocholedochostomy of the standard whole- free, and upon completion the leakage and stricture
liver transplantation. As a result, the incidence of biliary should be checked by cholangiography through an exter-
complications, including leaks and strictures, is higher in nal stent tube. The significance of the stent tube across
partial liver grafts. the anastomotic site remains controversial.
Biliary reconstruction in partial liver grafts has previ-
ously been performed with a Roux-en-Y hepaticojejunos-
tomy with or without stenting. More recently, however,
Postoperative Management
biliary reconstruction has become more commonly per- Postoperative management of a living donor recipient is
formed using the recipient’s native bile ducts with or similar to that for deceased donor liver transplantation.
without stenting, which is called duct-to-duct anastomo- In the immediate postoperative period, close invasive car-
sis.75-77 To facilitate the approach the recipient’s hilar diac monitoring is necessary to avoid excessive central
plate should be included en bloc with the common bile venous pressure. Necessary tacrolimus doses are usually
duct.74 The possible advantages of the duct-to-duct anas- smaller for partial liver graft, which should be adjusted
tomosis include no enteric anastomosis, a functional according the size of the graft.78
sphincter of Oddi, and possible endoscopic approach to When there is a large amount of bleeding and the
the anastomotic sites. blood pressure is low during the transplant procedure, we
Multiple ducts located close together and sharing a have to expect postoperative renal failure. The patient
common wall should be joined together so that a single body weight and in-out balance are checked every 6 to 8
anastomosis can be performed. In such cases the shared hours to maintain the patient's general condition and pre-
septum of the adjacent ducts may be divided vertically vent acute renal failure. Within 3 to 4 postoperative days
and then combined with fine absorbable sutures to create the diuretic stage will occur. Until that time the increase
a single large orifice for the anastomosis. It is imperative in body weight should be restricted to less than 10%.
688 PART VI Split and Living Donor Transplantation

6. Ghobrial RM, Saab S, Lassman C, et al. Donor and recipient out-

Pearls and Pitfalls comes in right lobe adult living donor liver transplantation. Liver
Transpl. 2001;8:901–909.
Donor Procedure 7. Adam R, McMaster P, O’Grady JG, et al. Evolution of liver trans-
• Successful transplantation using a left liver graft is de- plantation in Europe: Report of the European Liver Transplant
pendent on careful donor selection for a specific re- Registry. Liver Transpl. 2003;9:1231–1243.
8. Salame E, Goldstein MJ, Kinkhabwala M, et al. Analysis of donor
cipient, which includes an accurate assessment of graft
risk in living-donor hepatectomy: The impact of resection type on
size using computed tomography. clinical outcome. Am J Transplant. 2002;2:780–788.
• The left and middle hepatic arteries and left and main 9. Umeshita K, Fujiwara K, Kiyosawa K, et al. Operative morbidity of
portal trunk are exposed. The caudate portal veins living liver donors in Japan. Lancet. 2003;362:687–690.
branch to the spigelian lobe has to be preserved. Bile 10. Middleton PF, Duffield M, Lynch SV, et al. Living donor liver
duct transection including hilar plate dissection, is transplantation-adult donor outcomes: A systematic review. Liver
then carried out. Transpl. 2006;12:24–30.
• After hilar dissection the gastrohepatic ligament is 11. Brown Jr RS. Live donors in liver transplantation. Gastroenterology.
carefully divided so as not to injure the aberrant or 2008;134:1802–1813.
12. Hashikura Y, Ichida T, Umeshita K, et al. Donor complication
accessory left hepatic artery originating from the left
associated with living donor liver transplantation in Japan. Trans-
gastric artery. Parenchymal transection is performed plantation. 2009;88:110–114.
along the right side of the middle hepatic vein without 13. Participants in the International Summit on Transplant Tourism
exposing its main trunk. and Organ Trafficking Convened by the Transplantation Society
and International Society of Nephrology in Istanbul, Turkey, April
Back-Table Management 30–May 2, 2008. The Declaration of Istanbul on organ trafficking
• The right side of the middle hepatic vein and the cra- and transplant tourism. Transplantation. 2008;86:1013–1018.
nial side of the left hepatic vein is cut longitudinally, 14. Kawasaki S, Makuuchi M, Matsunami H, et al. Preoperative mea-
and rectangular vein patches are attached encompass- surement of segmental liver volume of donors for living liver trans-
plantation. Hepatology. 1993;18:1115–1120.
ing the entire venous stump, or where the hepatic veins
15. Kamel IR, Kruskal JB, Warmbrand G, et al. Accuracy of volumet-
are cut. ric measurements after virtual right hepatectomy in potential
• When a long vein graft is available, one side of the donors undergoing living adult liver transplantation. AJR Am J
conduit vein graft is cut longitudinally to widen the Roentgenol. 2001;176:483–487.
orifice, which will be anastomosed to the orifice of the 16. Bogetti JD, Herts BR, Sands MJ, et al. Accuracy and utility of
short hepatic vein. The other side of a conduit vein 3-dimensional computed tomography in evaluating donors for
graft is first cut longitudinally and then horizontally. adult living related liver transplantation. Liver Transpl.
2001;7:687–692.
Recipient Procedure 17. Hiroshige S, Shimada M, Harada N, et al. Accurate preoperative
estimation of liver-graft volumetry using three-dimensional com-
• In implantation, one of the most important technical
puted tomography. Transplantation. 2003;75:1561–1564.
aspects is caval drainage. Not only is the anastomosis 18. Kokudo N, Sugawara Y, Imamura H, et al. Tailoring the type of
important, but the ultimate graft positioning can play donor hepatectomy for adult living donor liver transplantation. Am
an important role in outflow. Usually the left and mid- J Transplant. 2005;5:1694–1703.
dle or three hepatic veins of the recipient are opened 19. Sugawara Y, Makuuchi M, Kaneko J, et al. Living-donor liver
and unified, which are anastomosed with the graft vein transplantation in adults: Tokyo University experience. J Hepatobi-
that has been modified by venoplasty. liary Pancreat Surg. 2003;10:1–4.
• Portal vein anastomosis is usually simple, requiring 20. Urata K, Kawasaki S, Matsunami H, et al. Calculation of child and
only a single reconstruction. Alignment is critical and adult standard liver volume for liver transplantation. Hepatology.
1995;21:1317–1321.
should take into account future graft rotation (graft
21. Sugawara Y, Makuuchi M, Takayama T, et al. Right lateral sector
will be regenerated). graft in adult living-related liver transplantation. Transplantation.
• The graft artery is thin and small. The anastomosis is 2002;73:111–114.
generally performed under operating microscope. The 22. Lo CM. Complications and long-term outcome of living liver
left graft sometimes has multiple hepatic arteries. donors: a survey of 1,508 cases in five Asian centers. Transplanta-
• In biliary reconstruction, duct-to-duct anastomosis is tion. 2003;75:S12–S15.
usually performed. An alternative option is hepaticoje- 23. Miyagawa S, Hashikura Y, Miwa S, et al. Concomitant caudate
   junostomy. lobe resection as an option for donor hepatectomy in adult living-
related liver transplantation. Transplantation. 1998;66:661–663.
24. Takayama T, Makuuchi M, Kubota K, et al. Living-related trans-
plantation of left liver plus caudate lobe. J Am Coll Surg.
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44. Kokudo N, Imamura H, Sano K, et al. Ultrasonically assisted ret- tion in adult living donor liver transplantation using cryopreserved
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2005;242:651–654. 70. Mori K, Nagata I, Yamagata S, et al. The introduction of microvas-
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48. Imamura H, Takayama T, Sugawara Y, et al. Pringle's manoeuvre 73. Kubota K, Makuuchi M, Takayama T, et al. Simple test on the back
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selective inflow occlusion in living donor liver hepatectomy. Liver 74. Akamatsu N, Sugawara Y, Hashimoto D. Biliary reconstruction, its
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52. Kokudo N, Sugawara Y, Imamura H, et al. Sling suspension of the struction in adult living-donor liver transplantation. Transplanta-
liver in donor operation: a gradual tape-repositioning technique. tion. 2004;78:574–579.
Transplantation. 2003;76:803–807. 77. Sugawara Y, Makuuchi M, Sano K, et al. Duct-to-duct biliary
53. Couinaud CM. A simplified method for controlled left hepatec- reconstruction in living-related liver transplantation. Transplanta-
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54. Takasaki K, Kobayashi S. Subsegmentectomy and small lot resec- 78. Sugawara Y, Makuuchi M, Kaneko J, et al. Correlation between
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 CHAPTER 52

Split Liver Transplantation for

Pediatric and Adult Recipients
Hector Vilca-Melendez • Nigel D. Heaton

CHAPTER OUTLINE

LEFT LATERAL SEGMENT/RIGHT LOBE Surgical Techniques

(EXTENDED) SPLIT In Situ Split
Historical Background Ex Situ Split
Donor Selection Technical Issues
Recipient Selection OUTCOMES FOR SPLIT LIVER TRANSPLANTATION
Surgical Techniques Recipients Receiving Left Lateral Segment
Ex Situ Split Grafts
In Situ Split Recipients Receiving Right Lobe Grafts
Technical Issues (Extended)
LEFT LOBE/RIGHT LOBE SPLIT Adult Recipients Receiving Grafts From Left
Lobe/Right Lobe Split
Historical Background
Donor and Recipient Selection FUTURE DEVELOPMENTS

Pediatric liver transplantation has driven technical LEFT LATERAL SEGMENT/RIGHT LOBE
innovations in surgery over the past 25 years. Early suc- (EXTENDED) SPLIT
cessful liver transplantation relied on the use of size-
matched whole-liver grafts. This requirement tended to
exclude small children of less than 10 kg from liver
Historical Background
transplantation because of the lack of donors and the The segmental anatomy of the liver of relevance to split-
higher rate of technical complications such as hepatic ting was described by Couinaud in 1957.1 This study pro-
artery thrombosis. In addition, as increasing numbers of vided the rationale for developing liver resection surgery
children were being referred for treatment, waiting and subsequently liver reduction (producing a functional
times and waiting list mortality began to rise. Reduction graft suitable for a smaller recipient).2 Initially livers were
techniques based on the segmental anatomy of the liver cut down to provide a left lateral segment (segments II
were developed to reduce waiting list mortality and and III) or a left lobe graft (segments I to IV or II to IV)
transplant smaller children. The ability to cut livers for critically ill children with promising early results.3
down to match a child’s abdomen significantly opened These reduced-size liver grafts provided patient survival
up the donor pool and led to an increase in pediatric that was comparable with full-size grafts and had a lower
transplantation. Liver reduction proved to be success- incidence of vascular complications and rapidly became
ful; however, it led to the discarding of the right liver established in the treatment of children with liver dis-
with a fall in the number of grafts from young donors ease.4,5 The development of new techniques of hepatic
available for adult recipients. The concept of “splitting” vein reconstruction for the implantation of left lateral
one liver for two recipients was developed to use both segment grafts,6 was critical in enabling safe transplanta-
lobes and is now an established technique associated tion of the smallest of children (piggyback technique).
with excellent outcomes. In 1988 Pichlmayr7 was the first surgeon to split a liver to
The development and current status of liver splitting provide two grafts, one for a child and the other for an adult
are reviewed, with emphasis on donor and recipient selec- (liver splitting). Emond et al8 published a series of
tion, surgical techniques, postoperative complications, 18 patients who received split liver grafts with patient and
and clinical outcomes. graft survival of 67%, and 50%, respectively. Early

690
 52 Split Liver Transplantation for Pediatric and Adult Recipients 691

retain the main vessels and common bile duct with the right
TABLE 52-1 E
 arly Results in Split Liver
lobe graft. The left lateral segments grafts were revascular-
Transplantation (Centers With
ized using interpositional venous or arterial grafts.
More Than 10 Splits)*
Improvements in the selection of patients and refine-
Patient Graft ment of surgical technique led to the widespread adop-
Author Year No. Survival (%) Survival (%) tion of splitting. Subsequently, Azoulay et al14 described
Emond et al8 1990 18 67 50
their experience of 27 split grafts with a 1-year patient
Broelsh et al11 1990 30 60 42
and graft survival of 79% and 78%, respectively. The
Langnas et al12 1992 10 50 50
incidence of arterial and biliary complications was 15%
Houssin et al9 1993 16 75 69
and 22%, respectively, although none of these led directly
de Ville de 1995 98 68 62
to graft loss. Again, donor selection was recognized as
Goyet et al10 key, and only optimal livers were considered for splitting.
Right lobe grafts were used for elective adult recipients,
*Calculated from original manuscripts. and the liver parenchyma was divided through the middle
of segment IV to try to overcome the problems of post-
operative ischemia and cut surface bile leaks.
experience reported by several European centers appeared Rogiers et al,15 in 1995, described in situ splitting as a
to be discouraging, in contrast to the results obtained using consequence of the development of left lateral segment liv-
whole-liver grafts (Table 52-1). Graft survival ranged from ing donor operations. They reported a 6-month patient and
40% to 60% at 1 year with patient survival of 50% to 75%. graft survival of 92% and 85% with no biliary complica-
In 1993 Houssin et al9 reported ex situ splitting in 16 recipi- tions.16 Segment IV was preserved in six out of seven cases,
ents; of these 12 were urgent, and 4 were elective opera- although one was subsequently resected after implantation
tions. Their technique was based on an anatomical and a second patient developed a cut surface abscess. A com-
assessment of the liver using arteriography and cholangiog- parison with 19 ex situ split grafts performed over the same
raphy on the back table with patient and graft survival at 1 period showed a lower peak postoperative aspartate amino-
year of 75% and 69%, respectively. The recognition of ana- transferase level. In 1997 Goss et al17 reported 15 in situ
tomical variations, including graft size and quality, hepatic splits resulting in 28 grafts with patient and graft survival of
and portal venous anatomy, and biliary and arterial anatomy, 92% and 86% and expressed the view that in situ splitting
was emphasized. A European workshop on split liver trans- was associated with better outcome. However, improving
plantation in 1993 analyzed clinical data from nine centers results from ex situ splitting were reported in 1998 by Rela
of 50 livers split to provide 100 grafts. This collective expe- et al18 of 44 split grafts (from 22 donor livers) with patient
rience (1988-1993) was published in 1995,10 by which time and graft survival at a median follow-up of 12 months of
it was clear that there was a learning curve to this technique 90% and 88%, respectively, and by Mirza et al19 in 1998 of
that contributed to a higher rate of complications and graft 24 split grafts with patient and graft survival of 78% and
loss. Part of the problem had been the selection of higher- 68%, respectively. Busuttil and Goss20 in 1999 reviewed 349
risk recipients, particularly for right lobe grafts, which con- ex situ and in situ split liver transplants performed in 10 cen-
tributed to suboptimal outcome. Patients transplanted from ters between 1990 and 1998 with 72 in situ splits performed
intensive care were unable to tolerate technical complica- in their own institution between 1992 and 1999. Busuttil
tions. These complications included portal vein (4%) and and Goss concluded that in situ splitting was the technique
hepatic artery (11.5%) thrombosis and biliary leak (18%). of choice because of the apparent superior results. However,
The overall retransplantation rate was up to 22% for elec- in a comparison of the best results from a single center per-
tive adult recipients receiving a right split graft compared to forming ex situ splitting, the outcomes were identical (90%
10% with a whole liver. Back-table cholangiography or patient survival and 88% graft survival).18
arteriography did not appear to reduce the incidence of Further modifications have combined the advantages of
arterial or biliary complications. Overall 41 out of 100 grafts each technique21 with minimal in situ dissection of the
in this collected series were lost. Long cold ischemic time hilum but completing the parenchymal division to secure
and technical shortcomings were thought to be important cut surface hemostasis. The dissection is completed on the
risk factors for early complications.10 However, at 6 months back table after standard perfusion and retrieval. This offers
graft and patient survival rates were similar to those reported the advantage of good hemostasis and the ability to probe
after whole-liver grafting by the European Liver Transplant the biliary tree to delineate the anatomy carefully before
Registry when patient groups were matched for severity of division of the hilar structures. In situ splitting offers advan-
liver disease. Outcomes for emergency transplantation in tages in recognizing relevant anatomy, preserving the seg-
adults remained poor, and it was concluded at this time that ment IV artery, ease of sharing grafts with other centers, and
split liver grafts should be used only in elective cases capable securing hemostasis before implantation. In contrast, ex situ
of tolerating early complications. splitting requires no additional resources or surgical exper-
Subsequently Kalayoglu et al13 described six ex situ splits tise at the retrieval, and the liver can be split while preparing
using a metal probe to define the arterial and biliary anat- the recipients for implantation. The majority of active split-
omy. They recommended excision of segment IV after ting centers are currently using ex situ splitting
observing ischemic complications in several right lobe grafts. techniques.
Although follow-up was short, the five adult and seven pedi- The long-term results of split liver transplantation are
atric cases had patient and graft survival of 91% and 75%, now comparable to those of whole grafts in both adult and
respectively. Their splitting procedure was designed to pediatric recipients (Table 52-2)22,23. Although this
692 PART VI Future Developments in Liver Transplantation

TABLE 52-2 C
 urrent One-Year Overall Patient
and Graft Survival in Left Lateral
Segment/Right Lobe Split Liver
Transplantation
Patient Graft
Author Year No. Survival (%) Survival (%)
Meneu-Diaz 2008 20 84 72
et al25
Nesher et al26 2011 55 80* 66*
Vagefi et al23 2011 106 88* 84*
Saidi et al24 2011 557 88* 83*
Doyle et al22 2013 53 96 96

*Calculated from original manuscripts.

FIGURE 52-1 n Left lateral segment/right lobe liver transplantation.

procedure has become routine in many centers and has child and an adult recipient, but they should be considered
been successful in reducing waiting times for children, it in the light of potential posttransplantation complications.
has not achieved universal acceptance, and splitting rates A thorough understanding of the surgical anatomy of the
remain disappointingly low internationally (1.3% of total liver and particularly that pertaining to the caudate lobe is
transplants are split livers in the United States).24 Initially essential before undertaking split liver transplantation.31
it was hoped that splitting would provide grafts for
children while maintaining adult transplant numbers;
however, many transplant centers remain reluctant to use
Recipient Selection
such grafts. The initial experience of split liver transplantation was
gained by transplanting high-risk patients on intensive
care, but with poor outcomes.11 It was quickly appreci-
Donor Selection ated that if this technique was to match the outcomes of
The need for predictable liver function and thus a good- reduced-size or whole-liver grafts, a more selective
quality liver was recognized early in the development of split approach to recipient selection was required.18 Left lat-
liver transplantation. At that time a marginal donor was eral segment split grafts are suitable for all children with
defined by age of greater than 50 years. Donors less than 40 acute or chronic liver disease with excellent short- and
years of age were arbitrarily defined as suitable for splitting long-term survival.31 The use of a split right lobe graft in
to provide a left lateral segment graft for a child. A right lobe adults requires assessment of recipient size and complex-
recipient with a graft weight–to–body weight ratio ity and when possible should be used in stable recipients.
(GWBWR) of less than 0.8% is potentially at risk for devel- Patients unlikely to tolerate biliary complications should
oping small-for-size syndrome.27 Although donors should be avoided.
ideally be less than 50 years of age, older donors can be used.
Mildly fatty livers (less than 20%) may be suitable if cold
ischemic times are kept as short as possible. Donors with
Surgical Techniques
mildly abnormal liver function (aspartate aminotransferase The left lateral segment is invariably allocated to a child
level less than three times normal or if higher with a falling and the residual right lobe to another child or adult
trajectory), intensive care stay of greater than 5 days, and (Fig. 52-1). The volume of liver allocated to the child is
significant vasopressor support can be used with caution. If calculated by the donor-recipient ratio of 10:1 (for exam-
several risk factors are present, then the liver should not be ple, a liver from a 70-kg donor could produce a left lateral
split. The use of marginal grafts (e.g., fatty livers) for split segment to be used in a 7-kg child approximately). The sur-
liver transplantation carries a higher and unpredictable risk gical techniques are different for ex situ and in situ split.
for graft failure because of the reduced functional mass and
the likelihood of significant ischemia-reperfusion injury.27-29 Ex Situ Split
Splitting livers from donors in donation after cardiac
death (DCD) may be possible in livers from young donors Ex situ splitting is performed after the donor liver has been
(under 30 years); however, few cases have been reported, retrieved and perfused with preservation solution. It should
and outcomes are less than satisfactory. Short warm and be split in the transplant center on a back table prepared
cold ischemia times are important factors to be consid- for this purpose. The liver anatomy relevant for liver split-
ered if early dysfunction or ischemic cholangiopathy are ting is assessed. The liver is maintained in University of
to be avoided.30 Simultaneous implantation of both grafts Wisconsin (UW) solution and fastidiously kept at 4° C for
and careful recipient selection (to avoid long or difficult the procedure. Crushed sterile ice should be replaced regu-
dissections) should be considered if these grafts are to be larly in the container to maintain the desired temperature.
used successfully. A thermometer to check the temperature of the preserva-
Vascular and biliary anatomical variations are not an tion fluid is useful. Regular drainage of water and replace-
absolute contraindication for splitting a donor liver for a ment of ice helps to maintain the temperature at 4° C.
 52 Split Liver Transplantation for Pediatric and Adult Recipients 693

A B

C D
FIGURE 52-2 n Ex situ split liver transplantation. Main anatomical structures. A, Left hepatic vein. B, Portal vein, line of division.
C, Hepatic artery, line of division (arrow). D, Left hepatic bile duct (arrow).

A systematic assessment of the following structures the bifurcation. If there is a clear division between the left
should be performed: and right hepatic arteries, then the left hepatic artery is
• Hepatic veins: The left hepatic vein should join the taken at its origin (see Fig. 52-2, C). If there are multiple
vena cava separately from the middle hepatic vein. arteries present, then allocation should be performed in
Identify if one or two veins are present. If two veins such a way as to minimize the vascular reconstruction
are present, back-table reconstruction will be required. A fine metallic probe can be used to determine
necessary. the bile duct anatomy. The identification of the bile ducts
• Hepatic artery: Check for the presence of left or draining the left lateral segment and segments I and IV
right accessory hepatic arteries. Identify the left, are key in avoiding posttransplantation biliary complica-
right, and segment IV hepatic arteries. tions. The left bile duct is divided and the hilar plate over-
• Portal vein: Identify the bifurcation between left and sewn with a fine PDS suture (see Fig. 52-2, D).
right portal vein. Once the vessels and bile duct have been allocated and
• Biliary system: Avoid dissection of the common bile divided, the dissection of the liver parenchyma starts at a
duct. The bile duct is divided in the hilar plate. As point 1 cm to the right of the falciform ligament. The
little dissection as possible should be performed parenchyma is crushed gently with a hemostatic clamp
between the bile duct and the hepatic artery to pre- revealing vascular structures, which are tied or clipped
serve the arterial supply to the bile duct. individually and then divided. This procedure is repeated
The allocation of vascular structures depends on the meticulously until the liver is divided. The left lateral seg-
liver anatomy and the transplant recipient. If conventional ment graft is then flushed with preservation solution
anatomy is present, the left hepatic vein is isolated at the through the artery and portal vein to test leakage at the
level of the vena cava and divided transversely cut surface. Further cut-surface sutures are often required
(Fig. 52-2, A). The orifice created in the vena cava should to achieve satisfactory hemostasis.
be sutured transversely later. The portal vein is dissected The left lateral segment graft is then repacked until
to the bifurcation, and the tributaries to the caudate lobe required for implantation. The vessels/structures for this
are ligated and divided. The left portal vein is divided at its graft are the left hepatic vein, hepatic artery (left hepatic
origin (see Fig. 52-2, B), and the defect in the portal vein artery or common hepatic artery), portal vein (left or main
is sutured transversely. The hepatic artery is dissected to trunk), and left hepatic duct. Ideally the recipient
694 PART VI Future Developments in Liver Transplantation

The disadvantages of in situ split over ex situ split are

the following:
• Prolonged organ retrieval
• Infrastructure requirements in donor hospital
• Greater expertise required of the surgical retrieval
team
• Potential to compromise donor stability and impact
on other organs

Technical Issues
Need for Cholangiogram
For left lateral segment/right lobe split there is no need for
cholangiography. Careful probing of the bile duct is help-
FIGURE 52-3 n Right lobe graft (segment IV removed) for split ful in gaining understanding of the anatomical variations of
liver transplantation. the biliary tree.32 If the left duct is divided immediately to
the right of the umbilical fissure, in 97% of the cases it will
produce a single left hepatic duct suitable for biliary recon-
struction. In 3% of cases, two bile ducts will be present and
hepatectomy should have been completed by the time the will need to be anastomosed individually32 (Fig. 52-4).
graft is ready for implantation to minimize cold ischemia. Immediately after the division of the bile duct the surgeon
The extended right lobe graft requires further prepa- should place a very loose suture (7/0 PDS) to mark the bile
ration. Segment I (caudate lobe) is removed to help with duct(s) on the left lateral segment and facilitate their iden-
implantation and to avoid kinking of the portal vein. We tification on the cut surface before implantation and biliary
routinely resect segment IV to avoid ischemic liver and to reconstruction (Roux-en-Y hepaticojejunostomy). Resec-
reduce the incidence of cut surface leaks. The extended tion of the caudate lobe and oversewing of the portal plate
right lobe graft consists of the vena cava (with the left reduces the potential for bile leaks from unrecognized cau-
hepatic vein orifice sutured transversely), hepatic artery date bile ducts.
(right hepatic artery or common hepatic artery), portal
vein (right branch of the portal vein or main portal vein), Need for Angiogram and Allocation of
and the common bile duct (left hepatic duct remnant Vascular Structures
oversewn) (Fig. 52-3). In ex situ splitting it is not necessary to perform angiogra-
phy to identify donor arterial variations. Again, careful and
delicate dissection of the porta hepatis should be per-
In Situ Split
formed to identify anatomical variations distal to the origin
The procedure is performed during the multiorgan of the gastroduodenal artery. A low bifurcation of the com-
retrieval and before the perfusion with preservation solu- mon hepatic artery into the left and right hepatic arteries is
tion. The donor liver parenchyma is divided while main- very favorable for splitting, but it is still necessary to iden-
taining an intact blood supply through the left lateral tify the segment IV artery origin, which may arise from
segment. The transection of the liver parenchyma is per- either branch. Identification of left or right accessory
formed using the clamp crush/fracture, Cavitron Ultra- hepatic arteries from the left gastric or superior mesenteric
sonic Surgical Aspirator (CUSA) dissector, or other artery, respectively, is fairly easy during dissection, and
techniques used in hepatectomy. The ligature of vessels their presence will determine the allocation of the vascular
needs to be meticulous on both cut surfaces to avoid trunk to each graft. The allocation of the main vascular
excessive bleeding and hemodynamic compromise of the structures in the absence of variant arterial anatomy (main
donor. Once the parenchyma has been divided, the perfu- trunk of the portal vein or the common hepatic artery) will
sion of segment IV can be assessed. If compromised, it depend on the characteristics of the recipients and exper-
can be removed on the back table. The organ retrieval tise of the transplant team. The impact of living donor
procedure then continues as normal, and the organs are liver transplantation has led to the routine use of “short
perfused with preservation solution, the liver vascular vessels” for the left lateral segment recipients. If the surgi-
structures and bile duct are divided as convenient, and cal team is not confident of anastomosing small vessels,
both liver grafts are stored separately. These grafts are then the whole common hepatic artery should be given to
ready for implantation and can be delivered to different the pediatric recipient. Donor superior mesenteric artery,
transplant centers. used as an interpositional graft, is useful in overcoming dis-
The advantages of in situ split over ex situ split are as crepancies in size between donor and recipient arteries and
follows: should be retrieved routinely. If there is an atretic or
• Better hemostasis on the cut surfaces thrombosed recipient portal vein, then the main portal
• Reliable assessment of the viability of segment IV trunk can be assigned to the left lateral segment graft.
after parenchymal division
• No need for bench work after retrieval Management of Segment IV and Cut Surface
• Better for organ sharing with other centers In ex situ liver transplantation it is difficult to predict the
• Potential reduction in cold and warm ischemic times viability of segment IV, and in view of this, we routinely
 52 Split Liver Transplantation for Pediatric and Adult Recipients 695

RA
RA RA
RP L L L
RP

RP
57% 12% 16%

CHD CHD CHD

A B C1

RA RA RA
L
L L

RP RP RP
4% 5% 1%

CHD CHD CHD

C2 D1 D2

IV IV
III III RA
RA RA L
II II

I RP I
RP 2% 1% RP 1%
CD
CHD CHD CHD

E1 E2 F
FIGURE 52-4 n Commonly described bile duct anatomical variations of relevance to liver splitting. CD, Cystic duct; CHD, common
hepatic duct; L, left hepatic duct; RA, right anterior sectoral duct; RP, right posterior sectoral duct; I, II, III, IV, liver segments. (From
Maguire D et al. Is cholangiography required for ex situ splitting of cadaveric livers? Transpl Int. 2004;17(1):46-48.)

remove segment IVb to try to avoid necrosis and subse- experience. Meticulous attention to avoiding venous out-
quent bile leak or abscess. To remove segment IVb the flow obstruction and the irregular dissection of the liver
parenchyma is divided through a line traced from the left parenchyma will help to avoid this complication. Support
border of the gallbladder fossa to the level of the porta hepa- from the anesthetist in correcting the underlying coagu-
tis. The cut surfaces have to be checked for vascular leaks lopathy before reperfusion is important. After graft reperfu-
before implantation by flushing cold UW solution through sion, extra sutures, argon diathermy, and a variety of
the artery and vein. Adequate-sized cannulas have to be hemostatic agents can help to achieve hemostasis.
used to perfuse the artery and avoid intimal injury. Cut sur-
face leaks are sutured with 5/0 or 4/0 Prolene sutures. Fibrin Biliary Reconstruction. A 40- to 50-cm retrocolic Roux-
glue or other hemostatic agents applied to the cut surface en-Y hepaticojejunostomy is used for biliary reconstruc-
after graft implantation and immediately before graft reper- tion with the left lateral segment grafts. Before implantation,
fusion will help achieve hemostasis and may reduce the inci- careful probing of the bile ducts is mandatory to try to
dence of minor bile leaks. Controlling bleeding from the identify the segment IV duct, which needs to be sutured.
cut surface after reperfusion can on occasions be a daunting In a small number of cases separate segment II and III
696 PART VI Future Developments in Liver Transplantation

ducts will need two separate anastomoses to the Roux loop. 0.86%, and mean GWBWR for left lobe was 0.88%). An
Biliary reconstruction of the right lobe graft is generally average-sized donor (70 kg) and liver (1500 g) provides a
performed by end-to-end anastomosis between the donor right lobe graft of about 800 g to 900 g, which should be
and recipient common bile ducts. The donor common bile sufficient for the majority of adult recipients. The
duct should be left as short as possible to try to maintain expected left lobe graft weight should be between 400 g
the microvascular arterial supply to the bile duct. The use and 500 g and should be suitable for a “small” adult less
of a T tube for the right lobe graft has not been widely than 60 to 65 kg.39 However, there is greater variation in
adopted. However, in our program, its use was associated the size of the left lobe than the right lobe. Other
with a reduction in the incidence of cut surface bile leaks. authors37,40,41 have questioned whether the minimal
GWBWR is applicable to living donor liver transplanta-
tion, because segmental cadaveric grafts experience addi-
tional injury from brain death, cold donor preservation,
LEFT LOBE/RIGHT LOBE SPLIT and ischemia-reperfusion injury.
Historical Background To provide more comprehensive venous outflow to the
right lobe, Humar et al42 modified their surgical technique
By the end of the 1990s, split liver transplantation for a by allocating the vena cava to the right lobe. This preserves
child and an adult was becoming a routine procedure, and smaller hepatic veins draining directly into the vena cava
the transplant community started to consider the possi- and also facilitates back-table reimplantation of the seg-
bility of splitting for two adult recipients.33 The feasibil- ment V and VIII veins with venous interpositional grafts
ity of splitting was demonstrated by Bismuth et al34 in to the donor vena cava. Other authors37,43,44 have also sup-
1989 with the transplantation of two patients with acute ported this venous reconstruction, which is very important
liver failure using one donor liver and later by the Paul in living related transplantation using right lobes.
Brousse Hospital group with a series of 26 adult patients Broering et al37 subsequently reported an important
receiving left and right split grafts (ex situ splits with the modification for venous reconstruction in ex situ splitting
middle hepatic vein allocated to the right graft).14 Graft by dividing the middle hepatic vein and reconstructing
failure rates were high with early graft dysfunction, bile the opened vein with donor iliac vein. This was refined
leaks, and functional small-for-size syndrome, particu- further by dividing the middle hepatic vein after the junc-
larly with left lobe grafts.33 tion with the segment VIII tributary, leaving the most
In situ splitting was proposed as the preferred method proximal middle hepatic vein with the left graft and pro-
of full left/right lobe splitting because it minimized isch- viding a broader common orifice for the left and middle
emic injury to the graft.35 Sommacale et al36 realized that hepatic vein anastomosis.
if the left lobe were to function in an adult the middle However, there is continuing concern regarding split
hepatic vein had to be included with the left lobe graft transplantation for two adults over long-term patient and
and proposed a modification of the standard in situ split- graft survival. Azoulay et al45 reported patient survival with
ting technique. In their experience, ligation of the seg- left split grafts that was significantly lower at 2 years fol-
ment V and VIII veins did not cause segmental outflow low-up when compared with those receiving whole grafts
obstruction of the right graft, and both recipients reported (43% and 85%, respectively). These results were attrib-
in the paper recovered well (one of them a “small” adult uted to pretransplant factors, including the graft quality or
of 56 kg). However, given the limited experience, this quantity (steatosis, GWBWR) and the recipient (Model
may have been as a result of fortuitous anatomy. for End-Stage Liver Disease [MELD] score and intensive
Gundlach et al35 considered that allocation of the mid- care stay).45 Current long-term results remain below
dle hepatic vein to the left lobe graft would cause venous expectations. Humar et al46 reported outcomes of 32 adult
outflow obstruction of the segment V and VIII veins in patients transplanted with split grafts with a median fol-
the right graft and described a technical modification of a low-up of 3 years. Of these, 11 had GWBWR of less than
longitudinal transection of the vena cava providing a wide 0.8% with a graft survival of 73%. In addition, 3 also had
venous patch for both grafts for implantation by cavoca- splenic artery ligation, all developed prolonged cholestasis,
vostomy. This technique maintained the patency of and 1 underwent retransplantation. Giacomoni et al47 per-
minor hepatic veins draining directly into the vena cava; formed 16 adult split liver transplants with patient and
however, it did not solve the problem of segments V and graft survival of 67% for the right and 72% for the left lobe
VIII venous outflow. Broering et al37 also adopted this grafts with a mean follow-up of 38 months. Better results
technique and described further modifications to improve have been reported by Broering et al37 with a patient and
venous drainage of the right lobe graft. graft survival for the right lobe of 87% and 75% and 89%
Experience from right lobe living related liver trans- and 79% for the left lobe; these results were comparable
plantation suggested that the minimum GWBWR to with long-term outcomes for whole grafts. The improved
have comparable survival with whole grafts was 0.8% or outcome for left lobe splitting appeared to be related to
above.38 In 2001 Humar et al39 reported six split livers for recipient selection in both pediatric (n = 12) and adult
adult recipients with graft and patient survival of 83% at recipients (n = 7) (median age 12 years, median body weight
9-month follow-up. They allocated the middle and left 35 kg, and GWBWR 1.6%). There continues to be a lack
hepatic veins with the vena cava to the left graft and the of information about the impact of right lobe/left lobe
right hepatic vein for the right lobe. They were careful splitting on the transplant waiting list and on overall out-
with recipient selection by maintaining a GWBWR over comes because the procedure continues to be performed in
the minimum limit (mean GWBWR for right lobe was small numbers using different techniques.44,48,49
 52 Split Liver Transplantation for Pediatric and Adult Recipients 697

The donor should receive at least 30,000 units of

Donor and Recipient Selection intravenous heparin before hepatectomy. The distribu-
In general, donor selection is identical to that for left lat- tion of the vessels to either right or left grafts depends
eral segment/right lobe splitting. The key is to be able to on the anatomical characteristics of the graft and recipi-
predict the graft weight and potential function (func- ent. The common bile duct generally remains with the
tional hepatic mass), and for this the donor liver has to be right lobe and therefore the left hepatic duct with the
of excellent quality. In addition, cold ischemic times have left lobe biliary reconstruction. The caudate lobe in gen-
to be kept short. Only young (less than 50 years old) and eral remains with the left lobe, but we prefer to resect it
hemodynamically stable donors should be considered for to facilitate implantation of the graft (and to avoid kink-
in situ or ex situ split. In practice, small-for-size syndrome ing of the portal vein) and reduce the incidence of bile
should be avoided if each graft has a GWBWR of more leak. The weight of each graft is noted, and they are
than 0.8%. Retrieval and implantation techniques have to stored separately in ice boxes until required for
be fastidious to ensure that the potential graft function is implantation.
fully realized.
Recipient selection should ideally be restricted to elec- Ex Situ Split
tive cases with a satisfactory GWBWR. In general, the
left lobe is allocated to small adults or children weighing The liver graft is removed from the cadaveric donor as
30 to 50 kg. Any factor that might contribute to pro- per standard procedure and transported to the splitting
longed cold ischemic time (such as complex previous transplant center. On the bench the liver is kept in UW
operations or retransplantation) should be avoided. solution at 4° C. The hepatic veins and bile ducts are
probed to determine the feasibility of the split proce-
dure. The portal vein and hepatic artery are dissected to
Surgical Techniques their bifurcation and divided according to the graft ana-
These include in situ and ex situ split for two adults, and tomical characteristics and recipient needs. Segment IV
there is still debate about the optimal technique, which has to be preserved with the left hepatic artery, prefera-
may depend on institutional strengths and geography, bly as a single trunk to ease implantation. The common
rather than surgical factors. Ex situ splitting appears to be bile duct remains with the right lobe, and the left
favored currently because it facilitates reconstruction of hepatic duct is divided and marked with a loose 6/0
the hepatic venous outflow. suture.
There are a number of different techniques used to
divide the liver based on the middle hepatic vein during
In Situ Split
ex vivo splitting. If it is decided that the whole of the middle
The chest and abdomen of the cadaveric donor are opened hepatic vein is to be included with the left lobe graft, then
with a midline incision. After careful exploration of the the segment V and VIII veins have to be identified and
chest and abdomen, the liver is inspected. A cholecystec- drained using interpositional vascular grafts on the back
tomy and intraoperative cholangiogram are performed to table. This is essentially the same technique used for
delineate the biliary anatomy. The common hepatic artery implantation of the right lobe living donor graft. Interpo-
is mobilized up to the bifurcation into left and right sitional donor iliac artery or vein should be used for the
branches and to identify the segment IV artery. The portal venous reconstruction.
vein is mobilized to confirm the anatomy and feasibility for An alternative is to divide the middle hepatic vein
splitting. The common bile duct is explored with a metal- down the middle on the back table while preserving the
lic probe after division and flushing with saline. The right proximal 2 to 3 cm with the left graft. This requires
lobe is then mobilized and the right hepatic vein identified reconstruction of both sides using donor iliac vein
and used as a landmark for subsequent parenchymal divi- patches. The advantages offered by this technique include
sion. In general, the inferior vena cava (IVC) remains with the avoidance of the need to reconstruct segment V and
the right lobe. Intraoperative ultrasound assessment can VIII veins and the effective drainage of all the small veins
help identify the segment V and VIII hepatic veins drain- that drain into the middle hepatic vein (Fig. 52-5).
ing into the middle hepatic vein. All venous tributaries of
more than 5 mm need to be identified and marked for Technical Issues
reconstruction. An alternative is to leave the IVC intact
until after cold preservation and to split it longitudinally to Need for Cholangiography
provide vein patches for each graft. In the case of splitting for two adults, either in situ or back-
The main dissection plane can be determined by the table cholangiography is helpful in identifying difficult
change in appearance of the liver after temporarily biliary anatomical characteristics. These include a right
clamping the right hepatic artery and right portal vein. posterior sectoral duct draining into the left hepatic duct
Ischemic preconditioning for 10 minutes is an option used and identifying the segment IV course accurately. Cholan-
by some units. The hepatic parenchyma is divided accord- giography has to be complemented by careful exploration
ing to the preferred surgical technique for hepatectomy, of the biliary tree with a malleable metallic probe.
but many use a combination of CUSA and argon coagula-
tion. Division of the main vascular and biliary structures Allocation of the Inferior Vena Cava
can be delayed if necessary and completed on the back table Various surgical techniques have been described, but
(to speed up the dissection or review recipient anatomy). with little evidence to suggest one or another is better.
698 PART VI Future Developments in Liver Transplantation

A B
FIGURE 52-5 n Left lobe/Right lobe split liver transplantation. Middle hepatic vein (right lobe). A, Division of middle hepatic vein.
B, Reconstruction using donor iliac vein.

Supporters of leaving the IVC with the left graft* or Recipients Receiving Right Lobe
right graft do not provide evidence to support their
conclusions.36,40,44,45 Dividing the IVC down the mid-
Grafts (Extended)
dle35,37,49 or excision of the whole cava and implanta- In general, partial grafts corresponding to left lateral
tion of caval cuffs represent refinements from techniques segments have better results that right lobes. However,
and difficulties encountered in living donor liver trans- long-term results of right lobes (segments V to VIII) or of
plantation.43,52 The decision regarding the IVC remains extended right lobes (including segment IV) are similar
that of the implanting transplant team and their experi- to those of whole grafts in both American57 and
ence of using segmental living donor or cadaveric European series.58
grafts. There are significant differences in terms of patient
survival between transplant centers and between surgeons
after using partial grafts corresponding to right lobes
OUTCOMES FOR SPLIT LIVER (extended), ranging from 55% to 88% with increased
TRANSPLANTATION relative risk for liver failure (with 1.7 higher risk com-
pared to whole graft). However, the reported results are
Recipients Receiving Left Lateral still similar to those obtained from using marginal whole
Segment Grafts grafts with the additional benefit of decreasing the time
on the waiting list.53 The results are worse if these partial
The introduction of liver-splitting techniques has had grafts are used in patients on the emergency list for liver
a significant impact on the availability of liver grafts transplantation or for retransplantation (mortality rates
for children, with a reduction in waiting list mortality up to 25%),56 reinforcing the view that these should con-
and the need for living donation in the West.18,53,54 No tinue to be considered marginal grafts.59
significant difference has been reported in the out- Consent for the use of partial grafts should be sought
come of split left lateral segment grafts when com- at the time of listing for liver transplantation28,60 and con-
pared with those from whole livers10,53 and reduced sent reconfirmed just before liver transplantation.
liver grafts.55 A North American survey56 reported good results
The best results have been obtained in experienced obtained from using 152 partial grafts (left lateral seg-
liver transplant centers with graft survival above 90% for ment and right lobe [extended]) (54% ex situ and 46% in
in situ20 or ex situ techniques.31 A national survey of 89 situ). The rate of vascular complications was low (5%
Ame­rican liver transplant teams56 using left lateral seg- equally distributed between hepatic artery and portal vein
ment grafts (n = 270) reported that the incidence of vas- thrombosis), and incidence of biliary complications was
cular complications was 13% (equally distributed between 11% (82% were cut surface or anastomotic leaks and
hepatic artery and portal vein thrombosis) and biliary 18% were anastomotic biliary strictures). Yersiz et al57
complications was 13% (69% leaks from the cut surface reported similar results; however, other series have
and 8% from the biliary anastomosis). These rates of reported higher rates of biliary complications rising up to
complications were similar to those described in left lat- 34%.58,61,62
eral segments from living donation and to whole grafts Devascularization of the bile duct during the hilar dis-
from pediatric donors. section, not recognizing the anatomical variations of the
bile duct, the presence of a cut surface, and the existence of
*References 39, 44, 45, 47, 50, 51. multiple biliary radicals draining from the caudate lobe all
 52 Split Liver Transplantation for Pediatric and Adult Recipients 699

contribute to the high incidence of biliary complications. for two adult recipients was 26% for the left lobes (4%
The routine use of a T tube is recommended when using vascular complications) and 22% for right lobes (9% vascu-
right lobe grafts because it seems to reduce the incidence lar complications).56 In Germany, Broering et al37 also
of early biliary complications.62 reported early and late biliary complications of 21% for
In the United Kingdom from 2007 onward splitting is the left lobe and 37% for the right lobe (mainly due to
mandated if livers from young donors are offered. A liver bile leaks from the cut surface). In Italy there was no dif-
from a donor less than 40 years old, with a weight greater ference in morbidity between the two different grafts for
than 20 kg and with intensive care unit stay less than hepatic artery thrombosis (7%), biliary complications
5 days should be split preferentially by the pediatric (26%), primary nonfunction (4.6%), and small-for-size
transplant center.63 This has increased the number of syndrome (4.6%).65
split procedures in the United Kingdom, reducing sig-
nificantly the pediatric liver waiting list. There is, how-
ever, some concern regarding the outcomes for the split FUTURE DEVELOPMENTS
right lobe graft in small-volume adult transplant centers.
In a recent report by Mallic et al,64 the outcomes of trans- Split liver transplantation for an adult and a child, using
plant using right lobe split liver grafts (n = 17) were com- right lobe and left lateral segment grafts, respectively,
pared to those using DCD grafts (n = 32). The outcomes has become a safe and efficient option accepted by many
of recipients receiving DCD grafts were better than those liver transplant centers around the world. The majority
using right lobe grafts (93% and 71% 3-year patient sur- of cases have been performed in a small number of cen-
vival, respectively). Variations in outcomes of right lobe ters, which tend to have larger volume and to have active
split grafts have been noted between centers and whether adult and pediatric transplant programs. The uptake and
grafts are imported. Several factors may contribute to widespread acceptance of splitting has been slow and
these outcomes, including the reported 18% hepatic inconsistent. The allocation of a good-quality donor
artery thrombosis rate, 30% early graft dysfunction rate, liver to a child for split left lateral segment transplant
and 23% retransplantation rate. Donor and recipient with the subsequent offer of the right lobe to an adult
selection criteria and surgical decision making and profi- recipient has been suggested as a way of increasing split-
ciency appear to be key. ting. Mandatory splitting of suitable livers has been
introduced in some countries, such as the United King-
Adult Recipients Receiving Grafts From dom, and this does appear to help maintain numbers.
Debate continues as to which surgeons and centers
Left Lobe/Right Lobe Split should be performing liver splitting and how to monitor
The early results with this technique were poor. Zamir outcomes and identify technical shortcomings. Balanc-
et al41 reported the use of partial grafts that were obtained ing the needs of pediatric liver transplantation with
in situ for transplanting six adult recipients with 1-year those of adult recipients who are too sick to receive par-
survival of 76% and suggested that technical factors were tial grafts continues to be a source of tension in alloca-
contributing to graft dysfunction and functional small-for- tion systems.66 The use of DCD grafts for splitting is
size syndrome. Humar et al39 reported 1-year graft and likely to become a reality particularly if preservation
patient survival of 83% with careful donor and recipient technology improves.30
selection and a more refined surgical technique.37 Good Other issues that need to be resolved include defining
long-term results were also obtained by Broering et al the appropriate training required for surgeons to perform
with patient survival of 89% for left lobe and 87% for liver splitting and the optimal number of operations
right lobe grafts at a mean of 27 months' follow-up. required each year to maintain expertise. In addition, the
These results were similar to those obtained by the optimal techniques for liver splitting have not been deter-
authors with whole cadaveric grafts.37 mined. Liver division to safely obtain grafts for two adult
In Europe a recent Italian multicenter experience (43 recipients remains a technical challenge, although results
transplants from 23 left lobe/right lobe split procedures) are improving. Further challenges include the optimiza-
showed that splitting for two adults is feasible but has a tion of cadaveric donors, recipient selection, and sharing
steep learning curve. Using the in situ technique to of livers. Progress in organ preservation to minimize
reduce cold ischemia time facilitates sharing organs with ischemia-­reperfusion injury will help to further improve
other centers (65% of the grafts were shared); patient and outcomes and avoid small-for-size syndrome. The use of
graft 1-year survival were 72% and 65%, respectively. normothermic perfusion may play an important role in
However, there was a near doubling in the number of the future of split liver transplantation, by selecting the
adult transplants performed.65 It has been confirmed that best grafts and predicting functional status. The ability to
partial livers with a GWBWR of greater than 0.8% have influence liver regeneration and manipulate portal inflow
better graft survival than those with a ratio of less than (and pressure) to improve outcomes with smaller grafts
0.8% (81% versus 73%, respectively) and that tying the would also promote wider acceptance of liver splitting.
splenic artery can improve graft survival in some of these Finally, the use of national and international registries of
marginal grafts.46 split liver outcomes would provide valuable information
The overall incidence of complications in a survey in regarding surgical techniques, complications, and sur-
80 American transplant centers when using partial grafts geon and center expertise.
700 PART VI Future Developments in Liver Transplantation

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31. Deshpande RR, Bowles MJ, Vilca Melendez H, et al. Results of
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32. Maguire D, Vilca-Melendez H, Heaton ND, Rela M. Is cholangi-
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10. de Ville de Goyet J. Split liver transplantation in Europe–1988 to
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11. Broelsch CE, Emond CJ, Whitington PF, et al. Application of
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13. Kalayoghlu M, D’Alessandro AM, Knechtle SJ, et al. Preliminary
40. Kilic M, Seu P, Stribling RJ, Ghalib R, Goss JA. In situ splitting of
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14. Azoulay D, Astarcioglu I, Bismuth H. Split-liver transplantation.
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The Paul Brousse policy. Ann Surg. 1996;224(6):737–776.
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15. Rogiers X, Malago M, Habib N, et al. In situ splitting of the liver
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two recipients. Transplantation. 1995;59(8):1081–1083.
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43. Yersiz H, Ramcharan TT, Sielaff TD. Technical and logistical
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Part II. Creation of left segment I-IV and right segment V-VIII
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18. Rela M, Vougas V, Muiesan P, et al. Split Liver Transplantation.
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20. Busuttil R, Goss J. Split liver transplantation. Ann Surg.
2001;233(4):565–574.
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46. Humar A, et al. Split liver transplant (slt) for 2 adult recipients -
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outcomes with small grafts (gw/rw ratio </=0.8%). Transplantation.
splitting liver grafts. Transplantation. 1999;68(1):162–163.
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22. Doyle M, Maynard E, Lin Y, et al. Outcomes with split liver trans-
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23. Vagefi PA, Parekh J, Ascher NL, et al. Outcomes with split liver
48. Fan ST, Lo CM, Liu CL. Split liver transplantation for two adult
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recipients. Hepatogastroenterology. 2003;50(49):231–234.
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49. Rios A, et al. Split-Liver Transplant for Two Adults in a Spanish
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24. Saidi RF, Jabbour N, Li Y, et al. Outcomes in partial liver trans-
50. Andorno E, Genzone A, Morelli N. Split liver transplantation in
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tation. HPB (Oxford). 2011;13(11):797–801.
Transplant Proc. 2001;33(1-2):1337–1338.
25. Meneu-Diaz JC, Garcia I, Moreno-Elola A, et al. Starting a new
51. Colledan M, Andorno E, Valente U. A new splitting technique for
program of split liver transplantation after a low learning curve: a
liver grafts. Lancet. 1999;353(9166):1763.
reality in centers with large experience in liver surgery and whole liver
52. Yersiz H, Renz JF, Hisatake G. Technical and logistical consider-
transplantation. Hepatogastroenterology. 2008;55(86-87):1699–1704.
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26. Nesher E, Island E, Tryphonopoulos P. Split liver transplantation.
Creation of left segment II, III, IV and right segment I, V-VIII
Transplant Proc. 2011;43(5):1736–1741.
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 52 Split Liver Transplantation for Pediatric and Adult Recipients 701

53. Cardillo M, De Fazio N, Pedotti P. Split and whole liver transplan- 60. Vulchev A, Roberts J, Stock P. Ethical issues in split versus whole
tation outcomes: a comparative cohort study. Liver Transpl. liver transplantation. Am J Transplant. 2004;4(11):1737–1740.
2006;12(3):402–410. 61. Como V, Colledan M, Dezza MC. Extended right split liver graft
54. Yersiz H, Renz JF, Farmer DG. One hundred in situ split-liver for primary transplantation in children and adults. Transpl Int.
transplantations: a single-center experience. Ann Surg. 2006;19(6):492–499.
2003;238(4):496–505. 62. Wojcicki M, Silva MA, Jethwa P. Biliary complications following
55. Oswari H, Lynch SA, Fawcett J. Outcomes of split versus reduced- adult right lobe ex vivo split liver transplantation. Liver Transpl.
size grafts in pediatric liver transplantation. J Gastroenterol Hepatol. 2006;12(5):839–844.
2005;20(12):1850–1854. 63. Zalewska K; Liver Advisory Group. Patient selection and alloca-
56. Renz JF, Emond JC, Yersiz H. Split-liver transplantation in the tion policies. Deceased donor liver: allocation. Available at http://
United States: outcomes of a national survey. Ann Surg. www.odt.nhs.uk/pdf/liver_allocation_policy.pdf.
2004;239(2):172–181. 64. Mallik M, Callaghan CJ, Hope M. Comparison of liver transplan-
57. Yersiz H, Cameron AM, Carmody I, et al. Split liver transplanta- tation outcomes from adult split liver and circulatory death donors.
tion. Transp Proc. 2006;38:602–603. Br J Surg. 2012;99(6):839–847.
58. Sebagh M, Yilmaz F, Karam V. Cadaveric full-size liver transplan- 65. Zambelli M, Andorno E, De Carlis L. Full-right-full-left split liver
tation and the graft alternatives in adults: a comparative study from transplantation: the retrospective analysis of an early multicenter
a single centre. J Hepatol. 2006;44(1):118–125. experience including graft sharing. Am J Transplant. 2012;12(8):
59. Abecassis M, Superina R, Axelrod D. Split liver sharing in the 2198–2210.
United States. Am J Transplant. 2005;5(7):1583–1584. 66. Malago M, Hert! M, Testa G. Split-liver transplantation: future
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 CHAPTER 53

Split Liver Transplantation

for Two Adult Recipients
Mark L. Sturdevant • Abhinav Humar

CHAPTER OUTLINE

SELECTION CRITERIA COMPLICATIONS

Donor Vascular Complications
Recipient Biliary Complications
SURGICAL TECHNIQUE Small-for-Size Syndrome
Donor UNANSWERED QUESTIONS
Recipient Ethics of Splitting
Right Lobe Graft Allocation
Left Lobe Graft Split Potential
RESULTS SUMMARY

Orthotopic liver transplantation has now become the Usually the liver is split into a smaller portion consisting
gold standard treatment for end-stage liver disease. How- of the left lateral segment (which can be transplanted into
ever, the ongoing shortage of suitable livers, together a pediatric recipient) and the remaining larger extended
with progressively longer waiting lists, prevents many right lobe (which can be transplanted into a normal-sized
patients from being transplanted; this has led to a signifi- adult recipient). The benefits for pediatric recipients have
cant waiting list mortality rate at most centers. Using liv- been tremendous, including an expansion of the donor
ers from living donors is one way to increase the supply of pool and a significant decrease in waiting times and mor-
liver grafts but carries with it the disadvantage of donor tality rates.2,3 As experience with SLT in this setting has
risk. Splitting the deceased donor liver to use for two grown, the results have improved. Many single-center
recipients represents another method for expanding the series now report equivalent outcomes with split and
donor pool. With split-liver transplantation (SLT), a whole organ deceased donor transplants. Although split-
whole liver from a deceased donor is divided into two ting the liver for an adult and a pediatric recipient has had
functioning grafts, which can then be transplanted into a significant impact on the expansion of the donor pool
two appropriate-sized recipients. The first SLT was per- for pediatric recipients, it has had no impact on the donor
formed by Pichlmayr et al in 1988.1 Subsequently several pool for adult recipients, because ultimately this type of
centers published their SLT series. The technical aspects split generates only one graft for the adult recipient.
of SLT are in many ways similar to the technical aspects Because the majority of individuals on a transplant list are
of living donor transplants, and these two areas of liver adults, and the majority of waiting list deaths are in adult
transplantation have developed side by side in many cen- patients, SLT can have the maximal impact on waiting
ters, with one program complementing the other. More list mortality if the two grafts generated can be used for
recently, living donor transplantation has become signifi- two adult recipients. To accomplish this, the liver is gen-
cantly more common than SLT, especially in areas of the erally split into the anatomical right and left lobes, which
world where deceased donor transplants are not com- are then transplanted into two adult-sized recipients.
mon. The two techniques to expand the donor pool are However, splitting the liver for two adult recipients is
not mutually exclusive and in fact are usually more suc- generally uncommon at this time. There are many rea-
cessful in programs where both live donor and deceased sons why SLT for two adult recipients has remained rela-
donor SLT procedures are performed. Ultimately the tively uncommon. Ideal donors appropriate for splitting
ability to offer all options for transplant can only benefit have become less common as an increasing number of
the potential recipient and minimize waiting list deceased donors have risk factors that would make them
mortality. unsuitable for splitting. Similarly, with current allocation
The vast majority of SLT procedures performed to rules, appropriate recipients may also be difficult to find
date have been for one adult and one pediatric recipient. because the potential recipients at the top of a waiting list

702
 53 Split Liver Transplantation for Two Adult Recipients 703

may be too ill to tolerate a partial liver transplant. Other Cold ischemic time should be minimized as much as
hurdles include the technical complexities and challenges possible in all SLT recipients. This is a crucial aspect
associated with the procedure, the logistics involved with because cold ischemic time represents one of the few
coordinating multiple teams, and the reported results to donor risk factors that can be affected by the transplant
date. Nonetheless, SLT can play a role in the expansion team. Ideally cold ischemic times should be less than 10
of the donor pool for adult recipients. Key aspects in try- hours, and less than 8 hours if possible. This requires sig-
ing to optimize results include careful donor and recipi- nificant planning with multiple teams and operating
ent selection, meticulous surgical technique in both the rooms so that there can be some degree of overlap
donor and recipient operations, and appropriate methods between the donor and recipient procedures and at least
of allocation to ensure the greatest chance of success. some degree of overlap between the two recipient
This chapter will cover these areas and present some of procedures.
the published series with regard to patient outcomes.
Recipient
SELECTION CRITERIA When selecting appropriate recipients for SLT, impor-
tant issues are graft size requirement, cause of liver fail-
Proper donor and recipient selection are crucial to ensur- ure, and severity of illness. Critically ill patients with
ing a good outcome with any SLT. Donors generally severe portal hypertension and high Model for End-Stage
have to be ideal; but equally important, suitable recipi- Liver Disease (MELD) scores are generally not good
ents that can tolerate partial grafts must be chosen. One candidates for partial grafts, especially from a deceased
obviously wants to prevent the situation in which donor.4 Patients with tumors, metabolic diseases, or
one deceased donor liver that would have worked in one MELD scores below 30 may be appropriate candidates
recipient is split and results in two grafts that do not work for these types of splits. Hepatitis C in the recipient does
in two recipients. not represent a contraindication for a split graft.5 A graft
weight–to–body weight ratio (GWBWR) of close to
0.8% should likely be the minimum when selecting
Donor appropriate recipients. Results with GWBWR ratios of
Donors should be medically ideal to minimize the risks of less than 0.8% have been associated with inferior results,
primary nonfunction, especially for recipients of the though not all series have supported this finding.6 It is
smaller left lobe graft. Young, hemodynamically stable also important to remember that this recommendation is
donors with near-normal liver function test results, short based on data mostly from the living donor literature. A
intensive care unit stay (<5 days), and absent or fairly partial graft from a deceased donor likely has more injury
short arrest times should be selected; with such donors, than a partial graft from a living donor. Additional stresses
primary nonfunction for the recipients should be uncom- on the deceased donor versus the living donor graft
mon. The upper donor age limit for splitting a liver is include the factors that led initially to the donor’s death,
unclear, and the criteria likely need to be more stringent potential hemodynamic instability during the prepro-
when performing a right lobe/left lobe split versus an curement management of the deceased donor, and the
extended right/left lateral lobe split. Generally donors subsequent cold ischemic time after removal of the organ.
much beyond an upper age limit of 45 years are likely not Therefore extrapolating the 0.8% value may not be
to be suitable for splitting. Liver function test results entirely appropriate for SLT from a deceased donor.
should be close to normal or at most less than three times Nonetheless, our practice has been to try to select recipi-
the upper limit of normal. Donor size plays an important ents in whom we know the GWBWR will exceed 0.8%.
role in determining suitability for right lobe/left lobe This can sometimes be difficult because estimating the
splits because the size of the grafts generated in this situ- size of the partial graft ahead of time can be difficult.
ation are key predictors of successful outcome in the Again, there may be an abdominal computed tomography
recipients. The size of the donor correlates to some extent scan available on the donor for review before the pro-
with the size of the liver because we know that the liver curement. This can be valuable in assessing the anatomy
constitutes roughly 2% of the total body weight. This and the size of the two grafts ahead of the procurement.
obviously holds true only to a certain weight, and obese The final decision regarding which recipient is most
donors (body mass index > 30) should generally not be appropriate can be made intraoperatively during the pro-
considered because of the risk for underlying fatty liver. curement surgery, once the donor liver has been carefully
An intraoperative biopsy can be useful to rule out any sig- inspected and the size of the grafts estimated by a trained
nificant macrosteatosis, and greater than 10% fat would surgeon.
be a contraindication for splitting the liver. Male donors Another important aspect of the recipient selection
are generally likely to be more suitable for splitting process is adequately informing the potential recipient of
because their livers tend to be bigger, but this cannot the splitting procedure and obtaining informed consent.
always be reliably predicted. Many donors have a com- With the current organ allocation system in the United
puted tomography scan of the abdomen available (espe- States, the graft is initially assigned to a primary recipi-
cially if the cause of death was trauma), and it is generally ent. If the liver is to be split, the second recipient is cho-
not difficult now to obtain at least crude measures of liver sen at the discretion of the center performing the split.
volumes from these scans before donation to help in mak- This is advantageous for the second recipient, who then
ing an appropriate selection decision. bypasses additional waiting time. For primary recipients,
704 PART VI Split and Living Donor Transplantation

however, there is no significant advantage: we are in fact

asking them to give a part of “their” new liver to someone
else. If the primary recipient is to receive the left lobe
(and is therefore likely of smaller size), the issue is not as
difficult. A full-size liver graft from a large donor may be
difficult to fit into this recipient. Performing the split may
allow for a better size match in this situation. But if the
primary recipient is to receive the right lobe, the issue is
more difficult, because such recipients could easily
accommodate the whole graft. In our experience there is
usually no hesitation on the part of the recipients to par-
ticipate in the split, and in some instances some recipients
have commented that they tremendously appreciated the
opportunity to help another individual by agreeing to the
split. Nonetheless, with the present allocation rules, it is FIGURE 53-1 n Full right lobe/left lobe split with preservation of
crucial to fully inform potential recipients about splitting the middle hepatic vein with the left lobe graft and the cava with
the right lobe graft. The common artery and portal vein are
and to obtain informed consent. This brings up an impor- preserved with the left lobe graft, but the bile duct is preserved
tant question, which is if it is up to the primary recipient with the right lobe graft.
to decide if a split should be performed by virtue of their
consent. Ideally the center and organ procurement orga-
nization should decide ahead of time if this is an appro-
priate organ for spitting, and the two partial grafts then
should be allocated to the two most appropriate recipi-
ents near the top of the list, but not necessarily at the very
top of the list. These points have been debated for years,
and unfortunately there is no good consensus on this at
present.

SURGICAL TECHNIQUE
The SLT procedure can be divided into two parts: the
donor operation and the recipient surgery (which in turn
consists of the surgery for the right lobe and left lobe
recipients). Both parts of the procedure are technically
demanding, and the success of this procedure rests on
performing a meticulous division of the donor liver and FIGURE 53-2 n Hilar dissection demonstrating takedown of the
then subsequent implantation in the two recipients. left hilar plate and encircling of the left hilar plate. The line of
When the liver is to be split for two adult recipients, it is transection is marked (dashed black line). The common duct is
maintained with the right lobe graft, but the main hepatic artery
usually transected in its midplane, generating two similar- and portal vein are maintained with the left lobe graft.
sized grafts—the larger anatomical right lobe and the
smaller anatomical left lobe. The transection plane should
stay to the right of the middle hepatic vein so that this grafts to prevent congestion. Preserving the cava with the
structure is retained with the left lobe (Fig. 53-1). Seg- right lobe graft helps to maximize outflow by preserving
ment IV makes up a crucial part of the left lobe, and all inferior hepatic veins. This also allows for back-table
hence the middle hepatic vein should be preserved with reconstruction of any segment V and VIII veins draining
the left lobe to ensure no congestion. Loss of the middle from the right lobe to the middle hepatic vein.
hepatic vein may affect drainage of segments V and VIII
in the right lobe graft. If significant draining vessels are Donor
identified, they can easily be reconstructed on the back
table using vascular conduits from the deceased donor. No standard operative technique yet exists for such split-
Regarding the dissection in the hilum (Fig. 53-2), our ting of livers; each center has developed its own tech-
preference has been to leave the full length of the hilar nique, with subtle variations. The majority of these
vascular structures intact with the left lobe. The right- techniques involve dividing the liver in its midplane,
sided hilar structures are usually larger than the left-sided thereby generating two grafts consisting of the anatomi-
structures. Therefore leaving the main vessels intact with cal right lobe (segments V, VI, VII, VIII) and the ana-
the left lobe makes that transplant easier. The common tomical left lobe (segments I, II, III, IV). The middle
bile duct is left maintained with the right lobe graft, how- hepatic vein and left hepatic vein are preserved with the
ever, so that there is a greater chance of having a single left lobe graft, as are the main trunks of the hepatic arte-
bile duct orifice to reconstruct on both the right and left rial and portal venous systems.
lobe grafts. One crucial technical point for the recipient The donor operation begins with a careful examina-
operation is ensuring adequate venous outflow of the tion of the liver to assess quality, size, and anatomy. An
 53 Split Liver Transplantation for Two Adult Recipients 705

intraoperative cholangiogram is an easy test to obtain

that can give useful information about the anatomy of the
biliary tree. The right lobe is not mobilized, and all short
hepatic veins draining the posterior aspect of the right
lobe into the inferior vena cava (IVC) are thus preserved.
The left lobe (including the caudate lobe) is completely
mobilized away from the underlying IVC. The conflu-
ence of the left and middle hepatic veins is encircled with
an umbilical tape. The plan is to preserve the IVC with
the right lobe graft and the middle hepatic vein with the
left lobe graft. By preserving the donor IVC with the
right lobe, all short hepatic veins (small and large) drain-
ing the right lobe are kept intact. Also, major hepatic vein
tributaries to the middle hepatic vein tributaries can be
reconstructed on the back table in cold preservative solu-
tion. Doing so maximizes outflow from the right lobe,
minimizes warm ischemic time, and simplifies implanta- FIGURE 53-3 n The line of transection on the hepatic parenchyma
tion of the right lobe. is just to the right of the middle hepatic vein.
The porta hepatis is then carefully examined to eval-
uate the hepatic arterial anatomy. Regarding the dissec-
tion in the porta, our preference has been to leave the
full length of the main vascular structures intact with
the left lobe (i.e., the common hepatic artery with the
celiac trunk and the main portal vein, see Fig. 53-2).
The right lobe then retains just the right-sided vascular
structures: the right hepatic artery and the right portal
vein. The right-sided hilar structures are usually larger
than the left-sided vascular structures. Therefore leav-
ing the main vessels intact with the left lobe makes that
transplant easier. The inflow blood supply to the right
lobe (arterial and portal) is isolated. The intraoperative
cholangiogram can help guide the biliary dissection by
giving valuable information regarding the biliary anat-
omy. Given the long extrahepatic course of the left
hepatic duct, the common bile duct is maintained with
the right lobe graft; the point of transection of the bile
duct is at the junction of the left hepatic duct with the
common hepatic duct so that there is a greater chance of FIGURE 53-4 n The completed split in situ, which allows one to
examine the two lobes to ensure that there are no areas of
having a single bile duct orifice to reconstruct on both devascularization and also helps to minimize cold ischemia
the right and left lobe grafts. It is useful to divide the time.
common bile duct just above the duodenum and pass a
biliary probe through the cut end proximally to help
decide on the exact site for transection of the biliary sys- after parenchymal transection and before vascular inter-
tem between the two lobes. ruption, to ensure no significant ischemia at the borders
The final step is transection of the hepatic paren- of the cut edge of the liver (Fig. 53-4). Previous SLT
chyma itself. The transection plane should stay to the series have shown superior results with in situ versus ex
right of the middle hepatic vein, so that this vein is situ liver splits.7,8 For all these reasons we feel that the
retained with the left lobe (Fig. 53-3). The transection actual splitting of the donor liver should be performed in
can be performed in situ, using a device such as a Cavit- situ. Disadvantages of the in situ procedure include the
ron Ultrasonic Surgical Aspirator (CUSA), or ex situ time added to the procurement during the parenchymal
after the liver is removed. Our preference is in situ split- transection and the potential for hemodynamic instabil-
ting, which has several advantages over the ex situ tech- ity in the donor if there is any significant bleeding. This
nique. First, it decreases the total cold ischemic time. can affect not only the liver itself but also the other
Performing the split on the back table could add up to 2 organs that are being removed during the procurement.
to 3 hours of cold ischemia. Also, there is likely some Once the transection is complete, the liver and other
warming of the liver on the back table, even if the split is abdominal organs are flushed with cold preservative
being performed in a cold ice bath of preservative solu- solution as usual and the liver is removed. On the back
tion. Even a warming of the liver by a few degrees may table the previously isolated vasculature to the right lobe
have a negative impact on the outcome. Performing the is divided to completely separate the two grafts. Any
split in situ also has other advantages. Significantly less important hepatic venous tributaries from the right lobe
bleeding occurs when the organs are reperfused. The draining into the middle hepatic vein (segment V or
two liver grafts can be assessed in the donor immediately VIII) that had been divided during the parenchymal
706 PART VI Split and Living Donor Transplantation

FIGURE 53-5 n The split is completed on the back table by final division of the vascular structures. Important middle hepatic vein tribu-
taries of the right lobe can be reconstructed using conduit from the donor.

HA

HA
CBD
Roux limb
PV PV
A B
FIGURE 53-6 n The right lobe (A) and left lobe (B) can then be implanted in the respective recipients. The left lobe is done in a piggy-
back fashion. The right lobe can be either caval replacement (as shown) or piggyback. CBD, Common bile duct; HA, hepatic artery;
PV, portal vein.

transection can now be reconstructed. This can be done hepatic vein with both lobes and maximizing outflow for
by using vascular conduit from the deceased donor and both grafts.10
anastomosing the cut surface veins to the preserved
donor IVC using vascular conduit (such as iliac vein)
from the deceased donor (Fig. 53-5). Recipient (Figure 53-6)
The preceding description is our preferred technique, Right Lobe Graft
but several variations have been described. Two impor-
tant ones include the cava splitting method and the mid- The deceased donor SLT right lobe graft is implanted
dle hepatic vein splitting technique. In the cava splitting in a manner similar to that used for a right lobe living
method the left lobe is not mobilized from the IVC. donor graft. The diseased liver in the recipient is
Rather the cava is split down the middle on the back removed, and the IVC can be either preserved or
table, thus preserving a portion of it as a patch with both removed. If the IVC has been preserved with the right
the right and left lobes.9 This technique has the advan- lobe graft, either a caval replacement, piggyback, or
tage of preserving all of the outflow of the left lobe, side-to-side cavaplasty technique can be used for out-
including the short hepatic veins. The middle hepatic flow reconstruction. Ensuring adequate outflow of
vein splitting technique involves ex situ transection of the right graft is crucial. The donor right portal vein
the hepatic parenchyma with division of the middle is then sewn to the recipient right or common portal
hepatic vein longitudinally along its length. This can vein (depending on which is the better size match).
then be reconstructed in both the right and left lobe The donor right hepatic artery is sewn to the recipi-
grafts using a vein patch, hence preserving the middle ent right hepatic artery. Biliary reconstruction is then
 53 Split Liver Transplantation for Two Adult Recipients 707

performed either with a duct-to-duct technique or similar to published data from conventional transplanta-
with a Roux-en-Y hepaticojejunostomy. tion for an adult and a child. SLT for two adults increased
the number of recipients compared with whole-liver
Left Lobe Graft transplantation and was logistically possible in 16 of the
104 (15%) optimal cadaver donors. Humar et al16
The left lobe is implanted in a standard piggyback fashion reported their experience of in situ splitting of livers from
with preservation of the recipient’s IVC. The donor six cadaver donors and transplanted into 12 adult recipi-
hepatic veins can be anastomosed to the recipient’s left ents at the University of Minnesota. The patient and
and middle hepatic vein confluence with good size match. graft survival were 80% each, and arterial and biliary
The remainder of the vascular connections are done in a complications occurred in 16% and 25% of recipients,
standard fashion. respectively. Analysis of the split-liver transplantation
data suggested a time-dependent learning curve, which
was applicable to surgical splitting technique, implanta-
RESULTS tion, and recipient selection.
Not all single-center reports have been positive, with
The initial series of adult/pediatric SLT until the mid- some reporting a high incidence of complications and
1990s demonstrated poor recipient and graft survival of graft loss. One center in Italy recently reported on 16
50%.11,12 However, by the mid-1990s reports from the adult patients who underwent SLT using 9 full right lobe
European Split Liver Registry showed 6-month patient grafts (segments V to VIII) and 7 full left lobe grafts (seg-
and graft survival similar to whole-liver transplant.13 ments I to IV).17 The splitting procedure was always car-
Single-center North American series, as well as analyses ried out in situ with a fully perfused liver. Postoperative
of registry data, similarly demonstrated improving out- complications were recorded in 8 (50%) patients: 5 right
comes with SLT for adult/pediatric recipients. Data on lobe recipients and 3 left lobe recipients. No one was
outcomes for SLT for two adults is significantly less retransplanted. After a median follow-up of 55.82 months
robust, with mostly small single-center series or case (range, 0.4 to 91.2), 5 (31%) patients died, and the 1-, 3-,
reports in the literature, highlighting the infrequency of and 5-year overall survival rate for patients and grafts was
these procedures. No registry reports for SLT for two 69%, leading the authors to question whether SLT for
adult recipients have been reported. The American Soci- two adult recipients should even be performed. However,
ety of Transplant Surgeons (ASTS) survey performed other single-center reports from the same area have had
between April 2000 and May 2001 elicited a response from more positive results. Cescon et al18 reported on 22 adult
83 of 89 surgical teams identified from the annual report of patients receiving SLT and demonstrated good results.
the Scientific Registry of Transplant Recipients as having Overall patient and graft survival were 90% and 86%.
performed at least one SLT procedure during the previous Patient survival was 84% in recipients of right grafts and
year. Thirty-six of the responding teams reported data on 100% in recipients of left grafts. Graft survival was 84%
207 left lateral segment, 152 right trisegment, and only 15 and 89%, respectively.
left lobe, and 13 right lobe grafts.14 Therefore left and
right lobe graft data from the ASTS survey do not permit
meaningful analysis. Nonetheless, the reported overall COMPLICATIONS
incidence of left lobe complications was 26% versus 22%
for right lobe grafts, with the majority used for urgent Complications after SLT are generally similar to those
recipients. Biliary complications were most frequent, with that may occur after any type of transplant, though the
vascular complications reported in 4% of left lobe versus overall incidence of certain types of complications may
9% of right lobe grafts. Primary nonfunction and graft differ. In addition, there are some conditions unique to
failure were 7% and 9% for left lobe versus 9% and 14% partial lobe transplants and generally not seen with
for right lobe grafts, respectively. Recipient death was whole-liver transplants that can contribute to complica-
observed in 7% of left versus 8% of right lobe grafts. tions. An example of this is the cut surface of the liver
Single-center reports from Europe, North America, present on both the left and right lobe grafts, which may
and Asia, even though each is relatively small in size, have be an additional source of complications such as bleeding
provided more meaningful data on outcomes after these or bile leak. Overall, given the technically demanding
procedures. Azoulay et al15 reported their outcomes of nature of the procedure and the partial nature of the
transplantation with right and left split-liver grafts and graft, surgical complications tend to be more common
also compared with those of whole-liver transplants. For after SLT compared to whole-liver transplants, though
whole-liver, right and left split-liver grafts, respectively, published reports suggest it is similar to the reported
patient survival rates were 88%, 74%, and 88% at 1 year incidence of complications after live donor transplants.
and 85%, 74%, and 64% at 2 years. Graft survival rates
were 88%, 74%, and 75% at 1 year and 85%, 74%, and
43% at 2 years. Patient survival was adversely affected by
Vascular Complications
graft steatosis and recipient’s inpatient status before The incidence of vascular complications after whole-liver
transplantation. Graft survival was adversely affected by transplantation is 5% to 10% and is likely to be at least
steatosis and a GWBWR of less than 1%. Primary non- twice that in SLT recipients. Thrombosis is the most
function occurred in three left split-liver grafts. The rates common early event; stenosis, dissection, and pseudoan-
of arterial (6%) and biliary (22%) complications were eurysm formation are less common. Any of the vascular
708 PART VI Split and Living Donor Transplantation

anastomoses (hepatic artery, portal vein, and hepatic Small-for-Size Syndrome

vein) may be involved, but the hepatic artery is most com-
mon. Hepatic artery thrombosis has a reported incidence Small-for-size syndrome (SFSS) has emerged as an inter-
of 5% to 10%, higher than reported in whole-liver trans- esting and significant problem that is fairly unique to
plantation, likely because of the smaller caliber of vessels partial liver transplants. SFSS and injury related to the
and the sometimes complex arterial reconstruction use of small-for-size grafts were reported initially by
required. Thrombosis of the portal vein is less frequent Emond et al.19 Although there is no uniform consensus
(compared with the hepatic artery) but again is likely on the definition of SFSS, the diagnosis is generally
more common than in whole-organ recipients. Compli- based on persistent hyperbilirubinemia and massive asci-
cations of the hepatic veins (such as thrombosis and ste- tes during the posttransplant subacute phase without evi-
nosis) are uncommon but again have a higher incidence dence of any other cause. The incidence is reportedly
in the partial grafts. The risk for problems may be higher close to 10%, though the exact incidence is unknown
in recipients of the left lobe graft because the segment because the definition of this condition is not agreed
may be quite mobile, and if it is not properly aligned, it upon. Multiple risk factors have been identified, includ-
may twist on the anastomosis, obstructing flow. Presenta- ing the size of the graft, the type of graft, the degree of
tion is usually with massive ascites and graft dysfunction. portal hypertension, and the spleen size. Of these, the
Ultrasound Doppler examination will usually demon- degree of portal hypertension and portal perfusion is
strate this, as well as the other early vascular problems, likely most important. The pathophysiological charac-
and some form of routine monitoring is warranted to aid teristics of the condition are believed to be related to
in early diagnosis. damage to hepatocytes and vasculature secondary to por-
tal shear stress. Portal hyperperfusion leads to poor
hepatic arterial inflow because of the arterial buffer
Biliary Complications response, which ultimately leads to hepatic necrosis and
Complications of the biliary system continue to be the poor hepatic regeneration.20
most common type of surgical complication after SLT. In the absence of any intervention, SFSS is associated
The incidence is 20% to 40% with an associated mortal- with a significant mortality early after transplant, with
ity of less than 5%. Biliary complications manifest as many of the patients succumbing to complications associ-
either a leak or an obstruction. Timing often determines ated with poor graft function, such as infections and mul-
type and clinical outcome of the complication. Bile leaks tiorgan failure. With increased understanding of the
tend to occur early postoperatively and often require sur- concept of small for size, strategies to prevent SFSS and
gical repair, whereas obstruction usually occurs later and strategies to rescue small-for-size grafts are being devel-
can often be managed with radiological or endoscopic oped (Table 53-1).
techniques.
Most bile leaks occur within the first 30 days after
transplantation and can be from the anastomotic site or UNANSWERED QUESTIONS
the cut surface of the liver. The area around the anasto-
mosis has the most tenuous blood supply: both the donor Ethics of Splitting
common bile duct (CBD) and the recipient portion of
the CBD are supplied by end arteries. Excessive dissec- Surgical complications are more common in SLT (ver-
tion or cauterization around the donor or recipient CBD sus whole graft) recipients, related to the cut surface of
can further disrupt the blood supply, leading to ischemic
complications. Another important cause of biliary tract
complications is hepatic artery thrombosis: the donor TABLE 53-1 M
 echanisms and Possible
CBD receives its blood supply from the hepatic artery. Methods of Avoiding or Treating
With any biliary tract complication the hepatic artery Small-for-Size Syndrome
should be carefully assessed to document patency. Other
causes of leaks include poorly placed sutures, excessive Mechanism of
number of sutures, and tension on the anastomosis. Small for Size Strategies
With partial transplants the cut surface of the liver rep- Prevention Suboptimal graft Younger donor, nonfatty
resents an important site for a bile leak. Careful paren- strategies quality liver, decreased
chymal transection can help to lower the incidence. The ischemia time
in situ technique of liver transection can also help to Insufficient graft Adequate graft volume
minimize the risk for cut surface bile leaks. Biliary volume (GWBWR ideally
should be ≥0.8%)
obstruction is usually secondary to stricture and occurs
Impaired venous Wide venous anastomo-
later in the postoperative period. It is most common at outflow sis, reconstruction of
the anastomotic site and is likely related to local isch- segmental drainage
emia. Nonanastomotic strictures usually have a worse Treatment Increased portal Portosystemic shunt,
prognosis; they are associated with hepatic artery throm- strategies flow or splenectomy, splenic
bosis or prolonged cold ischemic times. The treatment pressure artery ligation, medical
therapies (e.g.,
is usually not operative, but rather by percutaneous or octreotide)
endoscopic interventions. If these initial options fail,
surgical revision is required. GWBWR, Graft weight–to–body weight ratio.
 53 Split Liver Transplantation for Two Adult Recipients 709

the liver, smaller vessels for anastomosis, and more Pearls and Pitfalls
complicated biliary reconstruction. Therefore one
important aspect of the recipient selection process is • Paramount to the success of split-liver transplantation is
adequately informing the potential recipient of the proper donor and recipient selection.
splitting procedure and obtaining informed consent. • Split procedures can be performed in situ or ex situ; the
Who makes the decision of whether a liver should be in situ technique reduces cold ischemia, enhances iden-
split at the present time? The question of how much tification of biliary and vascular structures, and reduces
role the recipient plays in the decision to split the liver hemorrhage upon graft reperfusion.
is unclear. • Cold ischemia time can have a significant impact on
the outcomes, and every effort should be made to mini-
mize cold ischemia time, especially in the left lobe graft
Allocation recipient.
• The right lobe of the split usually has more outflow is-
How best to allocate a liver for splitting is completely sues, whereas the left lobe has more size issues.
undecided at the present time and varies from country to • Meticulous attention to technical detail is crucial for en-
country and from region to region. Should the liver from suring successful outcomes in this technically challenging
an ideal donor be preferentially allocated for a split pro-    procedure.

cedure, and if so, how does this affect the sickest patients
at the top of a waiting list who may be too sick for a par-
tial liver transplant? Not all centers may have the techni-
cal expertise or personnel to perform splits—should ideal
livers be preferentially allocated to centers that have such REFERENCES
expertise and personnel available? 1. Pichlmayr R, Ringe B, Gubernatis G, et al. Transplantation of a
donor liver to 2 recipients (splitting transplantation)–a new method
in the further development of segmental liver transplantation. Lan-
Split Potential genbecks Arch Chir. 1988;373:127-130.
2. Busuttil RW, Goss JA. Split liver transplantation. Ann Surg.
More data are needed to better define donor and recipi- 1999;229:313-321.
ent selection criteria, which are crucial to success. It is 3. Goss JA, Yersiz H, Shackleton CR, et al. In situ splitting of the
difficult to estimate how much impact adult SLT will cadaveric liver for transplantation. Transplantation. 1997;64:
871-877.
have on the donor pool. About 25% of all deceased 4. Lee KW, Cameron AM, Maley WR, et al. Factors affecting graft
donors in the United States are between 15 and 35 years survival after adult/child split-liver transplantation: analysis of the
of age. If even half of these livers could be used for splits, UNOS/OPTN data base. Am J Transplant. 2008;8:1186-1196.
the number of liver transplants could potentially increase 5. Humar A, Horn K, Kalis A, et al. Living donor and split-liver trans-
plants in Hepatitis C recipients: does liver regeneration increase
by 10%, or by close to 500. With better preservation the risk for recurrence? Am J Transplant. 2005 Feb;5(2):399-405.
techniques, more livers may be amenable to splitting. In 6. Hill MJ, Hughes M, Jie T, et al. Graft Weight/Recipient weight
the near future this technique will likely become part of ratio- how well does it predict outcome after partial liver trans-
every major liver transplant center's repertoire in order plant? Liver Transpl. 2009;15(9):1056.
to provide the maximum advantage for their candidates 7. Goss JA, Yersiz H, Shackleton CR, et al. In situ splitting of the
cadaveric liver for transplantation. Transplantation. 1997;64:
on the waiting list. 871-877.
8. Reyes J, Gerber D, Mazariegos GV, et al. Split-liver transplanta-
tion: a comparison of ex vivo and in situ techniques. J Pediatr Surg.
SUMMARY 2000;35:283-289.
9. Gundlach M, Broering D, Topp S, et al. Split-cava technique: liver
splitting for two adult recipients. Liver Transpl. 2000 Nov;6(6):
Given proper donor and recipient selection, SLT can be 703-706.
successfully applied for two adult recipients. Donors 10. Broering DC, Bok P, Mueller L, et al. Splitting of the middle
should be “ideal,” (i.e., young, large, and hemodynami- hepatic vein in full-right full-left splitting of the liver. Liver Transpl.
cally stable with normal liver function test results). Care- 2005 Mar;11(3):350-352.
11. Emond JC, Whitington PF, Thistlethwaite JR, et al. Transplanta-
ful evaluation of the donor hepatic artery and biliary tion of two patients with one liver. Analysis of a preliminary experi-
anatomy intraoperatively is essential to helping decide if ence with 'split-liver' grafting. Ann Surg. 1990 Jul;212(1):14-22.
the split is technically possible. The split itself may be 12. Broelsch CE, Emond JC, Whitington PF, et al. Application of
performed ex situ or in situ, but the latter method helps reduced-size liver transplants as split grafts, auxiliary orthotopic
grafts, and living related segmental transplants. Ann Surg. 1990;
to minimize graft ischemia. Recipients should not be 212:368-375.
critically ill; careful attention should be paid to the size, 13. de Ville de Goyet J. Split liver transplantation in Europe–1988 to
especially for left lobe graft recipients. Further experi- 1993. Transplantation. 1995;59:1371-1376.
ence will help to better define the limits of this procedure 14. Renz JF, Emond JC, Yersiz H, et al. Split-liver transplantation in
and improve results. At present this represents a tech- the United States: outcomes of a national survey. Ann Surg. 2004;
239:172-181.
nique that can help to expand the donor pool in a limited 15. Azoulay D, Castaing D, Adam R, et al. Split-liver transplantation
number of circumstances, but there is a potential for for two adult recipients: feasibility and long-term outcomes. Ann
growth. Surg. 2001;233:565-574.
710 PART VI Split and Living Donor Transplantation

16. Humar A, Ramcharan T, Sielaff TD, et al. Split liver transplanta- 19. Goldstein MJ, Salame E, Kapur S, et al. Analysis of failure in living
tion for two adult recipients: an initial experience. Am J Transplant. donor liver transplantation: differential outcomes in children and
2001;1:366-372. adults. World J Surg. 2003;27(3):356-364.
17. Alessandro G, Andrea L, Matteo D, et al. Should we still offer 20. Demetris AJ, Kelly DM, Eghtesad B, et al. Pathophysiologic
split-level transplantation for two adult recipients? A retrospective observations and histopathologic recognition of the portal hyper-
study of our experience. Liver Transpl. 2008;14:999-1006. perfusion or small-for-size syndrome. Am J Surg Pathol.
18. Cescon M, Grazi GL, Ravaioli M, et al. Conventional split liver 2006;30:986-993.
transplantation for two adult recipients: a recent experience in a
single European center. Transplantation. 2009;88:1117.
 CHAPTER 54

Biliary and Vascular

Reconstruction in Living
Donor Transplantation
Yasuhiko Sugawara

CHAPTER OUTLINE

OUTFLOW RECONSTRUCTION HEPATIC ARTERIAL RECONSTRUCTION

Recipient Inferior Vena Cava Arteries in the Recipient
Right Liver Anastomosis
Middle Hepatic Vein Tributaries Right Liver
Left Liver Left Liver
Before Closing BILIARY RECONSTRUCTION
PORTAL VEIN RECONSTRUCTION Roux-en-Y Hepaticojejunostomy and Duct-to-
Notes Before Anastomosis Duct Anastomosis
Right Liver Management of Grafts With Multiple Ducts
Left Liver SUMMARY
Cases With Preoperative Portal Vein
Thrombosis

The bile ducts and vascular conduits of the harvested the double inferior vena cava (IVC) method described
grafts from living donors are incomplete, thin, and short. later). The IVC is cross-clamped, then the confluence
The biliary and vascular reconstruction of living donor of the left and middle hepatic veins (MHVs) for the left
transplantation is therefore too technically demanding to liver1,2 or three hepatic veins are opened (Fig. 54-1).
perform by simple extrapolation of the techniques on When the three hepatic veins are open, the orifice can
whole-liver transplantation. be shortened by suturing the end of the orifice (right
Hepatic veins are often multiple (middle hepatic vein side for left side graft and vice versa). To secure a good
tributaries and inferior right hepatic veins of the right and safe surgical field, the cross-clamp on the suprahe-
liver grafts or short hepatic veins of left liver grafts), patic vena cava should be placed as far cranial as possi-
which requires the plasty for all to one in the bench pro- ble. Ligating and dividing the phrenic veins on both
cedure. Special attention must be paid to ensure that the sides, as performed in the donor operation,3 allows the
anastomosis is not causing outflow block in the recipient IVC to be safely cross-clamped on the cranial side
operation. The portal vein orifices can be multiple (cau- (Fig. 54-2).
date vein for left and caudate lobe graft or anterior and
posterior for right liver graft). The diameter of the graft
artery is usually 3 mm or smaller, which requires the pro-
Right Liver
cedure to be performed using microscopy for secure anas- The orifice of the recipient right hepatic vein is maxi-
tomosis. The bile duct orifices are often multiple, short, mally extended onto the IVC caudally and to the left to
and small. Duct-to-duct anastomosis for multiple orifices provide for optimal graft outflow. It is important to rec-
especially may be impossible when they are located far ognize that regeneration causes the right liver graft to
from each other without the hilar plate of the recipient. rotate axially from right to left (Fig. 54-3).

Middle Hepatic Vein Tributaries

OUTFLOW RECONSTRUCTION When the right liver graft is harvested without an MHV
Recipient Inferior Vena Cava graft, the venous tributaries must be considered. Without
reconstruction, the part will be congested and will not
In general the hepatic vein stump should be prepared to function well after reperfusion, causing poor regenera-
be widely opened for outflow reconstruction (except in tion4 and resulting in small-for-size syndrome.

711
712 PART VI Split and Living Donor Transplantation

FIGURE 54-1 n For outflow reconstruction the anterior wall of the vena cava and three hepatic veins are used to create a large orifice.

FIGURE 54-2 n The phrenic vein originating from the inferior vena FIGURE 54-3 n Both ends of the posterior wall of the graft right
cava is ligated and divided to secure a wider space to cross- hepatic vein are sutured to those of the recipient vein. This is the
clamp the suprahepatic vena cava. first maneuver in hepatic vein reconstruction, which is impor-
tant to determining the correct “axis” of the outflow route.

The indication for MHV tributary reconstruction standard liver volume), reconstruction of the MHV trib-
should be determined preoperatively by measuring the utaries is not necessary and vice versa (Fig. 54-4).
drainage area volume of the major tributaries of the The drainage area can be confirmed during the donor
MHV. If the uncongested area (i.e., area drained by the hepatectomy and in the recipient operation after reperfu-
right hepatic vein) is sufficient for the metabolic demands sion. In the donor operation the examination must be per-
of the recipient (usually 35% to 40% of the recipient formed after dissecting the parenchyma and cutting the
 54 Biliary and Vascular Reconstruction in Living Donor Transplantation 713

Inter- Left
segmental-1 V8-1 RHV superficial
Left
V4sup superficial V8-1
RHV V4sup
Inter- LHV V8-2
V8-2 MRHV-
segmental-2 1 LHV

V4inf MRHV-
2
V5 V4inf
MRHV-2

V5

FIGURE 54-4 n Analysis of the region (left) to which each vein drains and the vein anatomy (right). The volume of each area is calcu-
lated. inf, Inferior; LHV, left hepatic vein; MRHV, middle right hepatic vein; RHV, right hepatic vein; sup, superior.

MHV tributaries, and before cutting the inflow vessels.

There are two possible methods5 (Fig. 54-5). The first is
to check the flow of the anterior branch of the portal vein
by Doppler ultrasonography. If the area is congested, the
portal vein flow is hepatofugal. The second is to tempo-
rarily clamp the right hepatic artery. The congested area
will have a dark red surface because the area has no inflow.
In the recipient operation the congested area will be seen
as the area with a dark red surface just after portal vein
reconstruction and reperfusion. The color difference
between the congested and uncongested areas should dis-
appear after the hepatic arterial reconstruction because
the ischemia will be alleviated. Confirmation is important
because there can be communication veins between the
right hepatic vein and MHVs (20% to 30% in healthy
donors), which sometimes cannot be diagnosed preopera-
tively.5 When communication veins are present, recon-
struction of the MHV tributaries is not necessary.
MHV tributaries are usually reconstructed at the
bench. A vein graft will require interposition. Autografts
(recipient’s jugular vein or iliac vein), cryopreserved vein,
or arterial grafts (Fig. 54-6) and artificial grafts6 (polytet-
rafluoroethylene) may be used.
When the area drained by the inferior right hepatic
vein is predicted to be wide based on the preoperative
evaluation, reconstruction should be considered.
Direct anastomosis between the inferior right hepatic
vein and the recipient IVC is sometimes technically
demanding. Because determining the optimal anasto-
motic site and direction is difficult and requires time,
this may increase the warm ischemic time. In such FIGURE 54-5 n The congestive area can be seen intraoperatively
after transection of the parenchyma by temporal clamping of
cases, if the IVC graft is available, the right inferior the right hepatic artery (top). After the right hepatic artery is
vein can be reconstructed at the bench, which is called clamped, the liver surface in the right anterior segment turns
the double IVC method.7 If the IVC graft is not available, dark red. Also, intraoperative Doppler ultrasonography is per-
but a thinner vein graft such as the femoral vein is formed (bottom left). If the portal flow of the anterior segment is
available, similar reconstruction8 is possible (Fig. hepatofugal (bottom right), the area is congested.
54-7). We must note that, in this case, extensive dissec-
tion of the IVC around the hepatic vein branches, in the recipient operation. When the left-sided caudate
including the phrenic veins, is unnecessary. lobe is included with the left liver graft, venous drainage
of the caudate lobe should be considered for comparable
Left Liver regeneration between the left liver and caudate lobe.9
Direct anastomosis between the short hepatic vein and
A rooflike venous patch around the graft’s left hepatic the recipient IVC can be performed. When a short
vein and MHVs at the bench simplifies the reconstruction hepatic vein, left hepatic vein, and MHVs are located
714 PART VI Split and Living Donor Transplantation

LHV + MHV

V8

V8

V5

V5

FIGURE 54-6 n The tributaries of the middle hepatic vein can be reconstructed using vein grafts, either cryopreserved homografts (left)
or autografts (right). LHV+MHV, Orifices of left and middle hepatic veins of the recipient; V5, orifice of middle hepatic vein tributary
of segment V; V8, orifice of middle hepatic vein tributary of segment VIII.

Before Closing
Caval drainage is one of the most important techniques in
partial graft implantation. Not only the anastomosis, but
also the graft positioning can be important for the out-
flow. The graft should be placed in an orthotopic posi-
tion, and care should be taken to consider the final
position of the graft once the abdomen is closed. Espe-
cially for left liver grafts, it is important to fix the falci-
form ligament to the midline of the abdominal wall to
prevent graft rotation to the right side.

A
PORTAL VEIN RECONSTRUCTION
Notes Before Anastomosis
After removal of the liver graft, the portal flow volume
should be confirmed by temporarily unclamping the por-
B tal vein. If adequate portal flow (so-called front flow) can-
not be confirmed, collateral veins, including splenorenal
shunts or the left gastric vein, need to be ligated. The
maneuver can be performed after portal vein reconstruc-
tion. In such cases the consequent hepatic artery recon-
C struction should be performed quickly to decrease the
warm ischemic time.
FIGURE 54-7 n A, When multiple short hepatic veins exist in the Upon completion of all hepatic vein anastomoses, all
right liver graft, a cryopreserved inferior vena cava (IVC) graft is the hepatic veins are clamped to prevent reperfusion of
used for outflow reconstruction. The homograft is anastomosed
side to side with the recipient vena cava. B, When an IVC graft is the liver graft by backflow from the hepatic vein. The
not available, a femoral vein graft may be used. In this tech- vascular clamp controlling the IVC is then released to
nique the femoral vein graft is folded and placed on the IVC sul- allow restoration of the blood flow in the IVC. The stump
cus of the graft. C, This is another technique. A thinner vein graft of the portal vein in the graft is always short and in many
is unified into one sheet and used as an alternative for an IVC
graft.
cases too short for placement of a vascular clamp. Tem-
porarily clamping all the hepatic veins allows for portal
vein reconstruction without a vascular clamp on the por-
tal vein stump of the graft.
close to each other, simple venoplasty at the bench is pos-
sible.10 Another option includes venoplasty using vein Right Liver
grafts at the bench. On the graft side a wide venous ori-
fice with a long cuff is formed by gathering the left, mid- In right liver grafts, single portal vein reconstruction
dle, and short hepatic veins using a conduit vein graft and can be performed in many cases between the graft and
patch vein grafts.11 recipient’s right portal vein branch or main portal vein.
 54 Biliary and Vascular Reconstruction in Living Donor Transplantation 715

FIGURE 54-9 n Several techniques for enlarging the atretic portal

vein.

FIGURE 54-8 n The right liver graft sometimes has right anterior
and posterior branches that are separately located. In such anterior wall of the graft and recipient left portal branches
cases an autologous or cryopreserved homologous vein inter- are marked with 6-0 polypropylene. The first stitch is
position graft can be used. started with an adjustment of the anterior walls of the
graft and recipient left portal branches.
The portal vein of the recipient, especially in a patient
The recipient’s right portal vein branch is a better size with biliary atresia, is sometimes atretic and cannot be
match or aligned in an anatomically more favorable used for anastomosis. In such cases the venoplasty tech-
position than the main portal vein. It is rare that the nique14 is useful for securing an adequate inflow. A venous
anastomosed portal vein seems redundant, having the graft conduit15-16 or patch17 can be used to overcome the
risk for kinking after the liver graft regeneration because problem of an atretic portal vein (Fig. 54-9).
the length of the recipient right portal vein is short. In the left liver plus caudate lobe graft, an isolated
Alignment is critical, and the anterior wall of the graft caudate portal vein originating from the left side wall of
and recipient portal vein are marked with 6-0 polypro- the portal branches of the caudate lobe is sometimes
pylene (Prolene). The anastomoses are performed in a observed.18 It is advisable to reconstruct this vein to
running fashion with 6-0 polypropylene sutures with ensure full graft regeneration and function of the cau-
incorporated growth factor. date lobe.
Infrequently the right liver graft has right anterior
and posterior branches, which are separately located. A Cases With Preoperative Portal Vein
single portal orifice can be created in many cases by Thrombosis
performing venoplasty of the anterior and posterior
branches in the bench operation. When the anterior Preoperative portal vein thrombosis is an important issue.
and posterior branches are too distantly located to Portal vein thrombosis of grades 1 to 3 according to
allow for venoplasty, a vein graft can be used as an Yerdel’s classification19 requires endovenectomy20 or
interposition. An autologous graft12 (such as right mesenteric interposition grafts, similar to whole-organ
anterior and posterior branches of the recipient) or deceased donor liver transplantation. The patency of
cryopreserved vein (i.e., bifurcated iliac vein) can be mesenteric interposition grafts, however, is not always
used as the vein graft (Fig. 54-8), but autografts are satisfactory.13
advantageous in terms of long-term patency over cryo- Patients with Yerdel’s grade 4 (complete portal vein
preserved vein grafts.13 Direct anastomosis to the and entire superior mesenteric vein thrombosis) require
recipient anterior and posterior branches is not recom- cavoportal transposition, in which the IVC is divided
mended because the alignment cannot be perfect. Fur- and the infrahepatic portion and portal vein are anasto-
thermore, preservation of the recipient’s anterior and mosed end to side. The graft cannot receive intestinally
posterior branches in the hilar dissection is difficult derived blood, and excessive blood from the IVC may be
and not always possible. related to shear stress injury of the graft, putting the
patients at significantly higher risk for morbidity and
mortality. These patients are not candidates for partial
Left Liver liver transplantation. In cases with extensive splenorenal
Left liver cases almost always require a single portal shunts,21 anastomosis of the divided left renal vein with
reconstruction between the graft and recipient left portal a portal vein using a vein graft as a conduit can be per-
branch or portal vein trunk. To adjust the alignment the formed as an exception.
716 PART VI Split and Living Donor Transplantation

larger vessel, 8-0 (diameter 0.04 mm to 0.049 mm) sutures

can be used. For small vessels, 10-0 sutures can be used.
In detail, the recipient and graft arteries are clamped
with single microclamps to temporarily halt blood flow.
The first suture is placed using monofilament sutures at
the point in the artery most difficult to visualize. Each
stitch is placed from the inner side of the arterial wall to
the outer side because there might be a minute separation
of the intima from the media in the recipient or graft
artery. The posterior stitch is tied by pulling toward the
back. Subsequent sutures are advanced anteriorly on
either side adjacent to the previous suture. A nylon micro-
suture with double needles (W10V43-9N, Keisei Medi-
cal Industrial, Tokyo, Japan) is useful when it is difficult
to turn the graft artery over.23

Right Liver
FIGURE 54-10 n The hilar plate of the recipient should be dis- The majority of arterial reconstructions in the right liver
sected as far as possible to the peripheral edge to allow for ten- can be single reconstructions between the graft right
sion-free reconstruction and multiple sites as candidates for
anastomosis. hepatic artery and recipient proper hepatic arterial
branch.24 Occasionally there are two arterial stumps in
the right liver. Direct anastomoses with branches of the
proper hepatic artery (i.e., left and middle hepatic arter-
HEPATIC ARTERIAL RECONSTRUCTION ies) are the standard approach. Also, in such cases so-
called nonanatomical anastomosis using arteries other
Arteries in the Recipient than the branches of proper hepatic arteries should be
The recipient left, middle, or right hepatic artery is suit- avoided to avoid poor patency over the long term.
able for reconstruction. Among them, the optimal artery
is selected based on the condition, size, and tension when Left Liver
anastomosed. The circumference discrepancy between
the graft arterial stump and the recipient artery should be Because of the highly variable arterial supply to segment
less than 50%, which can be adjusted during the IV, left liver grafts are more likely to have multiple arte-
anastomosis. rial stumps. When arterial communication is confirmed,
Arteries other than the branch of proper hepatic arter- multiple arterial reconstructions are not always neces-
ies should not be used for inflow but should be saved for sary. Intrahepatic arterial communication is confirmed
the revision operation. The hepatic arterial branch near twice before the recipient operation.25,26 First, in the
the trunk of the proper hepatic artery is usually thicker donor operation the patency of the left hepatic artery is
than the arterial stump of the graft and inappropriate for checked by Doppler ultrasonography after temporarily
anastomosis. It should be dissected to the peripheral part clamping the middle hepatic artery, and then, after the
as much as possible to allow tension-free reconstruction graft is harvested and placed at the bench, cold normal
(Fig. 54-10). Dissection of the common hepatic artery or saline is gently injected from the stump of the left hepatic
ligation of the gastroduodenal artery to mobilize the artery and backflow is confirmed from the stump of the
hepatic arterial branch for anastomosis should be avoided. middle hepatic artery. After reconstruction of the domi-
When the proper hepatic artery is thrombosed because nant artery, if pulsating flow is observed from the rem-
of, for example, repeated transhepatic arterial chemoem- nant stump (suggesting intragraft communication
bolization for treatment of hepatocellular carcinoma, the between the left and middle hepatic arteries) or middle
splenic artery, left gastric artery, gastroduodenal artery, hepatic arterial flow is confirmed by intraoperative Dop-
or right gastroepiploic artery can be used as an inflow. In pler ultrasonography, reconstruction of the remaining
such cases an arterial graft as an interposition may be nec- stump is not necessary.27
essary. Cases with thrombosis near the common hepatic
artery are even more challenging.
BILIARY RECONSTRUCTION
Anastomosis
Roux-en-Y Hepaticojejunostomy and Duct-
The technical aspects of arterial reconstruction are to-Duct Anastomosis
important and critical for successful liver transplantation.
The donor vessel is thin (2 to 5 mm in diameter) and Biliary reconstruction remains the Achilles’ heel of partial
short. The anastomosis is generally performed in an liver transplantation. A partial liver graft often has multi-
interrupted fashion with 9-0 nylon sutures (diameter 0.03 ple and small ducts (usually 2 to 5 mm in diameter).28
mm to 0.039 mm) on a 3/4 curved needle under an oper- Reconstruction is technically more demanding than cho-
ating microscope22 and sometimes a surgical loupe. For a ledochocholedochostomy in whole-liver transplantation
 54 Biliary and Vascular Reconstruction in Living Donor Transplantation 717

from deceased donors. As a result the incidence of biliary Pearls and Pitfalls
complications, including leaks and strictures, is higher in
partial liver grafts. • Outflow reconstruction is one of the most important tech-
Biliary reconstruction in partial liver grafts was pre- nical aspects in partial graft implantation. The ultimate
viously performed with a Roux-en-Y hepaticojejunos- graft positioning can play an important role because the
tomy with or without stenting because the main outflow can be easily blocked by torsion of the liver graft.
indication for living donor liver transplantation was • In right liver transplantation the middle and right or
pediatric patients with biliary atresia. More recently, three hepatic veins of the recipient are usually opened and
however, biliary reconstruction has become more com- unified, which are anastomosed with the graft vein.
• Reconstruction of tributary veins of middle hepatic veins
monly performed using the recipient’s native bile ducts (V5 and V8) should be considered when the congestive
with or without stenting, which is called duct-to-duct area in the right anterior segment is supposed to be wide.
anastomosis.29 The possible advantages of the duct-to- • In left liver transplantation the left and middle or three
duct anastomosis include no enteric anastomosis, a hepatic veins of the recipient are usually opened and uni-
functional sphincter of Oddi, and possible endoscopic fied, which are anastomosed with the graft vein.
approach to the anastomotic sites. Leakage is more • When the left-sided caudate lobe is included with the
likely related to the portal vein or hepatic arterial left liver, venous drainage of the caudate lobe should be
thrombosis in Roux-en-Y hepaticojejunostomy. The considered.
first choice for biliary reconstruction should be duct- • In biliary reconstruction, duct-to-duct anastomosis is
to-duct anastomosis. usually performed. An alternative option is hepaticojeju-
nostomy.
• For duct-to-duct anastomosis, the recipient’s hilar plate
Management of Grafts With Multiple Ducts should be resected en bloc with the common bile duct. In
such cases the anastomosis can be performed even when
Multiple ducts located close together and sharing a com- there are multiple ducts located far from each other in the
mon wall should be joined together so that a single anas-    graft.

tomosis can be performed. In these cases the shared

septum of the adjacent ducts may be divided vertically
and then combined with fine absorbable sutures to create
a single large orifice for the anastomosis. It is imperative REFERENCES
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ducts can be oversewn and remain unreconstructed. Bili- Y-­reconstruction for living related partial hepatic transplantation.
ary tree anastomosis should be fashioned tension-free, J Am Coll Surg. 1994 Aug;179(2):226–229.
and leakage and strictures should be checked by cholan- 2. Takemura N, Sugawara Y, Hashimoto T, et al. New hepatic vein
reconstruction in left liver graft. Liver Transpl. 2005 Mar;11(3):
giography through the external stent tube upon comple- 356–360.
tion. The significance of the stent tube across the 3. Dulundu E, Sugawara Y, Kishi Y, et al. Phrenic vein dissection in
anastomotic site remains controversial. partial liver graft harvesting. Hepatogastroenterology. 2006
Two or three separated bile ducts in the right liver Sep-Oct;53(71):778–780.
4. Akamatsu N, Sugawara Y, Kaneko J, et al. Effects of middle hepatic
graft will not exclude the possibility of duct-to-duct anas- vein reconstruction on right liver graft regeneration. Transplanta-
tomosis. To facilitate the approach the recipient’s hilar tion. 2003 Sep 15;76(5):832–837.
plate should be included en bloc with the common bile 5. Sano K, Makuuchi M, Miki K, et al. Evaluation of hepatic venous
duct30 (see Fig. 54-10), providing multiple orifices for congestion: proposed indication criteria for hepatic vein recon-
anastomosis. struction. Ann Surg. 2002 Aug;236(2):241–247.
6. Yi NJ, Suh KS, Lee HW, et al. An artificial vascular graft is a useful
interpositional material for drainage of the right anterior section in
living donor liver transplantation. Liver Transpl. 2007 Aug;13(8):
SUMMARY 1159–1167.
7. Sugawara Y, Makuuchi M, Sano K, et al. Vein reconstruction in
modified right liver graft for living donor liver transplantation. Ann
Living donor liver transplantation for adults is now Surg. 2003 Feb;237(2):180–185.
decreasing in the Western world in consideration of 8. Kishi Y, Sugawara Y, Matsui Y, et al. Alternatives to the double
donor safety. It is an indispensable option, however, for vena cava method in partial liver transplantation. Liver Transpl.
end-stage liver disease patients in the Eastern world, 2005 Jan;11(1):101–103.
where the source of deceased donors is inadequate. 9. Sugawara Y, Makuuchi M, Takayama T. Left liver plus caudate
lobe graft with complete revascularization. Surgery. 2002
The left liver graft is optimized for both flow and Nov;132(5):904–905. author reply 5–6.
outflow, although the possibility of a separated arterial 10. Sugawara Y, Makuuchi M, Kaneko J, et al. New venoplasty tech-
supply remains problematic. The left liver graft, how- nique for the left liver plus caudate lobe in living donor liver trans-
ever, is sometimes too small to satisfy the metabolic plantation. Liver Transpl. 2002 Jan;8(1):76–77.
11. Hashimoto T, Sugawara Y, Tamura S, et al. One orifice vein
demands of patients with advanced liver cirrhosis and reconstruction in left liver plus caudate lobe grafts. Transplantation.
low Model for End-Stage Liver Disease score (i.e., 2007 Jan 27;83(2):225–227.
<15).31 The right liver graft, on the other hand, pro- 12. Hwang S, Lee SG, Ahn CS, et al. Technique and outcome of autol-
vides enough volume to the recipient. However, par- ogous portal Y-graft interposition for anomalous right portal veins
ticularly the management of MHV is complicated, and in living donor liver transplantation. Liver Transpl. 2009
Apr;15(4):427–434.
the drainage area should not be included as functioning 13. Sugawara Y, Makuuchi M, Tamura S, et al. Portal vein reconstruc-
parenchyma when reconstruction of the tributaries is tion in adult living donor liver transplantation using cryopreserved
not performed. vein grafts. Liver Transpl. 2006 Aug;12(8):1233–1236.
718 PART VI Split and Living Donor Transplantation

14. Harihara Y, Makuuchi M, Kawarasaki H, et al. Portal venoplasty 23. Okazaki M, Asato H, Takushima A, et al. Hepatic artery recon-
for recipients in living-related liver transplantation. Transplanta- struction with double-needle microsuture in living-donor liver
tion. 1999 Oct 27;68(8):1199–1200. transplantation. Liver Transpl. 2006 Jan;12(1):46–50.
15. Tanaka K, Uemoto S, Tokunaga Y, et al. Surgical techniques and 24. Kishi Y, Sugawara Y, Kaneko J, et al. Hepatic arterial anatomy for
innovations in living related liver transplantation. Ann Surg. 1993 right liver procurement from living donors. Liver Transpl. 2004
Jan;217(1):82–91. Jan;10(1):129–133.
16. Mitchell A, John PR, Mayer DA, et al. Improved technique of portal 25. Ikegami T, Kawasaki S, Matsunami H, et al. Should all hepatic
vein reconstruction in pediatric liver transplant recipients with por- arterial branches be reconstructed in living-related liver transplan-
tal vein hypoplasia. Transplantation. 2002 Apr 27;73(8):1244–1247. tation? Surgery. 1996 Apr;119(4):431–436.
17. Marwan IK, Fawzy AT, Egawa H, et al. Innovative techniques for 26. Kubota K, Makuuchi M, Takayama T, et al. Simple test on the
and results of portal vein reconstruction in living-related liver back table for justifying single hepatic-arterial reconstruction in
transplantation. Surgery. 1999 Mar;125(3):265–270. living related liver transplantation. Transplantation. 2000 Aug
18. Kokudo N, Sugawara Y, Kaneko J, et al. Reconstruction of isolated 27;70(4):696–697.
caudate portal vein in left liver graft. Liver Transpl. 2004 27. Sugawara Y, Tamura S, Kaneko J, et al. Single artery reconstruction
Sep;10(9):1163–1165. in left liver transplantation. Surgery. 2011 Jun;149(6):841–845.
19. Yerdel MA, Gunson B, Mirza D, et al. Portal vein thrombosis in adults 28. Akamatsu N, Sugawara Y, Hashimoto D. Biliary reconstruction, its
undergoing liver transplantation: risk factors, screening, management, complications and management of biliary complications after adult
and outcome. Transplantation. 2000 May 15;69(9):1873–1881. liver transplantation: a systematic review of the incidence, risk fac-
20. Inoue Y, Sugawara Y, Tamura S, et al. Intraoperative ultrasound tors and outcome. Transpl Int. 2011 Apr;24(4):379–392.
guided portal venous thrombectomy in living donor liver trans- 29. Dulundu E, Sugawara Y, Sano K, et al. Duct-to-duct biliary recon-
plantation recipient surgery. Transpl Int. 2008 May;21(5):428–433. struction in adult living-donor liver transplantation. Transplanta-
21. Marubashi S, Dono K, Nagano H, et al. Living-donor liver transplan- tion. 2004 Aug 27;78(4):574–579.
tation with renoportal anastomosis for patients with large spontaneous 30. Sugawara Y, Makuuchi M, Sano K, et al. Duct-to-duct biliary
splenorenal shunts. Transplantation. 2005 Dec 27;80(12):1671–1675. reconstruction in living-related liver transplantation. Transplanta-
22. Mori K, Nagata I, Yamagata S, et al. The introduction of microvas- tion. 2002 Apr 27;73(8):1348–1350.
cular surgery to hepatic artery reconstruction in living-donor liver 31. Sugawara Y, Makuuchi M, Kaneko J, et al. MELD score for selec-
transplantation–its surgical advantages compared with conven- tion of patients to receive a left liver graft. Transplantation. 2003
tional procedures. Transplantation. 1992 Aug;54(2):263–268. Feb 27;75(4):573–574.
 CHAPTER 55

Small-for-Size Syndrome
Yuji Soejima • Ken Shirabe • Tomoharu Yoshizumi • Hideaki Uchiyama •
Toru Ikegami • Akinobu Taketomi • Yoshihiko Maehara

CHAPTER OUTLINE

DEFINITION Graft Selection

Portal Inflow Modulation
CLINICAL MANIFESTATIONS
Patient Status
PATHOPHYSIOLOGY Outflow Modulation
EXPERIMENTAL STUDIES TREATMENT
STRATEGIES TO PREVENT SMALL-FOR-SIZE CONCLUSION
SYNDROME

Split-liver transplantation and living donor liver trans- The concept of SFSG was first published in 1987.19
plantation (LDLT) in adult patients are now recognized Emond et al20 first described the clinical symptoms attrib-
as established treatments for end-stage liver disease. utable to SFSG after LDLT in their landmark paper in
During the early days of adult LDLT, left lobe (LL) 1996. Subsequently the term SFSS came into use in the
LDLT was the only option, although LL grafts consti- late 1990s when cadaveric split and LDLT in adults using
tute only 30% to 50% of the whole-liver volume (Fig. partial grafts became a popular procedure. Ben-Haim
55-1).1,2 Subsequently the effect of a relatively “small” et al21 first used the term SFSS in their preliminary report
partial graft (as compared with whole-liver graft) on on adult LDLT outcomes. With accumulated experience
recipient outcome has become recognized as the most of adult LDLT, SFSS is widely recognized as a distinct
important problem to overcome.3,4 Therefore larger entity in the field of liver transplantation, especially in
grafts such as right lobe (RL) grafts with or without the adult LDLT. However, there is no consensus on the defi-
middle hepatic vein have been exploited,5-9 and their use nition of SFSS, and an accurate picture (incidence, prog-
is now prevalent worldwide. As such, LL LDLT has nosis, risk factors, etc.) of SFSS remains largely
been largely abandoned in the adult population. How- undetermined. Therefore it is of paramount importance
ever, many RL living donor deaths have occurred,10-15 to define SFSS by objective values to discuss the issue
and the legitimate continuation of this modality is now prospectively in the same arena.
questioned. In this context a return to the original proce- Only two publications have attempted to define SFSS
dure (LL LDLT) has been reevaluated and has received by arbitrarily setting a cutoff value. Soejima et al22 ini-
much recent attention.16-18 Nonetheless, an accurate tially defined SFSS by the presence of cholestasis (total
understanding of the small-for-size graft (SFSG) prob- bilirubin >5 mg/dL, later revised to >10 mg/dL)23 on
lem is important for the continued use, and improvement postoperative day (POD) 7 and intractable ascites (daily
of the results, of LDLT. In this chapter we outline the production of ascites of > 1 L on POD 14 or >500 mL on
current clinical and experimental picture of small-for- POD 28) without other specific causes.
size syndrome (SFSS) based on our current experience of Dahm et al24 proposed a definition of SFSS that
SFSS after LDLT. divided SFSS into two categories: small-for-size dys-
function and small-for-size nonfunction. Small-for-size
dysfunction was defined by the dysfunction of a "small"
DEFINITION partial liver graft (graft–to–recipient weight ratio
[GRWR] <0.8%) during the first postoperative week
SFSS refers to the clinical syndrome caused by a partial after the exclusion of other causes, with graft dysfunc-
liver graft that is too small to sustain metabolic demand in tion being defined as the presence of two of the follow-
the recipient. However, SFSS is often difficult to differ- ing on 3 consecutive days: bilirubin level of greater than
entiate from other complications such as acute rejection, 100 μmol/L, international normalized ratio of more
outflow block, and sepsis. than 2, encephalopathy grade 3 or 4. Small-for-size

719
720 PART VI Split and Living Donor Transplantation

nonfunction was defined as a failure of a small partial SFSS is generally characterized by a combination of
graft (GRWR < 0.8%) during the first postoperative prolonged functional cholestasis, intractable ascites,
week. and delayed recovery of both prothrombin time and
Ikegami et al25 proposed a new phenomenon called encephalopathy. Of note, most of the cases developing
primary graft dysfunction, which may be specific in LDLT SFSS show a completely different picture from those
settings and is probably attributable to SFSG. with primary nonfunction after deceased donor liver
However, none of these criteria have been prospec- transplantation.25 Our cumulative experience of adult
tively applied to subsequent studies, and critical evalua- LDLT using LL grafts suggests that hyperbilirubine-
tions have therefore not yet been performed. mia accompanying intractable ascites (>1 L/day) is
relatively common and the most typical manifestation
of SFSS.22,23 Figure 55-2 depicts the typical clinical
CLINICAL MANIFESTATIONS course of a patient with SFSS. The transaminase levels
usually do not increase chronologically, whereas the
There is a certain consensus regarding the clinical man- bilirubin levels and daily ascites output begin to
ifestations of SFSS. As first proposed by Emond et al,20 increase 3 to 7 days after transplant and persist for 1 to
2 months. Of note, the serum ammonia levels and pro-
thrombin time are relatively preserved. Development
of grade 3 or 4 encephalopathy is a very rare event in
patients with SFSS and should be judged as a sign of
graft failure. Other clinical manifestations include sep-
sis, which occurs most often approximately a week
after LDLT, gastrointestinal bleeding, decreased
bowel movement, and prerenal renal failure because of
massive ascites (Table 55-1). These manifestations are
closely interrelated and may all be a consequence of
persistent portal hypertension. The prognosis for
patients with SFSS was reported to be inferior to those
without SFSS22; however, recent studies with portal
flow modulation demonstrated comparable results with
or without SFSS. Nonetheless, it is important to
understand that a considerable number of patients with
SFSS may recover following graft regeneration, pro-
vided that the proper conservative treatments are
FIGURE 55-1 n A small-for-size left lobe graft in an adult patient. undertaken.25

Steroid

MMF Ascites AST

FK506 (L) (IU/L)
25 PE PE PE PE
Bilirubin 7.0 600
AST
Ascites 6.0 500
20
Total bilirubin (mg/dL)

5.0
400
15
4.0
300
10 3.0
200
2.0
5
1.0 100

0 0 0
0 10 20 30 40 50 POD
FIGURE 55-2 n Clinical course of small-for-size syndrome. The recipient was a 37-year-old female patient with primary biliary cirrhosis.
The graft was a 320-g (graft volume–to–standard liver volume ratio, 31.6%; graft weight–to–body weight ratio, 0.77%) left lobe plus
caudate lobe graft from her 47-year-old sister. AST, Aspartate aminotransferase; MMF, mycophenolate mofetil; PE, plasma exchange;
POD, postoperative day.
 55 Small-for-Size Syndrome 721

PATHOPHYSIOLOGY features of SFSS included (1) portal hyperperfusion

resulting in portal vein and periportal sinusoidal endo-
The mechanism of SFSS remains unknown but is proba- thelial denudation and focal hemorrhage into the portal
bly multifactorial, including both donor (graft)- and tract connective tissue that dissected into the periportal
recipient-related factors (Table 55-2). hepatic parenchyma when severe (Fig. 55-4, A) and (2)
Accumulated experience of hepatic resection has poor hepatic arterial flow and vasospasm, which in
shown that the minimum remnant liver volume is 25% to severe cases led to functional dearterialization, ischemic
30% of the whole liver.26-28 However, when transplanted cholangitis, and parenchymal infarcts. They referred to
under conditions of portal hypertension, small grafts may late sequelae in grafts surviving the initial events,
to be exposed to excessive portal perfusion and portal including small portal vein branch thrombosis with
venous pressure (PVP) compared with grafts under nor- occasional luminal obliteration or recanalization, nodu-
mal PVP. Experimental data29-31 suggest that hyperper- lar regenerative hyperplasia, and biliary strictures. Our
fusion of the liver is detrimental, and improved results experience revealed that centrilobular hepatocyte bal-
have been observed with portal decompression of small looning and cholestasis (Fig. 55-4, B) were the most
grafts. In addition, gut-derived endotoxins and substrates, prominent and characteristic features of SFSS. Further-
including fatty acids, may further deteriorate small grafts more, ductular reaction was also a common finding,
after reperfusion.32 Portal hyperperfusion, venous con- whereas necrosis, steatosis, and portal infiltration were
gestion, and arterial hypoperfusion, as well as simple uncommon.
insufficiency of liver mass (graft size), are all suggested as
contributory mechanisms of SFSS (Fig. 55-3). Table
55-2 lists the possible causative factors for SFSS. EXPERIMENTAL STUDIES
The definite pathological features of SFSS remain
undetermined owing to a lack of experience of “pure Most knowledge about SFSS has been derived from clini-
SFSS.” Nonetheless, a few comprehensive studies have cal studies. However, recent animal studies have provided
focused on the pathophysiological changes specific to valuable insights into the pathogenesis of SFSS. Tran-
SFSS. Emond et al20 investigated the pathological sient portal hypertension during the early phase after
changes occurring when a “small graft” was used. They liver transplantation and subsequent upregulation of
revealed a diffuse ischemic pattern with centrilobular vasoconstriction genes and a severe inflammatory
ballooning on day 7, which progressed to cholestasis in response are considered to be the primary mechanism in
subsequent biopsy specimens. Demetris et al33 compre- SFSG failure.
hensively studied the pathological changes in SFSS. Ku et al34 first suggested using a canine partial liver
They analyzed serial biopsy specimens from five patients transplantation model with portocaval shunt in SFSG,
with possible SFSS and suggested that the pathological because portal hypertension was a risk factor predispos-
ing to graft failure, most likely by increasing microvascu-
lar injury after recirculation.
TABLE 55-1 C
 linical Manifestations of Liang et al35 investigated the intragraft gene expres-
Small-for-Size Syndrome sion pattern in SFSG using rat partial liver graft models.
They found that SFSG injury was related to early overex-
Hyperbilirubinemia (functional cholestasis) pression of early graft response (Egr)-1. It was also asso-
Intractable ascites ciated with upregulation of endothelin-1 (ET-1) and
Paralytic ileus overexpression of nitric oxide synthase. Furthermore, the
Delayed recovery of encephalopathy (rare) deterioration of intracellular homeostasis was reflected
Prolonged INR by downregulation of heat shock proteins such as heme
Sepsis oxygenase-1 (HO-1) and A20.
Prerenal renal failure Man et al36 investigated the gene expression profiles in
Pulmonary complications SFSG using carrier DNA microarrays to compare 1081
Gastrointestinal bleeding intragraft gene expression profiles among SFSGs (<30%
INR, International normalized ratio. of recipient liver weight) and whole grafts (control group)
1, 3, and 24 hours after reperfusion in a rat liver trans-
plantation model. The intragraft expression of messenger
TABLE 55-2 Causes of Small-for-Size Syndrome RNA (mRNA) for ET-1 and endothelin-1 receptor A was
upregulated during the first 24 hours after reperfusion
Donor (Graft)-Related Factors and accompanied by downregulation of HO-1. The
Insufficient graft volume intragraft mRNA and plasma levels of inflammatory
Old donor (>50 yr) cytokines (interleukin [IL]-6, IL-15, tumor necrosis
Fatty liver factor-α) were also overexpressed during the first 24
Recipient-Related Factors
hours after reperfusion. These results were confirmed in
Poor general conditions (MELD > 30)
humans.37 In summary, transient portal hypertension
Excessive portal flow and pressure
after reperfusion, subsequent ET-1 overexpression and
Insufficient outflow
plasma nitric oxide level reduction, together with down-
regulation of HO-1 and heat shock protein 70, may
MELD, Model for End-Stage Liver Disease. account for SFSG injury.
722 PART VI Split and Living Donor Transplantation

Small-for-size grafts

Excessive portal flow

FK 409
Shear stress related to Acute phase inflammatory response
hemodynamic force Egr-1
Transient portal hypertension iNOS, MIP-2, TNF-
at the early phase after
reperfusion Sinusoid constriction
ET-1, ETA

Sinusoidal mechanical injury

Loss of integrity of sinusoids

Intracellular homeostasis
Antiapoptosis
Antiinflammation
HO-1, HSP70, A20
IL-10, IP-10, CXCR-2

Hepatic microcirculatory disturbance

Small-for-size syndrome
FIGURE 55-3 n Proposed mechanism of small-for-size graft syndrome. CXCR-2, CXC chemokine receptor 2; Egr-1, early graft response-1;
ET-1, endothelin-1; ETA, endothelin 1 receptor A; HO-1, heme oxygenase-1; HSP70, heat shock protein 70; IL-10, interleukin-10; iNOS,
inducible NO synthetase; IP-10, INF-[γ]-induced protein 10; MIP-2, macrophage inflammatory protein 2; TNF-α, tumor necrosis factor-α.

A B
FIGURE 55-4 n Typical histopathological findings in grafts with small-for-size graft syndrome. A, Periportal hemorrhage (arrow).
B, Centrilobular hepatocyte ballooning and cholestasis (arrows).
 55 Small-for-Size Syndrome 723

Furthermore, Cheng et al38 investigated the signifi- LDLT were comparable with those of RL LDLT,
cance of hepatic stellate cell activation in small-for-size although SFSS occurred more often (19.5% versus
fatty liver graft injury. A rat orthotopic liver transplanta- 7.1%) in LL LDLT.42 Therefore, although RL graft is
tion model with a fatty liver (40% of fatty change) graft still the mainstay in adult LDLT worldwide, many cen-
and cirrhotic recipient combination was used. Hepatic ters, particularly in Japan, have reconsidered LL grafts
stellate cell activation was predominantly present in as the first choice for adult LDLT because of donor
small-for-size fatty grafts during the first 2 weeks after safety.
transplantation and was strongly correlated with progres- Donor age has been shown to be associated with
sive hepatic sinusoidal damage and significant upregula- SFSS.46-48 Ikegami et al47 categorized LDLT recipients
tion of the intragraft Wnt4 signaling pathway. as O/LL (left lobe, donor age > 50 years, n = 20), Y/LL
(left lobe, donor age ≤ 50 years, n = 140), O/RL (right
lobe, donor age > 50 years, n = 12), and Y/RL (right lobe,
STRATEGIES TO PREVENT donor age ≤ 50 years, n = 61). The incidence of SFSS was
significantly greater for the O/LL group compared with
SMALL-FOR-SIZE SYNDROME the Y/LL group (60.0% versus 16.3%, P < .01), whereas
Graft Selection the O/RL group was comparable with the Y/RL group.
Kiuchi et al49 revealed a negative impact of donor age
Generally speaking, SFSGs are defined as grafts with (>50 years) in GRWR < 0.8% compared with larger
graft volume to standard liver volume (GV/SLV) ratio grafts, whereas younger grafts (<50 years) showed com-
of less than 40% or GRWR of less than 0.8%.39-41 One parable results. These data suggest that marginal SFSG
may intuitively consider the size of the graft itself to be from older donors (age > 50 years) should not be used in
the most important factor for SFSS. One study4 demon- LDLT.
strated that the results of LDLT using SFSG were sig- The grade of graft steatosis may be associated with
nificantly inferior to those using larger grafts. SFSS,50 although direct evidence is lacking to support
Consequently RL rather than LL grafts have been pre- this concept in human studies. However, it is widely
dominantly used for adult patients,5-10 while accepting accepted that graft steatosis of more than 30% is a con-
the significantly higher risks for donor morbidity and traindication for LDLT, particularly for marginal SFSG.
mortality. In fact, SFSS occurred more often in LL A short-term intensive diet program consisting of caloric
LDLT than in RL LDLT.42 However, many publica- restriction, exercise, and bezafibrate was shown to be
tions have reported that graft size per se is not the sole effective for LDLT donor candidates with 10% to 50%
determinant for developing SFSS or worse outcome.43-45 steatosis.51
In fact, the mean GRWR in patients who developed Dual grafts using grafts from two independent donors
SFSS was 0.74%, which was comparable to those with- (Fig. 55-5)52-54 and auxiliary transplantation55 that pre-
out SFSS (0.78%; P, not significant) in our series.42 serves a part of the recipient native liver are extreme mea-
Moreover, it was shown that SFSS did not necessarily sures that have been applied sporadically to overcome the
lead to graft loss. In our cohort only 3 patients out of SFSG problem. Both of these modalities have been
357 LDLT recipients lost their grafts directly as a result reported to be effective but are limited owing to the ethi-
of SFSS. A recent study showed that the outcomes of LL cal problem of putting two donors at risk for one

A B
FIGURE 55-5 n A, Schema of living donor liver transplantation using dual grafts (right and left lobe grafts). B, Computed tomography
scan 6 months after transplant.
724 PART VI Split and Living Donor Transplantation

A reported two successful cases using end-to-side HPCS for

RL grafts with GRWR of 0.55% and 0.70%. Yamada
et al57 selectively used HPCS for LL grafts with GRWR
between 0.6% and 0.8% and showed 100% patient sur-
vival. Botha et al59 also reported excellent results in
patients with small LL grafts (the median GRWR was
0.67%) with HPCS: the 1-year patient and graft survival
were 87% and 81%, respectively. All of these studies con-
cluded that a small LL graft with modulation of PVF by
HPCS may prevent SFSS, while at the same time provid-
ing adequate liver volume. However, the PVF stealing
B-1 B-2 phenomenon from a graft to the systemic circulation is of
concern. We used HPCS in only two patients, one with a
very SFSG (GV/SLV ratio of 24%) whose HPCS was
closed 4 days after LDLT because of the portal steal phe-
nomenon.68 In contrast, Yamada et al57 reported that 55%
of shunts remained in patients at 6 months, and only 20%
were present at 1 year. Furthermore, Oura et al69 observed
late graft atrophy and dysfunction after introduction of
HPCS for SFSS, which forced them to close the shunt at
11 months post-LDLT. This experience indicates that
HPCS may overcome SFSS in the early period of LDLT
C-1 C-2 and cause graft atrophy and graft dysfunction in the late
period of LDLT. Therefore the optimum time at which
to close the HPCS remains unknown.
Most of the patients undergoing liver transplantation
succumb to severe hypersplenism. Therefore splenec-
tomy is the most effective modality to decrease the PVF
and PVP. As shown in Figure 55-7, the PVP is decreased
by 5 mm Hg, while the PVF is decreased by 500 mL/min,
after splenectomy. In our current practice, after perform-
ing a standardized bloodless splenectomy using a vessel-
FIGURE 55-6 n Schema of technical variations of the portal flow sealing system (LigaSure Atlas) and stapling device
modulation. A, Mesocaval shunt in a left lobe graft. B, Hemipor- without ties,70 splenectomy is the preferred modality for
tocaval shunt (HPCS) in a left lobe graft using the right portal
vein (B-1) and using the venous graft extension such as the
preventing SFSS. In the last 50 LL cases, splenectomy
greater saphenous vein (B-2). C, HPCS in a right lobe graft using was performed for 35 patients (70%), whereas 7 patients
the left portal vein (C-1) and the venous graft extension (C-2). (14%) had already undergone splenectomy before
LDLT. We have observed only 3 patients (6%) with
SFSS in the last 50 cases; 2 of the 3 patients recovered
recipient, as well as the problems of transmissible diseases from the complication, whereas the other required
or malignancies, including carcinogenic diseases. retransplantation. Therefore we believe concomitant
splenectomy is very useful for reducing PVF, as well as
for early recovery and aggravation of platelet count,
Portal Inflow Modulation thereby improving the overall results.
Excessive portal perfusion and pressure to small grafts PVP has also been shown to be an important factor for
has been suggested to be one of the most important fac- graft survival. Ito et al71 showed that recipients with
tors for SFSS by many experimental studies. However, SFSG (GRWR < 0.8%) displayed significantly higher
no reliable evidence from human studies has revealed that PVP than recipients with larger grafts. They showed that
excessive portal venous flow (PVF) is associated with PVP above 20 mm Hg in patients early in the first week
SFSS. Nonetheless, many authors have suggested that was associated with worse outcome (84.5% versus 38.5%
PVF modulation produces beneficial effects for SFSG. at 6 months; P < .01). Furthermore, Ogura et al72 demon-
Consequently certain kinds of portal modulation, such as strated that PVP of less than 15 mm Hg is key for suc-
mesocaval shunt (Fig. 55-6, A),55 hemiportocaval shunt cessful adult LDLT with smaller grafts. Patients with
(HPCS; Fig. 55-6, B and C),56-59 splenic artery ligation PVP of less than 15 mm Hg demonstrated a better 2-year
(SAL),60-62 splenectomy,63,64 and preoperative splenic survival (n = 86, 93.0%) than patients with PVP of more
artery embolization (SAE),65,66 are currently believed to than 15 mm Hg (n = 43, 66.3%). These authors recom-
be useful for avoiding SFSS and SFSG. mended splenectomy for patients with PVP of more than
Boillot et al67 reported a successful case with a small 15 mm Hg and moreover, HPCS for patients with PVP
split graft by creating a mesocaval shunt that converted all of more than 15 mm Hg after splenectomy.
of the mesenteric venous flow to the systemic circulation. A few reports claim that SAL has beneficial effects on
Troisi et al61 reported that an intentional decrease in PVF SFSS.62,73 SAL is known to reduce the PVP by 5 mm Hg
by HPCS improved the survival of patients with a GRWR while reducing the portal flow by 52% on average.74 How-
of less than 0.8% who received LL grafts. Takada et al58 ever, this effect is not uniformly predictable. Furthermore,
 55 Small-for-Size Syndrome 725

Portal pressure Portal vein flow

(mm Hg) Sp () (n=69) (mL/min) Sp () (n=46)

Sp () (n=44) Sp () (n=13)
23 3000

21
2500

19
2000
17

1500
15

13 1000
Before After Before After
A splenectomy splenectomy B splenectomy splenectomy
FIGURE 55-7 n Effect of splenectomy and splenic artery ligation on portal flow and pressure.

the effect of an increase in platelet count following liver tributaries, including V5, V8, and the right inferior hepatic
transplant is significantly low compared with splenectomy. veins. Including the middle hepatic vein with the RL graft
Therefore prophylactic use of this technique for SFSG is (the extended RL graft) preserves maximum drainage of
limited, and we currently prefer splenectomy. the middle hepatic vein tributaries and is a viable option
Some authors reported the usefulness of SAE as a res- provided that the donor remnant liver volume is sufficient.
cue treatment for posttransplant SFSS. Kasahara et al55
concluded that preoperative portal decompression by
SAE was efficacious for reducing blood loss during opera- TREATMENT
tion and shortened the operating time. SAE thereby contrib-
uted to a favorable prognosis without serious complications There is no definitive treatment for SFSS. The basic strat-
related to the procedure itself, such as sepsis and portal egy is symptomatic or a wait-and-see policy until the graft
vein thrombosis. These authors reported that the effect of regenerates. Massive ascites usually persists for 1 to 2
SAE on the reduction of PVP is equivalent to that of SAL. months and decreases thereafter, for which aggressive
Furthermore, hepatic arterial flow was significantly higher fluid and albumin resuscitation is mandatory to prevent
during the postoperative phase in the SAE group, reflect- renal failure. Hyperbilirubinemia without coagulopathy
ing arterial flow shift from the spleen to the hepatic artery usually resolves within a month. In severe cases, serial
or a hepatic arterial buffer response. plasma exchange or bilirubin absorption therapy may be
In summary, various kinds of portal flow modulations beneficial for decreasing the metabolic burden to the graft.
have been successfully undertaken by surgeons. None- Early enteral feeding (as early as POD 1-2) using a feeding
theless, intraoperative monitoring of the PVP and PVF tube is strongly encouraged to decrease the incidence of
are essential to systematically avoiding SFSS. sepsis.75 Pleural effusion (often in the right side) should be
aggressively drained while paying attention to bleeding.
Signs of graft failure include early renal failure, pro-
Patient Status gressive hyperbilirubinemia (more than 20 mg/dL) with
Recipient status is surrogated with the Model for End- worsening coagulopathy, severe hepatic encephalopathy,
Stage Liver Disease (MELD) score and the Child-Turcotte- and development of sepsis. Timely listing for retrans-
Pugh score. Ben-Haim et al21 showed that small grafts plantation should be indicated for patients with these
produced an inferior outcome when they were trans- symptoms. Sepsis is a common manifestation that often
planted into Child-Turcotte-Pugh class C patients, but leads to the development of severe circulatory failure and
not Child-Turcotte-Pugh class A-B patients. In our subsequent graft and kidney failure.
recent study, in patients with MELD score of more than No medical treatments have proved to be effective for
30, LL grafts resulted in worse 1-year graft survival rates the prevention or treatment of SFSS. We reported the
than RL grafts.42 beneficial effect of the intraportal infusion therapy con-
sisting of prostaglandin E1, nafamostat mesylate, and ste-
roids.76 However, this modality was later abandoned
Outflow Modulation owing to the potential risk for hepatic infarction.
Obtaining the maximum outflow for a partial graft is the Experimentally, FK 409, a potent nitric oxide releaser,
most important part of the procedure in LDLT. In RL has been demonstrated to ameliorate SFSG injury by
LDLT adequate drainage of the anterior segment is attenuation of portal hypertension and downregulation
believed to be vital,74 particularly for SFSG. Therefore of the Egr-1 pathway.77 However, this drug is not yet in
every effort should be made to reconstruct all of the venous clinical use.
726 PART VI Split and Living Donor Transplantation

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728 PART VI Split and Living Donor Transplantation

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 CHAPTER 56

Minimally Invasive Living

Donor Hepatectomy
Talia B. Baker • Juan Carlos Caicedo

CHAPTER OUTLINE

LAPAROSCOPIC LEFT LATERAL SEGMENTECTOMY ROBOTICALLY ASSISTED DONOR HEPATECTOMY

LAPAROSCOPICALLY ASSISTED RIGHT HEPATIC Upper Midline ("Minilaparotomy Approach")
LOBECTOMY FOR DONATION SUMMARY AND CONCLUSION
Technique for LADRH

Although over 6000 people receive a liver transplant in Laparoscopic surgery has been used for an increasing
the United States each year, more than 16,000 patients number of surgical procedures with the aim of reducing
are listed. The growing gap between the demand and postoperative pain, recovery time, and surgical morbid-
supply for liver grafts is one of the biggest challenges in ity. Specifically, the more recent development of laparo-
liver transplantation. Despite enormous effort to increase scopic liver resection has shown the potential for a
the pool of deceased donor organs, more than 2000 reduction in morbidity as compared to standard open
patients die on the waiting list each year. An absolute techniques.3-6 An innovative strategy to increase the
imperative to the liver transplant community therefore is number of liver grafts by making living liver donation
to find and improve methods to increase the number of safer and more appealing to potential donors therefore
potential liver grafts to meet the ever-growing demand. should be promoted.
Living donor liver transplantation (LDLT) is an alter- Considering the magnitude and complexity of any
native option to liver transplantation from deceased donor hepatic surgery, the traditional approach has been
donors. Faced with the organ shortages, LDLT can pro- an open donor surgery. For instance, the accepted approach
vide additional organs from a potentially unlimited source for open donor right hepatectomy has been a bilateral sub-
of healthy donors. Living donors provide excellent qual- costal incision with midline extension (Mercedes incision).7
ity grafts with similar or even better short-term graft A subsequent modification to decrease the length of the
function and long-term survival, especially in children, as incision was a right subcostal incision with midline exten-
compared with whole and split-liver transplant.1,2 Cur- sion (J-shape incision) avoiding the left subcostal exten-
rently, however, only about 4% of the liver recipients in sion.8 The prospect of this large incisional scar may make
the United States receive a living donor transplant. some live liver donors reluctant to undergo the surgery
Kidney transplantation shares the same problem of because of concerns about self-image. The open approach
organ shortage as liver transplantation. To reduce mor- is associated with significant wound complications, surgical
bidity and the invasiveness of living donor nephrectomy, pain, surgical time, recovery time, and length of stay, and it
the transplant community developed minimally invasive affects the quality of life of living donors.9-11 Although
approaches, including pure laparoscopic donor nephrec- open donor right hepatectomy is accepted, well described,12
tomies, laparoscopic hand-assisted donor nephrectomies, and characterized as a relatively safe procedure, it is associ-
and robotic laparoscopic donor nephrectomies. Laparo- ated with a complication rate of up to 40%.13
scopic living donor nephrectomy has become the standard In response to these factors associated with open donor
of care for kidney transplantation. This evolution in tech- hepatectomies, the transplant community has therefore
nique has significantly increased the appeal of donation reasonably committed to developing minimally invasive
and subsequent number of living kidney donors. approaches to minimize the morbidity burden in living
The living donor liver community is certainly primed liver donors and to increase the appeal of the procedure.
and ready for such a strategy. Minimally invasive tech- Minimally invasive techniques benefit patients in need of
niques, such as laparoscopic surgery, hand-assisted lapa- liver resection in several ways when compared to open
roscopic surgery, and robotic surgery, have evolved over resection. First, they reduce both long-term and short-
the past 2 decades. These minimally invasive procedures term morbidity, and second, they improve the cosmetic
have many advantages over conventional open surgery, result of the surgical intervention. Liver surgery typically
such as rapid postoperative recovery, fewer pulmonary requires subcostal incision(s) most often combined with a
complications, and an excellent cosmetic outcome. midline extension. The subcostal incision is necessary for

729
730 PART VI Split and Living Donor Transplantation

most liver resections, both lobar and segmental, espe- falciform and left triangular ligaments, and vascular
cially of the right lobe. Short-term complications of sub- structures were dissected and encircled. The liver tran-
costal incisions include pain with increased need for section was performed with a harmonic scalpel (Ultra-
narcotics and splinting with subsequent atelectasis and cision; Ethicon, Somerville, New Jersey) and an ultrasonic
other pulmonary complications, all contributing to dissector (Dissectron; Satelec, Meriignac Cedex, France)
extended hospitalizations. Long-term sequelae include without vascular clamping. The bleeding was controlled
numbness and paresthesia in the inferior aspect of the with bipolar electrocoagulation and clips. A 10-cm supra-
anterior abdominal wall secondary to transection of the pubic incision was made to introduce a 15-mm trocar to
superior branches of the inferior epigastric neurovascular introduce a large specimen bag to retrieve the liver.
bundle, resulting in rectus abdominis weakness and inci- The advantages of a laparoscopic approach to left lat-
sional hernias, as well as cosmetic considerations, includ- eral segmentectomy are clearly in the lack of upper mid-
ing the perception of disfigurements.1,2,14-16 line incision and the rapid recovery to normal function.
The limiting step to wider application of LDLT will Unfortunately, only surgeons very well versed in the art
always be donor risk. Any effort to minimize the morbidity of advanced laparoscopic techniques can safely perform
associated with living donor hepatectomy is therefore this operation, limiting its applicability.
always worth considering. Some of the innovations to
minimize or improve open donor hepatectomies to make
them less invasive include laparoscopic left lateral segmen- LAPAROSCOPICALLY ASSISTED RIGHT
tectomy,1,2 laparoscopic hand-assisted right hepatec- HEPATIC LOBECTOMY FOR DONATION
tomy,10,17 laparoscopic hand-assisted right hepatectomy
using a midline incision “hybrid method,”18-20 laparo- In response to the continued significant interest in laparo-
scopic hand-assisted right hepatectomy using a transverse scopic liver surgery as it may apply to living donation, but
or subcostal incision,10,21 single-port laparoscopic-assisted also with an eye toward developing a procedure that may
right hepatectomy using a right subcostal incision,21right be more widely applicable to all donor surgeons, we first
hepatectomy through upper midline laparotomy,8,22 right performed a laparoscopically assisted donor right hepa-
hepatectomy through an upper midline minilaparotomy tectomy (LADRH) at Northwestern University in 2006.18
with or without laparoscopic assistance,23 and robot- In our first and other publications,3,6,18-20 we and others
assisted right hepatectomy.24 have demonstrated the safety and efficacy of laparoscopi-
In this chapter we will describe the advantages and dis- cally assisted hepatectomy for the resection of hepatic
advantages of multiple variations of minimally invasive tumors with reduced blood loss, shorter operative times,
donor hepatectomies (Table 56-1). Each must be consid- and decreased postoperative hospital stays, and have also
ered for its potential efficacy, feasibility, and ability to demonstrated its applicability to living donation.18-20
provide an applicable safe procedure that will be appeal- The approach typically uses the “hybrid method,” a
ing and safe for any potential donor. laparoscopically assisted method for liver resection. The
technique represents a hybrid between the minimally
invasive and open techniques. The hybrid technique
LAPAROSCOPIC LEFT LATERAL abrogates the need for standard subcostal incisions in
SEGMENTECTOMY most liver resections and therefore is consistent with the
principles of minimally invasive surgery. The incisions
Laparoscopic approaches to living donation were initially required are identical to those used for a hand-assisted
described for removing a left lateral segment graft for laparoscopic procedure. This surgical approach can be
transplantation into a child.1,2 Many reports had already performed by surgeons with minimal laparoscopic skills,
demonstrated the feasibility of laparoscopic hepatic lobec- does not require laparoscopic techniques and devices for
tomy but not in the setting of living donor procedures. A either dissection of the hepatic hilum or transection of
French group first performed the surgery laparoscopically, the liver parenchyma, and thus allows surgeons to adhere
and the graft was removed through a suprapubic Pfannen- to more familiar, safer open techniques.
stiel incision. Donor surgery lasted 6 to 7 hours, and the
ischemic times were 4 and 10 minutes. Blood loss was 150 Technique for Laparoscopically Assisted
to 450 mL, and no transfusions were required. Both grafts
procured in this fashion were successfully transplanted,
Donor Right Hepa­tectomy
and the donors were discharged home 5 to 7 days postsur- Because this is the technique that we at Northwestern have
gery. Dr. Cherqui’s team initially demonstrated the feasi- espoused, we will specifically describe the technical aspects
bility of this laparoscopic living donor hepatectomy of the of the approach. The donor is placed in the supine posi-
left lateral segment.2 They hypothesized that the safety tion, arms tucked at the sides, with large-bore intravenous
and feasibility of this type of procedure would be shown in lines, a right radial arterial line, and a Foley catheter, and
larger series, as it has been, and now it has become an placed under general anesthesia. Pneumoperitoneum is
acceptable standard of care procedure in centers with established through a 12-mm port placed in the upper
applicable expertise in advanced laparoscopy. midline at or above the umbilicus using Hassan’s tech-
The procedure has been described with the patient nique for safety. The abdomen is explored using a
under general anesthesia in the supine position with the 30-degree, 10-mm laparoscope for optimal optics. Once
legs apart. Five trocars were used (Figs. 56-1 and 56-2). the liver is visualized and there are no obvious contraindi-
The left lateral segment was mobilized by dividing the cations to proceeding with donation, one additional 5-mm
 TABLE 56-1 Descriptive Comparison of Minimally Invasive Living Donor Hepatectomies
Anatomical Hospi-
Unit Procured Surgical Extraction Site tal LOS
Technique for Donation N Time Ports Location (Size) WIT EBL RBC (Days) Complications Author Year
Laparoscopic LLS 2 6-7 hr 5 Pfannenstiel 4-10 150-450 0 5-7 None Cherqui1 2002
(10 cm) min mL
LLS 16 4-6.5 hr 5 Pfannenstiel 6-10 20-60 mL 0 7.5 (5-16) 19% Soubrane2 2006
(10 cm) min 1 Open
conversion
2/2 LPV injury
1 bile leak
RL 2 12.8 and 15 5 R transverse (9 0 10 and 14 Suh10 2009
hr cm)
Single-port RL 40 4.6 hr ± 72 Single (4 R subcostal (15 NR 450 ± 316 0.25 ± 11.8 ± 4.5 2 Open Choi21 2012
laparo- min ports) cm) mL 0.81 conversion
scopic (5 cm) 1 R diaphrag-
assisted matic injury
Laparoscopic RL 4 3.9 h 2 Subxiphoid 1.5 min 150 mL 0 3 (2-4) None Koffron18 2006
assisted midline (5
cm)
RL and LL 13 6 hr ± 32 4 Upper midline 3 min 302 ± 191 0 11 ± 2.7 None Kurosaki19 2006
min (8 cm) + R mL

56 Minimally Invasive Living Donor Hepatectomy

subcostal (4
cm)
RL 7 5.1-9.6 hr 5 R transverse 0 8-17 Suh10 2009
RL 33 4.4 hr 2 Subxiphoid NR 417 mL 0 4.3 2 Open Baker20 2009
(3.6-5.2) midline (5 (200- conversion
cm) 634) 2 bilomas (2
reoperations)
RL 19 6.5 hr 3 Upper midline NR 350 mL NR 6.3 (5-7.6) 25% Nagai23 2012
(5.3-7.6) (10 cm) (176-
524)
RL 20 6.4 hr ± 41 NR R subcostal (15 NR 870 mL ± 1.25 ± 12.1 ± 2 Open Choi21 2012
min cm) 653 2.05 2.81 conversions
1 R diaphrag-
matic tx and
capsular
hematoma
Upper midline RL 23 3.9 hr ± 29 0 13.5 cm (12-17) 0 185 ± 59 10 ± 2.9 1 Bile leak Kim8 2009
laparotomy mL 2 bleeding
RL or ERL 141 4 hr 14 min 0 12-18 cm NR 352 ± 144 10.3 ± 3.1 4 Reoperations Lee22 2011
± 47 min mL for bleeding
Mini RL 9 5.9 hr 0 Upper midline NR 177 mL NR 6 (4.5-7.5) 25% Nagai23 2012
laparotomy (5.1-6.8) (10 cm) (88-266)
Robotic RL 1 8 hr 5 Midline NR 350 mL 0 5 PV stenosis Guilianotti24 2012
infraumbili-
cal (7 cm)

EBL, Estimated blood loss; ERL, extended right lobe; LL, left lobe; LLS, left lateral segment; LOS, length of stay; LPV, left portal vein; NR, not reported; PV, portal vein; R, right; RBC, red blood

731
cells; RL, right lobe; tx, transplant; WIT, warm ischemia time.
732 PART VI Split and Living Donor Transplantation

port is placed in right midclavicular line and a 5-cm subxi- short hepatic veins are divided using the LigaSure, sepa-
phoid midline incision is created for hand assistance d­uring rating the IVC and the right lobe, allowing visualization of
right lobe mobilization and for graft extraction using a the right hepatic vein (RHV) as it enters the IVC. At this
GelPort hand port device (Applied Medical, Rancho Santa point the hand port and all other laparoscopic devices are
Margarita, California) (Fig. 56-3). This configuration removed, the upper midline hand-assist port incision is
allows the operating surgeon, who is standing on the left extended to include the camera port, and a liver transplant
side of the patient, to use the hand port for graft manipu­ retractor is placed while making sure that no nerve damage
lation with simultaneous use of the midclavicular line is caused by excessive traction on the brachial plexus—this
port for dissection. Using LigaSure (Valleylab, Boulder, is accomplished by carefully watching the waveform in the
Colorado) the ligamentum teres, falciform ligament, coro- right radial arterial line to ensure that there is no dampen-
nary and right triangular ligaments are divided. The ing with progressive retraction. Under direct visualization
hepatic bare area is completely mobilized, the right lobe the RHV is encircled with an umbilical tape, creating a
elevated, exposing the length of the retrohepatic inferior “hanging maneuver” (previously described).25 A cholecys-
vena cava (IVC). The posterior vena cava ligament and the tectomy is then performed, and the cystic duct is cannu-
lated in preparation for a cholangiogram. Once
cholangiography confirms the presence of suitable anat-
omy, the right hepatic duct (RHD) is isolated, and using
fluoroscopic cholangiographic guidance, the right hepatic
duct (RHD) is transected sharply, taking care to leave an
appropriate stump of RHD on the donor hepatic duct
confluence, which is subsequently oversewn with 7-0
monofilament, nonabsorbable suture. The right hepatic
artery (RHA) and right portal vein (RPV) branches are
completely dissected under direct visualization with no
undue traction on the vessels. It should be noted that no
inflow occlusion is used at any point during the case. A
“tape switch maneuver” is performed, whereby the umbili-
cal tape is transferred superior to the RPV/RHA conflu-
ence to protect these vessels during liver transection. The
liver parenchyma is then divided at Cantlie’s line using the
hanging umbilical tape to bring the plane of dissection up
into the midline incision (Fig. 56-4). The parenchymal
transection is achieved in an inferior/anterior to superior/
posterior plane using a combination of Helix Hydro-Jet
(Erbe USA Inc Surgical Systems, Marietta, Georgia) and
the LigaSure device. The middle hepatic vein tributaries
from segments five and eight are ligated or preserved for
reimplantation at the surgeon’s discretion (usually when
FIGURE 56-1 n Schematic image of port placement for laparo- larger than 5 mm) Once the hemilivers are completely
scopic left lateral segmentectomy. Measurements are the diam-
eters of the trocars. (From Cherqui D, Soubrane O, Husson E, et al. separated and the recipient operative team is notified, the
Laparoscopic living donor hepatectomy for liver transplantation in RHA is ligated, just distal to where it passes behind the
children. Lancet. 2002;359:9304.) common bile duct, and sharply divided, allowing back
bleeding from the graft side. Immediately the RPV is sta-
pled, but not divided, using a 30-mm TA vascular stapling

Hand assist/
Extraction incision

12-mm port
5-mm
port

FIGURE 56-2 n Laparoscopic left lateral segmentectomy. Localiza-

tion of the five-port site for laparoscopic left lateral segmentec-
tomy. (From Soubrane O, Cherqui D, Scatton O, et al. Laparoscopic
left lateral sectionectomy in living donors: safety and reproducibility FIGURE 56-3 n Hybrid method. Port placement during laparoscopic-
of the technique in a single center. Ann Surg 2006;244:5.) assisted right lobe hepatectomy.
 56 Minimally Invasive Living Donor Hepatectomy 733

device (US Surgical, Norwalk, Connecticut). The right falciform ligament is then reconstructed to resuspend the
hepatic lobe is then retracted laterally, and the RHV is left hepatic lobe from the anterior abdominal wall. A
stapled and divided at the IVC using a laparoscopic endo- closed suction drain is then placed through the previously
vascular GIA stapler (US Surgical). The RPV is then tran- placed 5-mm right midclavicular line port site to service
sected sharply on the graft side using scissors. The right the remnant liver cut surface and secured to the skin with
lobe is decompressed by allowing back bleeding of the a 3-0 nonabsorbable suture. The extraction incision is
graft through the RPV, and the right lobe is extracted then closed in layers.
using gentle traction by grabbing it at the gallbladder fossa On the back table the vascular staple lines on the
and removing it through the upper midline incision. The RHV/RPV are excised, and the right lobe is flushed with
RHA stump is oversewn with 7-0 nonabsorbable mono- Custodial HTK solution (Odyssey Pharmaceuticals, East
filament and the RPV and RHV stumps inspected for Hanover, New Jersey) within 90 seconds of vascular
hemostasis. A completion cholangiogram is then obtained exclusion.
to confirm the integrity of the remaining biliary system
and to ensure that there are no obvious bile leaks. The
ROBOTICALLY ASSISTED DONOR
HEPATECTOMY
There is increasing interest in complex hepatobiliary sur-
gery performed using a robot. A reasonable extension of
this was the potential applicability to living donor hepatec-
tomy. The first report of robot-assisted right lobe donor
hepatectomy was published recently by the University of
Illinois at Chicago.24 Dr. Giulianotti’s group has extensive
experience in robotic surgery, and they have been per-
forming hepatobiliary surgery using the da Vinci Surgical
System. They demonstrated that this type of approach is
feasible, but the main limitation is experience with the
technology associated with the equipment, which may
limit its use in most transplant centers in the United States
at this time. They emphasized that only experienced surgi-
cal teams should perform this type of procedure.
Four trocars were used for robotic and laparoscopic
FIGURE 56-4 n Liver is split with assistance of the “hanging instruments and a 7-cm subumbilical midline laparotomy
maneuver” through the open minilaparotomy incision. for hand assistance (Fig. 56-5). A robotic Harmonic

car t
otic
Rob

Robotic ports
Accessory ports Fourth robotic arm

Right robotic arm

Accessory
instruments

Robotic Left robotic arm

camera

FIGURE 56-5 n Robotic right donor hepatectomy. Surgery was performed through five trocars and midline infraumbilical incision for
hand assisting. (From Giulianotti PC, Tzvetanov I, Jeon H, et al. Robot-assisted right lobe donor hepatectomy. Transpl Int. 2012;25:1.)
734 PART VI Split and Living Donor Transplantation

scalpel was used for the transection of the parenchyma,

and no inflow clamping was used at any time. The right
lobe was externalized through the subumbilical midline
laparotomy. The length of the procedure was 8 hours
with blood loss of 350 mL. The donor did not require
any blood transfusion. The donor postoperative course
was uneventful, and the donor was discharge home on
the fifth postoperative day. Six months post donation, the A
donor developed a short stenosis of the main trunk of the
donor portal vein, which was dilated through a percuta-
neous hepatic approach. Some of the potential advan-
tages of this procedure are astable magnified field,
three-dimensional vision, and enhanced instrument artic-
ulation, which facilitate the dissection of the biliovascular
structures and enhanced ability for suture ligation of
bleeding vessels during the parenchymal transection.
The disadvantages are the expense of the robot and the
extra time and resources required for proper execution of B
the procedure. Furthermore, application of this tech-
nique is limited to those surgeons who are facile in the
use of the robot.

Upper Midline (“Minilaparotomy

Approach”) (Fig. 56-6)
In response to the proliferation of laparoscopic and lapa-
roscopically assisted approaches to living liver donation,
many programs have reported on a minilaparotomy
approach without laparoscopic assistance in appropriately C
selected candidates. Specifically in patients with low body
FIGURE 56-6 n Minilaparotomy for right lobe donor hepatectomy.
mass index (≤25) and small anterior/posterior diameter, A, The right hepatic lobe is mobilized with scissors. B, The right
certain surgeons have described an upper midline hepatic lobe is completely mobilized, and the inferior vena cava
approach through which they are able to accomplish is directly visualized below the incision. C, The liver is retracted
complete mobilization of the right lobe from its retro- medially by hand and is mobilized with scissors (or cautery).
(From Nagai S, Brown L, Yoshida A, et al. Mini-incision right hepatic
peritoneal attachments and off the right side of the vena lobectomy with or without laparoscopic assistance for living donor
cava. They then proceed with hilar dissection and tran- hepatectomy. Liver Transpl. 2012;18:10.)
section of the liver using a hanging maneuver similar to
what is described in the laparoscopically assisted approach.
The obvious advantages of this are the lack of cost and minimal wound-based long-term morbidity. Certainly all
expertise required for laparoscopy, but this approach is of these techniques warrant further evaluation for living
limited in applicability to a specific body habitus in the liver donation.24
prospective donor. For left lateral sectionectomies, either minilaparotomy
through a modified and limited upper midline incision or
a pure laparoscopic approach is certainly reasonable. The
SUMMARY AND CONCLUSION pure laparoscopic approach requires significant advanced
laparoscopic skills, which limit its applicability. Further-
Minimally invasive kidney graft procurement using the more, an incision must ultimately be made (albeit in the
laparoscopic techniques introduced by Ratner et al26 has suprapubic position) for graft removal, bringing into
become the preferred method for kidney donation and question the ultimate benefit for a perhaps less safe
has been adopted by the majority of the kidney transplant approach.
centers in United States. Decreased pain and disability Right lobe donors can be approached in a number of
have increased the acceptance among potential living minimally invasive manners as described earlier. Robotic
donors. We think that this may happen in minimally assistance requires significant institutional and surgeon-
invasive liver graft procurement if these types of tech- based expertise and is associated with significant costs.
niques are accepted and disseminated with good results The length of the procedure also will likely prove to be
and in keeping with the tenet that the most sacred imper- limiting for most surgeons. It will likely be difficult to
ative is the safety of the donors. define significant advantage to this approach. The mini-
Minimally invasive approaches to living donation can laparotomy approach is attractive in that it allows the
vary from pure laparoscopy, laparoscopically assisted advantage of a limited incision and removes the added
(hybrid) techniques, minilaparotomies, and robotically cost and required expertise associated with laparoscopic
assisted procedures. All have been developed to avoid the assistance. The donor pool to which this approach is
painful subcostal incision, allowing faster recovery and applicable is very limited.
 56 Minimally Invasive Living Donor Hepatectomy 735

In our experience we believe that the hybrid approach 4. Lesurtel M, Cherqui D, Laurent A, et al. Laparoscopic versus open
to right lobe living donor hepatectomy has significant left lateral hepatic lobectomy: a case-control study. J Am Coll Surg.
2003;196:2.
advantages and emerges as the optimal minimally inva- 5. Rau HG, Buttler E, Meyer G, et al. Laparoscopic liver resection
sive approach. First and foremost, it offers a minimal compared with conventional partial hepatectomy–a prospective
upper midline incision, addressing the primary objective analysis. Hepato-gastroenterology. 1998;45:24.
of the development of novel approaches. Furthermore, 6. Buell JF, Cherqui D, Geller DA, et al. The international position
on laparoscopic liver surgery: The Louisville Statement, 2008. Ann
the limited nature of the laparoscopic mobilization allows Surg. 2009;250:5.
most surgeons to perform the procedure after a minimal 7. Marcos A, Fisher RA, Ham JM, et al. Right lobe living donor liver
learning curve. The majority of the hilar dissection and transplantation. Transplantation. 1999;68:6.
parenchymal dissection is done under direct visualization 8. Kim SH, Cho SY, Lee KW, et al. Upper midline incision for living
through the midline incision with assistance of the hang- donor right hepatectomy. Liver Transpl. 2009;15:2.
9. Parikh ND, Ladner D, Abecassis M, Butt Z. Quality of life for
ing maneuver. The tenet of surgical innovation with a donors after living donor liver transplantation: a review of the
commitment for improved donor safety therefore is met li­terature. Liver Transpl. 2010;16:12.
with the application of this technique. 10. Suh KS, Yi NJ, Kim T, et al. Laparoscopy-assisted donor right
hepatectomy using a hand port system preserving the middle
hepatic vein branches. World J Surg. 2009;33:3.
Pearls and Pitfalls 11. Trotter JF, Talamantes M, McClure M, et al. Right hepatic lobe
donation for living donor liver transplantation: impact on donor
• Living donation can increase the donor pool in a select quality of life. Liver Transpl. 2001;7:6.
group of patients awaiting liver transplantation. 12. Suh KS, Kim SH, Kim SB, et al. Safety of right lobectomy in living
• Laparoscopic approaches to living donation may achieve donor liver transplantation. Liver transpl. 2002;8:10.
the following: 13. Abecassis MM, Fisher RA, Olthoff KM, et al. Complications of
living donor hepatic lobectomy–a comprehensive report. Am J
• Increase the appeal of donation to potential candidates Transplant. 2012;12:5.
• Increase the safety of the procedure 14. Grewal HP, Thistlewaite Jr JR, Loss GE, et al. Complications in
• Reduce the morbidity of the traditional incision 100 living-liver donors. Ann Surg. 1998;228:2.
• Potentially decrease cost 15. Renz JF, Roberts JP. Long-term complications of living donor
• Improve quality of life for donors liver transplantation. Liver transpl. 2000;6:2.
• The hybrid method allows most living donor surgeons to 16. Fujita S, Kim ID, Uryuhara K, et al. Hepatic grafts from live
perform the operation. donors: donor morbidity for 470 cases of live donation. Transpl Int.
• Minimal laparoscopy is involved—although the sur- 2000;13:5.
geon still must be technically proficient in advanced 17. Suh KS, Yi NJ, Kim J, et al. Laparoscopic hepatectomy for a modi-
fied right graft in adult-to-adult living donor liver transplantation.
laparoscopy. Transplant Proc. 2008;40:10.
• Technically challenging portions of the operation are 18. Koffron AJ, Kung R, Baker T, et al. Laparoscopic-assisted right
done through the familiar open, upper midline ap- lobe donor hepatectomy. Am J Transplant. 2006;6:10.
proach. 19. Kurosaki I, Yamamoto S, Kitami C, et al. Video-assisted living donor
• Conversion to open incision (“hockey stick”) for safety hemihepatectomy through a 12-cm incision for adult-to-adult liver
is easy and potentially fast. transplantation. Surgery. 2006;139:5.
• Variations to the approach have the same potential ben- 20. Baker TB, Jay CL, Ladner DP, et al. Laparoscopy-assisted and
efits: open living donor right hepatectomy: a comparative study of out-
Pure laparoscopic left lateral sectionectomy comes. Surgery. 2009;146:4.
21. Choi HJ, You YK, Na GH, et al. Single-port laparoscopy-
Robotic-assisted right/left lobectomy assisted donor right hepatectomy in living donor liver transplan-
Upper midline approach in patients with low body mass tation: sensible approach or unnecessary hindrance? Transplant
   index (no laparoscopic assistance) Proc. 2012;44:2.
22. Lee KW, Kim SH, Han SS, et al. Use of an upper midline incision
for living donor partial hepatectomy: a series of 143 consecutive
cases. Liver Transpl. 2011;17:8.
23. Nagai S, Brown L, Yoshida A, et al. Mini-incision right hepatic
REFERENCES lobectomy with or without laparoscopic assistance for living donor
1. Cherqui D, Soubrane O, Husson E, et al. Laparoscopic living hepatectomy. Liver Transpl. 2012;18:10.
donor hepatectomy for liver transplantation in children. Lancet. 24. Giulianotti PC, Tzvetanov I, Jeon H, et al. Robot-assisted right
2002;359:9304. lobe donor hepatectomy. Transplant Int. 2012;25:1.
2. Soubrane O, Cherqui D, Scatton O, et al. Laparoscopic left lateral 25. Belghiti J, Guevara OA, Noun R, et al. Liver hanging maneuver: a
sectionectomy in living donors: safety and reproducibility of the safe approach to right hepatectomy without liver mobilization.
technique in a single center. Ann Surg. 2006;244:5. J Am Coll Surg. 2001;193:1.
3. Buell JF, Koffron AJ, Thomas MJ, et al. Laparoscopic liver resection. 26. Ratner LE, Ciseck LJ, Moore RG, et al. Laparoscopic live donor
J Am Coll Surg. 2005;200:3. nephrectomy. Transplantation. 1995;60:1047.
 CHAPTER 57

Dual Grafts for Transplantation

Sung-Gyu Lee • Deok-Bog Moon • Chul-Soo Ahn

CHAPTER OUTLINE

TWO LEFT LOBES DUAL-GRAFT LIVER CURRENT RESULTS AND ISSUES IN DUAL-GRAFT
TRANSPLANTATION LIVER TRANSPLANTATION
Indication SUMMARY
Operative Procedure
RIGHT AND LEFT LOBES DUAL-GRAFT LIVER
TRANSPLANTATION
Indication
Operative Procedure

The shortage of cadaveric liver grafts has stimulated the liver transplantation (LT) alone and the critical right
development of innovative surgical procedures with vari- lobectomy posing an independent donor risk.2-5 The
ous forms of living donor liver transplantation (LDLT), ethical issue of putting two donors at risk simultane-
especially in adult patients, which produce satisfactory ously for one recipient can be debatable. However,
results comparable to whole-liver deceased donor liver because the clear relationship between donor mortality
transplantation (DDLT). For adult LDLT, insufficient and the extent of resection has been demonstrated, the
graft size has been a major obstacle for an expansion of sum of potential risks from two donors’ left lobectomies
this procedure when the liver graft is confined to the left will be much lower than the risk of an inappropriate
lobe (LL). To expand adult LDLT, right-lobe (RL) grafts right hepatectomy. To alleviate the SFSG problem by
have been used, with a rapid increase in the number of summing the suboptimal volumes of two LL grafts,
cases, but the risk to the donor increases with the extent dual LL grafts LT preserving the donors' safety is real-
of donor hepatectomy. It is reported that operative istic and justified. Although LDLT with dual LL grafts
mortality for the RL donor is estimated to be as high as is a technically complex and elaborate procedure, dual-
0.5% to 1%. Regarding the recipients, the most impor- graft LT can solve problems related to SFSG. It can
tant factor for a successful outcome after adult LDLT is also help expand the donor pool for LDLT and even for
the size of the liver graft. Meanwhile the safe remnant split-liver DDLT by application of two RL and one
liver volume after RL donation has been reported to be dual LL/LLS split transplantation to three recipients
greater than 30% to 35% of the total liver volume (TLV) from two deceased donors.6 Furthermore, if a large-size
of the donor, whereas the safe limit of the graft volume is recipient requires a bigger graft liver volume than the
greater than 40% to 50% of the recipient’s standard liver volume of a RL from a small-size donor when a RL
volume. Leelaudomlipi et al1 reported that in 25% of harvest from one of two potential donors is decided to
donors evaluated the volume ratio of RL was over 70% of be safe, one RL and one LL graft from two independent
TLV, or in other words, the remnant liver volume after donors can be transplanted to a large-size recipient to
RL donation was less than 30% of TLV. Even though the avoid the SFSG problem.3,6,7 This chapter introduces
donor has a sufficiently large RL that it has adequate the technical aspects and the issues of dual-graft (two
volume as a liver graft for an adult recipient, the remnant LLs or a RL and a LL) transplantation by reviewing our
LL is too small to ensure donor safety in these procedures. 300 dual-graft LTs.
Undoubtedly the safety of donors must have top priority
when considering LDLT, and the inevitable risk to the
donor should not be allowed in an LDLT procedure. TWO LEFT LOBES DUAL-GRAFT LIVER
The donor demonstrating RL to LL volume dispropor- TRANSPLANTATION
tion (RL > 70% of TLV) on preoperative volumetric
computed tomography should not be allowed to donate Not all potential living donors can donate their RL
the RL for a large-size adult recipient. because safe donation is possible only when the esti-
As an alternative, dual LL or left lateral segment mated remnant liver volume is more than 30% of the
(LLS) transplantation can be an option to avoid the donor’s TLV. At the Asian Medical Center the mini-
small-for-size graft (SFSG) problem caused by a LL mally accepted remnant liver volume in RL donors is

736
 57 Dual Grafts for Transplantation 737

individualized by age and degree of steatosis (Fig. 57-1).8 of steatosis increases, and congestion injury of liver
If the remnant LL hepatic mass is fully functioning segment IV by extended RL hepatectomy (MHV is
without congestion injury by middle hepatic vein included in RL graft) is expected, the lower limit of the
(MHV) preservation, the lower limit of 30% remnant remnant liver volume in donors should be increased.
liver volume is acceptable if the donor’s age is 35 years or
less and preoperative donor liver biopsy reveals no ste-
atosis. However, when donor age increases, the degree
Indication
Selection criteria for dual LL or LLS transplantation
requires two concurrent situations. First, the volume
 35 years and  no fatty change disproportion between RL and LL (RL > 70% of TLV)
: 30% remnant liver volume: Acceptable in the donor liver exists, and the right hepatectomy
 35 years and  15% fatty change endangers donor safety (Fig. 57-2). Second, the donor’s
: 30%-35% remnant liver volume: Acceptable LL is too small to meet the metabolic demands of the
 35 years and 15% < fatty change  30%
recipient. Under these circumstances, dual-graft LDLT
using two LLs can provide an adequate graft volume to
:  35% remnant liver volume: Acceptable
the recipient while leaving a safe remnant liver volume in
35–55 years and  15% fatty change the donor (Fig. 57-3). Besides the graft-to-recipient size
: > 35% remnant liver volume: Acceptable mismatching and the unacceptable right-to-left-lobe
volume discrepancy, severely steatotic (>60% steatosis)
FIGURE 57-1 n Minimally accepted remnant liver volume in right-
lobe donor should be individualized when the remnant liver is fully
LLS or LL grafts have been successfully transplanted to
functioning without congestion caused by hepatic vein outflow low (<20) Model for End-Stage Liver Disease (MELD)
deprivation. patients in nonurgent dual-graft LDLT.9

360 mL 220 mL

960 mL 527 mL
> 70% > 70%

Potential donor 1 Potential donor 2

FIGURE 57-2 n Two potential donors demonstrated a large right lobe (>70% of total liver volume) and small left lobe (<30%) on
preoperative volumetric computed tomography.

A B C
FIGURE 57-3 n Regeneration of two left-lobe grafts in dual-graft liver transplantation. A, Preoperative computed tomography (CT)
scan of the recipient demonstrated large amounts of ascites and shrunken cirrhotic liver. B, CT scan on the seventh day after
transplant demonstrated two well-functioning left-lobe liver grafts with no manifestation of the small-for-size graft syndrome. The
right-sided left-lobe graft was not fully regenerated and needed tissue expander support from behind to relieve tension on hilar
anastomoses (white arrow). C, CT scan taken 3 weeks after transplant showed that two regenerated left-lobe liver grafts looked like a
triangular-shaped normal liver.
738 PART VI Split and Living Donor Transplantation

Two left lobes dual-graft LDLT

• Bigger-size graft
• Single bile duct opening Orthotopic
Heterotopic • Better-quality graft
graft
• Longer hepatic artery graft
• Multiple bile
duct openings

FIGURE 57-4 n Which graft will be located in the orthotopic left-sided position? LDLT, Living donor liver transplantation.

Operative Procedure length for future bilateral vascular anastomoses. The bile
duct is similarly dissected to the level of the hilum without
This new procedure needs a few technical modifications disturbing the course of the right hepatic artery behind the
during implanting the heterotopic right-positioned LL common hepatic duct. The proximal part of the recipient’s
graft. The rotation of the heterotopic liver graft through vena cava should be mobilized from its retroperitoneal
180 degrees of sagittal orientation brings hilar structures attachment because venoplasty of the recipient’s hepatic
into reversed position. The bile duct lies behind the por- veins and graft implantation are performed under clamping
tal vein (PV) and hepatic artery. If the PV anastomosis is of the suprahepatic and infrahepatic vena cava. Venovenous
performed before the bile duct anastomosis, biliary recon- bypass (Bio-Pump, Bio-Medicus, Inc) is necessary when the
struction of the heterotopic liver graft will be difficult or recipient hemodynamics is unstable during the test clamp-
impossible in such a limited and hidden area. Thus the ing of the vena cava. It is also helpful to reduce bowel edema
first technical modification is that the bile duct is recon- for future hepaticojejunostomy to the left-sided graft when
structed by duct-to-duct anastomosis before the PV anas- more than 2 hours of anhepatic phase is expected.
tomosis lying ventrally. Therefore the liver graft with a Which graft will be positioned heterotopically is
single duct opening is the first choice for the heterotopic determined by consideration of the number of bile duct
right-sided graft to facilitate an easy and fast duct-to-duct openings, the length and number of hepatic arteries, the
anastomosis and to decrease the graft ischemic time. In degree of steatosis, and the expected graft volume of each
addition, a longer length of hepatic artery is needed for liver graft (see Fig. 57-4). Harvest of liver grafts and the
tension-free anastomosis compared to the orthotopic left- recipient’s hepatectomy are usually performed simultane-
sided graft because the recipient’s right hepatic artery ously. Before implantation of the liver grafts, venoplasty
arises from the most dorsal position. As the orthotopic of the hepatic veins in the recipient and/or the liver grafts
left-sided graft, the bigger-size and better-quality graft is at the bench should be performed to make wide outflow
commonly preferred because it has less possibility of vas- orifices of approximately 35 to 40 mm in diameter for
cular complications as a result of its natural position. In prevention of the occasional outflow obstruction during
addition, it has no strict limitation on the number of bile liver graft regeneration. At the back table the hepatic vein
duct openings because biliary reconstruction with hepati- of the liver graft is enlarged by augmentation venoplasty
cojejunostomy after hepatic artery (HA) anastomosis does if its diameter is less than the target diameter of 35 to 40
not need to be hurriedly performed (Fig. 57-4). mm. The venoplasty is performed using a rectangular
The thickness of the LL or LLS graft is too thin com- vein patch after slit incision at one or both corners of the
pared to that of the RL of the recipient’s resected liver. graft hepatic vein (Fig. 57-5). In the recipient the right
Therefore the second technical modification is that tissue hepatic vein (RHV) is enlarged and elongated by longi-
expander filled with saline solution (from 200 to 450 mL) tudinal incision at the inferior corner with or without
is inserted underneath the graft. This relieves undue ten- augmentation venoplasty. The left and middle hepatic
sion on the hilar anastomoses of the heterotopic liver graft veins (LMHV) are converted to a single common opening
because the LL graft is usually too small to replace the by division of the septum between the MHV and the
right upper quadrant space after total hepatectomy in the LHV. The common hepatic vein opening is then enlarged
recipient. The tissue expander is gradually deflated after and elongated by an additional transverse incision at the
the fifth postoperative day and removed after 2 weeks, right corner and circumferentially fenced with a vein
when the undue tension on the hepatic hilum is relieved patch to facilitate hepatic vein anastomosis under redun-
by sufficient regeneration of the right-sided liver graft. dancy to prevent the tearing of the posterior wall anasto-
In the recipient operation both the right and left branches mosis. Venoplasty corresponding to the size of the hepatic
of the PV and hepatic artery are dissected free from the sur- vein between the liver graft and the recipient is an essential
rounding tissue as peripherally as possible to obtain enough step so that the surgeon can perform engraftment without
 57 Dual Grafts for Transplantation 739

1 2 Slit incision
20 mm

3 4 35-40 mm

Rectangular
vein patch

FIGURE 57-5 n Augmentation hepatic venoplasty of left-lobe graft at the back table.

difficulty during hepatic vein anastomosis and can also

avoid postoperative outflow disturbance. An autologous RIGHT AND LEFT LOBES DUAL-GRAFT
bisected great saphenous vein segment is the preferred LIVER TRANSPLANTATION
augmentation and fencing material at our department
because it has a thicker and stronger wall than other Two LLs dual-graft liver transplantation is a good
homologous vascular grafts. strategy to avoid SFSG and to ensure donor safety
Engraftment procedures using two LL grafts are as when potential donors show a volume disproportion
follows. First, a 180-degree rotated LL graft is hetero- between right and left liver lobes. However, we often
topically placed into the right upper quadrant space, and encounter large-body-size recipients requiring bigger
its hepatic vein anastomosis to the recipient RHV is liver volume than the sum of the two LLs or a single RL
performed. Second, the hepatic vein of the orthotopically graft of the potential donors. As an alternative approach
positioned LL graft is anastomosed to the common to avoid SFSG in large-size recipients, dual-graft liver
opening of the LMHV. Third, the PV anastomosis of the transplantation using RL and LL grafts can be employed
orthotopic graft is performed to the recipient’s left PV. when one of the potential donors can donate his or her
Fourth, the orthotopic left-sided graft is reperfused ear- RL without endangering donor safety.
lier to avoid bowel congestion and reduce the graft
ischemic time. Before reperfusion of the orthotopic liver Indication
graft proceeds, a vascular clamp is applied to the recipi-
ent’s RHV to prevent regurgitation of caval flow into the When a large-size recipient cannot receive adequate
heterotopic right-sided graft after release of the caval graft volume from an acceptable RL donor, and another
clamps. Vascular clamps to the vena cava and the PV potential donor is available, dual right- and left-lobe
trunk are then removed together under new clamping of transplantation has been performed since 2001 to avoid
the recipient’s right PV. Fifth, bile duct anastomosis of SFSG. The eligibility criteria for the RL donor are the
the right-sided (heterotopic) graft to the recipient’s bile same as those for single RL LDLT. As for the simulta-
duct is performed in duct-to-duct fashion earlier than PV neous LL or LLS donor, however, even suboptimal
anastomosis because of the reversed hilar structures of donors, such as those who are 50 years of age or older or
the graft. Sixth, the PV of the right-sided heterotopic those with moderate to severe steatosis, can be selectively
liver graft is anastomosed to the recipient’s right PV and acceptable in low-MELD (<20) patients. As additional
is reperfused after removal of the vascular clamps on the considerations before proceeding to RL and LL dual-graft
recipient’s RHV and right PV. Seventh, hepatic artery transplantation, we need to reappraise the recipient’s pre-
anastomoses are performed, and finally a Roux-en-Y operative condition, such as the MELD score and the
hepaticojejunostomy to the left-sided (orthotopic) liver presence of long-standing portal hypertension, and the
graft is performed. As an additional procedure, a tissue adequacy of the estimated liver graft volume from trans-
expander filled with saline solution should be inserted plantation of a single RL or two LLs. If the recipient
underneath the right-sided (heterotopic) graft to relieve shows low MELD status without coexisting portal hyper-
undue tension on the hilar anastomoses (Fig. 57-6). tension, the minimum requirement of liver graft volume
740 PART VI Split and Living Donor Transplantation

360-Degree GSV fence on

MHV+LHV trunk

Anastomosis of Anastomosis of Anastomosis of

right-sided graft HV left-sided graft HV left-sided graft PV

Reperfusion of Duct-to-duct anastomosis of PV anastomosis of

left-sided graft right-sided graft right-sided graft

Reperfusion of Anastomosis of Tissue expander applied

right-sided graft hepatic arteries
FIGURE 57-6 n Anastomosis of dual-graft living donor liver transplantation using two left lobes. GSV, Great saphenous vein; HV,
hepatic vein; LHV, left hepatic vein; MHV, middle hepatic vein; PV, portal vein.

can be lowered to 0.7% of graft weight–to–body weight donor safety if the sum of the liver grafts meets the
ratio (GWBWR) or 35% of graft volume/standard liver metabolic demands of the recipient.
volume of the recipient.
When procurement of a right posterior sector graft is
feasible because LL volume is disproportionately small
Operative Procedure
(<30% of total liver volume) and PV branching of the In the donor operation, procurement of a RL graft with or
donor demonstrates type III anomaly (early separate without the MHV, or right posterior sector graft as a
branching of posterior PV), right posterior sector and right-sided positioning graft, and LL or LLS graft as a
LL/LLS dual-graft LDLT can also be applicable for left-sided positioning graft is performed considering
 57 Dual Grafts for Transplantation 741

Rt

Lt

FIGURE 57-7 n Dual-graft living donor liver transplantation using right (Rt) and left (Lt) lobes.

donor safety and avoidance of SFSG for the recipient. At grafts is performed using only a Roux-en-Y hepaticojeju-
the back table, hepatic venoplasty to create a large outflow nostomy or a combination of duct-to-duct and Roux-en-Y
orifice is performed in both grafts. The RHV of the RL or hepaticojejunostomy (Fig. 57-7).
posterior sector graft is incised caudally, augmentation The sequence of reconstruction might vary from
venoplasty is performed with a rectangular vein patch, and center to center concerning the prolonged ischemia of
the MHV tributaries of the RL graft are reconstructed liver grafts, but the most important point of implement-
with an interposition graft such as an autologous great ing these complicated procedures is correct and safe
saphenous vein, PV, dilated umbilical vein, cryopreserved anastomosis under a good operating field to prevent
iliac vessel, or artificial polytetrafluoroethylene graft. The postoperative inflow and outflow vascular complica-
MHV trunk of the extended RL graft is elongated using a tions. Because these reconstruction procedures are per-
sizable interposition vascular graft for separate reconstruc- formed using ice-slush filling to protect the liver grafts
tion, or it is transformed into a single common opening against ischemic rewarming, prolongation of liver graft
with the RHV using quilt venoplasty for an integrated ischemia (up to 90 minutes) does not result in primary
single anastomosis. Venoplasty of the LMHV of the LL dysfunction of liver grafts.
graft is the same as that for two LLs dual-graft LT.
In the recipient operation the extent and method of
hepatic hilar and perihepatic dissection is the same as that CURRENT RESULTS AND ISSUES IN
for two LL dual-graft LT, but retrohepatic mobilization of DUAL-GRAFT LIVER TRANSPLANTATION
the vena cava should be extended down toward the infra-
hepatic side for reconstruction if a sizable (≥5 mm) inferior Donor safety and SFSG have been the critical issues in
RHV is present in the RL or posterior sector graft. After adult LDLT. LDLT using a RL graft has contributed to
total hepatectomy, venoplasty to create a wide orifice cor- reducing SFSG, but more than 25% of potential donors
responding to the right- and left-side liver grafts is per- cannot donate their RL to recipients because of the risk
formed at both the RHV and LMHV under cross-clamping to donor safety, considering their RL and LL volume
of supra hepatic and infrahepatic vena cava, and the method discrepancy, age, and steatosis. When there are two living
is the same as that for two LLs dual-graft LT. donors willing to donate their partial liver despite inade-
Both RL and LL grafts are implanted orthotopically; quacy for RL donation, two LLs dual-graft LDLT is a
thus the engraftment procedures are not complex. First, useful strategy to expand the application of adult LDLT
the RL graft is placed into the right upper quadrant fossa, by meeting the minimum required GWBWR. Of 2227
and reconstruction of the hepatic veins is performed. The adult LDLT recipients in our department, 300 adult
interposition graft of the MHV tributaries is anasto- LDLTs using dual grafts were performed from March
mosed to the anterior wall of the inferior vena cava below 2000 to February 2011 (Fig. 57-8). The mean GWBWR
the recipient’s LMHV. Second, the LL graft is placed with two LLs dual-graft LDLT (median, 0.98%; range,
orthotopically, and its hepatic vein and PV are recon- 0.59% to 1.39%) approaches that of a RL LDLT (median,
structed sequentially. Third, the recipient’s right PV is 1.01%; range, 0.63% to 2.27%). Furthermore, in view of
anastomosed to the PV of the RL or posterior sector donor risk, the sum of two LL donors’ risk is lower than
graft. Then the suprahepatic and infrahepatic vena caval that of a RL graft donor. In our 2525 donors there was no
cross-clamps are removed, and both liver grafts are simul- donor mortality. Major morbidity occurred in two donors
taneously reperfused. Fourth, after completion of the after 598 living donor hepatectomies in 300 dual-graft
hepatic artery anastomoses, biliary reconstruction to both LDLTs. One donor needed a repeat hepatectomy for a
742 PART VI Split and Living Donor Transplantation

Lateral segment Lateral segment

Left lobe Left lobe

Left lobe Lateral segment

154 62 (2; cadaveric split graft) 10

Posterior segment Posterior segment
Left lobe Lateral segment

Left lobe
Right lobe

61 3 10
FIGURE 57-8 n Three hundred adult living donor liver transplantations using dual grafts.

persistent cut-surface bile leak from the remnant medial grafts in dual-graft LDLT do not demonstrate competitive
segment after donation of LLS, and another donor growth but regenerate cooperatively. Unilateral liver graft
underwent percutaneous drainage for bile leakage from atrophy developed infrequently, and it was mostly related to
the cut surface. SFSG even after a RL LDLT is often the discrepancy of portal inflow to the liver grafts primarily
encountered in a large-size recipient if the donor body by inappropriate anastomotic technique or secondarily
size is much smaller than that of the recipient. Dual because of unrecognized hepatic vein outflow obstruction
LDLT of RL and LL grafts from two acceptable living by compression of the regenerating liver graft. However, it
donors has been performed to avoid SFSG, and it consti- did not affect patients’ liver function or survival.
tuted 25% (74 of 300) of our dual-graft LDLTs.
The most common indication for dual-graft LDLTs
was hepatitis-B virus–related cirrhosis in 239 patients SUMMARY
(80%), and 44 patients had complications of acute-on-
chronic liver failure. Fulminant hepatic failure was the sec- Because of the shortage of deceased organ donation, adult
ond-most common cause of dual-graft LDLT, and urgent LDLT has been established as a good alternative to treat
transplantations for status 1 and 2A patients constituted end-stage liver disease patients, but donor safety and
21% of our dual-graft LDLTs (62 of 300). The recipients SFSG have remained as critical issues in adult LDLT
were predominantly male, and fifties to sixties was the most practice. Dual-graft LDLT can be the solution to over-
common age-group (Fig. 57-9). The operation time aver- come these obstacles, although its operative procedure is
aged 17 hours (range, 13 to 26 hours), but it did not technically complex and elaborate. This procedure can
adversely affect the postoperative infection rate or the out- not only maximize the safety of individual donors, partic-
come of patients. The most difficult part of all the operative ularly in two LL lobes dual-graft LDLT, but also alleviate
procedures was PV reconstruction in patients who were SFSG related to the recipient’s metabolic demands when
associated with PV thrombosis and/or stenosis.10 single-graft LDLT is not promising a good outcome
The incidence of biopsy-proven acute cellular rejec- because of inadequate graft size and/or increased donor
tion was similar to that in single-graft LDLT (17%), and risk. In addition, dual-graft LDLT is a useful strategy for
three fourths of acute rejection developed simultaneously increasing the living donor pool by making the donation
in both grafts. of their livers realistic, even though the volume and the
The most common complications in dual-graft recipi- quality of the individual liver graft are suboptimal.
ents were biliary strictures (28%) and hepatic venous out-
flow obstruction of the heterotopic right-sided LL graft Acknowledgment
(15%). Hepatic vein obstruction rarely occurred in ortho-
topically positioned liver grafts, as in left-sided LL or right- I sincerely thank my colleagues Jung Man Namgoong,
sided RL grafts. This might be related to the progressive MD, and Bo-Hyun Jung, MD, for their contributions to
compression of the hepatic vein anastomosis by the regen- the preparation of the figures and proofreading for this
eration of a heterotopically positioned LL graft. Two liver chapter.
 57 Dual Grafts for Transplantation 743

Indication Male : Female = 261 : 39

120 113

2 100
2
PB
2
PS 100
3
Bu C C
1 dd
Wil -Chi
son ar
i 239 80
18
FHF HBV cirrhosis
60
hos is
C V-cirr 42
14 H 44 Acute-on-chronic
35
lic 40
o ho sis liver failure
c
Al irrho
c
15 20
r

9
he

100 HCC
Ot

1
7

0
10 20 30 40 50 60 70 years
Age distribution
(from 15 to 68 years)
MELD 19.3 ± 10.2 (range 5-61)
FIGURE 57-9 n Patient’s demographic data for 303 dual-graft living donor liver transplantations from March 21, 2000, to February 9,
2011. FHF, fulminant hepatic failure; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; MELD, Model for
End-Stage Liver Disease; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.

REFERENCES
Pearls and Pitfalls
1. Leelaudomlipi S, Sugawara Y, Kaneko J, et al. Volumetric analysis
• The shortage of cadaveric liver grafts has stimulated of liver segments in 155 living donors. Liver Transpl. 2002;8(7):
612-614.
the development of innovative surgical procedures 2. Lee S, Hwang S, Park K, et al. An adult-to-adult living donor liver
with various forms of living donor liver transplantation transplant using dual left lobe grafts. Surgery. 2001;129(5):
(LDLT), especially in adult patients. 647-650.
• For adult LDLT, insufficient graft size has been a 3. Broering DC, Walter J, Rogiers X. The first two cases of living
major obstacle for an expansion of this procedure donor liver transplantation using dual grafts in Europe. Liver
when the liver graft is confined to the left lobe (LL). Transpl. 2007;13(1):149-153.
• To expand adult LDLT, right-lobe (RL) grafts have 4. Yang CH, Chen CL, Wang CC, et al. Dual grafts in adult-to-adult
been used, with a rapid increase in the number of cases, living donor liver transplantation: a single center experience in
but the risk to the donor increases with the extent of Taiwan. Surgery. 2009;145(2):212-218.
5. Song GW, Lee SG, Hwang S, et al. Dual living donor liver trans-
donor hepatectomy. plantation with ABO-incompatible and ABO-compatible grafts to
• The safety of donors must have top priority when overcome small-for-size graft and ABO blood group barrier. Liver
considering LDLT. Transpl. 2010;16(4):491-498.
• A donor demonstrating RL to LL volume disproportion 6. Lee SG, Hwang S, Park KM, et al. Seventeen adult-to-adult living
(RL > 70% of total liver volume) on preoperative volu- donor liver transplantations using dual grafts. Transplant Proc.
metric computed tomography should not be allowed to 2001;33(7-8):3461-3463.
donate the RL for a large-size adult recipient because of 7. Soejima Y, Taketomi A, Ikegami T, et al. Living donor liver trans-
the inevitable risk to the donor. plantation using dual grafts from two donors: a feasible option to
• As an alternative, dual LL or left lateral segment overcome small-for-size graft problems? Am J Transplant.
2008;8(4):887-892.
transplantation can be an option to avoid the small- 8. Hwang S, Lee SG, Lee YJ, et al. Lessons learned from 1,000 living
for-size-graft (SFSG) problem caused by a LL liver donor liver transplantations in a single center: how to make living
transplantation alone when the critical right lobec- donations safe. Liver Transpl. 2006;12(6):920-927.
tomy poses an independent donor risk. 9. Moon DB, Lee SG, Hwang S, et al. Resolution of severe graft ste-
• A RL and LL dual-graft transplantation from two atosis following dual-graft living donor liver transplantation. Liver
independent donors can be performed to a large-size Transpl. 2006;12(7):1156-1160.
recipient to avoid the SFSG problem, if a large-size 10. Moon DB, Lee SG, Hwang S, et al. Umbilical portion of recipient’s
recipient requires a bigger graft liver volume than the left portal vein: a useful vascular conduit in dual living donor liver
volume of a RL from a small-size donor when a RL transplantation for the thrombosed portal vein. Liver Transpl.
2004;10(6):802-806.
harvest from one of two potential donors is decided to
   be safe.
 CHAPTER 58

Outcomes of Living Donor

Transplantation: The Western
Perspective
Paige M. Porrett • Kim M. Olthoff

CHAPTER OUTLINE

RECIPIENT OUTCOMES OF LIVING DONOR LIVER DONOR OUTCOMES OF LIVING DONOR LIVER
TRANSPLANTATION IN THE WEST TRANSPLANTATION IN THE WEST
Pediatric Recipient Outcomes CONCLUSIONS
Adult Recipient Outcomes
North America
Europe

The benefit of liver transplantation among patients with greater degree in both Europe and the United States,
end-stage liver disease cannot be disputed in the modern representing up to 11% of all liver transplants in
era. However, access to a deceased donor liver allograft ­Germany9 and 9.3% of U.S. liver transplants in 2001
remains an extremely challenging problem that has pre- (OPTN data). However, the annual number of LDLTs
vented expansion of this medical advance to all patients in performed both in the United States (Fig. 58-1) and
need. The persistent disparity between patients in need Europe has fallen since that time, because of changes in
and the availability of deceased donor livers has forced liver allocation, as well as concerns regarding donor
the transplant community to expand the use of living liver safety, particularly among right lobe donors.10,11
donors.
The first successful liver transplant from a living donor
to a child was performed by Raia et al1 in 1989 in Brazil. RECIPIENT OUTCOMES OF LIVING
Following this initial success, other centers expanded DONOR LIVER TRANSPLANTATION IN
both the use of additional liver segments and the recipi-
ent population (Table 58-1).2-6 Early in the experience,
THE WEST
living donor liver transplantation (LDLT) was pioneered Pediatric Recipient Outcomes
in children, given the size disparity and the high mortality
among children awaiting liver transplantation at the Contemporary data suggest that graft and patient out-
time.7 As experience with liver reduction techniques and comes are excellent in pediatric recipients of living donors
living donor transplantation grew, however, the trans- in Western centers. One year after transplantation,
plantation of a right lobe into an adult was ultimately patient and graft survival is well above 90% and 85%,
­successfully attempted.6 Right lobe adult-to-adult liver respectively, and later outcomes remain comparably high
transplantation is now performed throughout the world. (Table 58-2).12-17 These recipient outcomes are compa-
Although LDLT has been adopted all around the rable to those for whole-organ deceased donor recipi-
globe, it has been particularly well embraced by Asian ents17 and those observed in Eastern series (5-year patient
countries given the lack of infrastructure or cultural limi- survival is 84% in Japan,18 5-year patient survival is 86%
tations for the use of deceased donors in these areas. in Korea19). These outcomes also demonstrate stability
Given the much greater availability of deceased donors in when compared with older data.20,21 Such transplant
Western countries compared to Asia, LDLT has consti- success in a patient population with historically high
­
tuted only 2% to 9% of total liver transplants in both waiting list mortality because of limited graft availability
Europe and the United States over the last decade (Organ has consequently encouraged the ongoing use of living
Procurement and Transplantation Network [OPTN] donors in pediatric patients, especially in the youngest
data, 1998-2011).8 Similar to the evolution of LDLT in recipients. Overall, LDLT is currently performed in
Asia, children were the first recipients of LDLT in West- approximately 16% of recipients under 1 year of age in
ern centers.8 In the early 2000s, LDLT expanded to a the United States (OPTN data, 2009-2011).

744
 58 Outcomes of Living Donor Transplantation: The Western Perspective 745

The excellent graft and patient survival outcomes whole-organ allograft or a living donor allograft (RR,
associated with LDLT in pediatric recipients, however, 1.36; P = .08).17
are balanced by a higher frequency of complications when Taken altogether, current data demonstrate an overall
compared to whole-organ cadaveric transplantation. In a benefit of LDLT in pediatric recipients, mostly by sup-
recent report from the Studies in Pediatric Liver Trans- plying small grafts for these recipients. Although these
plantation (SPLIT) multicenter registry, more complica- technically complex surgical procedures have higher
tions were observed in living donor recipients than in complication rates than whole-organ transplantation,
recipients of whole-organ cadaveric grafts.17 As shown in both single-center and registry data demonstrate that
Table 58-3, biliary and vascular complications were more patient and graft survival can be maintained at the highest
frequent in recipients of living donor allografts, and this level. LDLT is most beneficial in the youngest children,
trend was noted at both early (30 days) and late in whom outcomes are equivalent if not superior to
(24 months) time points after transplantation. Despite whole-organ transplantation. Thanks to these results,
the fact that these complications contribute to a higher LDLT in pediatric recipients has endured the test of time
risk for graft loss in this population (relative risk [RR], and remained popular throughout the West for over 20
1.32; P < .05), overall patient survival at 4 years is similar years, and it is expected to remain a critical component of
between pediatric recipients of either a deceased donor U.S. and European pediatric programs into the distant
future.

TABLE 58-1 H
 istorical Milestones in Living
Donor Liver Transplantation Adult Recipient Outcomes
North America
Group Year Graft Type Recipient
Strong et al2 1989 Left lobe Pediatric Overall Outcome. LDLT in adult recipients continues
Yamaoka et al3 1994 Right lobe Pediatric to have significant merit despite its more restricted use in
Hachikura et al4 1993 Left lobe Adult the United States in recent years. LDLT probably has
Lo et al5 1997 Extended right lobe Adult
Wachs et al6 1998 Right lobe Adult
TABLE 58-3 C
 omplications Among Pediatric
Recipients* in the SPLIT Registry
400
Distantly related Whole Liver Living Donor
Spouse/partner Complication (n = 672) (n = 197)
300 Biliary complications (%)† 17.3 40.1
Paired donation/
other Leak† 5.8 21.8
Transplants

Intrahepatic stricture† 3.6 10.2

Anastomotic stricture† 7.7 21.3
200
Vascular complications 16.5 24.4
(%)† 8.6 6.1
Related Hepatic artery thrombosis
100 Unrelated directed Portal vein thrombosis† 5.2 13.7

Modified from Diamond IR, Fecteau A, Millis JM, et al. Impact of

graft type on outcome in pediatric liver transplantation: a report
0
from Studies of Pediatric Liver Transplantation (SPLIT). Ann Surg.
98 00 02 04 06 2007;246(2):301.
Year *Among patients surviving to 24 months after transplantation.
†P < .05 between whole liver and living donor recipients.
FIGURE 58-1 n Living donor liver transplants in the United States
(1998-2007). SPLIT, Studies in Pediatric Liver Transplantation.

TABLE 58-2 Outcomes of Pediatric Living Donor Liver Transplantation in Western Countries
Early Outcome (1 yr) Late Outcome (3, 4, or 5 yr)
Center PS (%) GS (%) PS (%) GS (%) Graft Type
Madrid12 96 85 96 (5 yr) 85 (5 yr) LLS: 85%
Toronto13 100 100 NR NR LLS: 77%
New York14 91 91 NR NR LLS: 91%
UNOS15 NR NR 82 (3 yr) 77 (3 yr) NS
SRTR16 90%* 85%* NR NR NS
SPLIT17 90 85 89 (4 yr) 78 (4 yr) NS

*For age < 2 yr.

GS, Graft survival; LLS, left lateral segment; NR, not reported; NS, not specified; PS, patient survival; SPLIT, Studies in Pediatric Liver
Transplantation; SRTR, Scientific Registry of Transplant Recipients; UNOS, United Network for Organ Sharing.
746 PART VI Split and Living Donor Transplantation

the greatest impact on recipients who are currently disad- Many centers believe that functional graft size and the
vantaged by the current Model for End-Stage Liver Dis- degree of portal hypertension in the recipient signifi-
ease (MELD)-based system of liver allocation and in cantly affect graft and patient outcomes after LDLT.30-32
regions of the country where access to organs at lower To achieve greater graft volume, 90% of adult LDLT
MELD scores is not possible. Discrete advantages of recipients transplanted in the United States between
LDLT include the avoidance of the physiological 1998 and 200133 and 95% of LDLT recipients trans-
derangement induced by brain death in the donor, planted between 2004 and 2007 received right lobe
reduced cold ischemic time, and the ability to provide allografts.34 With increasing donor safety concerns given
transplantation before the recipient becomes too ill. the magnitude of right hepatectomy, the use of left lobe
These advantages are balanced by the additional techni- allografts has increased in very recent years (Fig. 58-2).
cal complexity of LDLT and careful surgical judgment. Given the experimental and clinical data that portal
After a decade of LDLT refinement, it has become hyperperfusion may damage grafts of smaller size, some
clear that the outcome of LDLT depends on a number of Western centers have opted to diminish recipient portal
critical factors: (1) proper recipient selection, (2) proper inflow with hemiportocaval shunting or splenic artery
donor selection, (3) appropriate parenchymal functional ligation in both left lobe and smaller volume right lobe
mass for both donor and recipient, and (4) adequate vas- recipients.35-37
cular inflow and outflow. Ideal recipients for LDLT Although there was an initial learning curve in almost
include small-to-average–size patients with MELD all programs performing LDLT, current patient and
scores less than 25 who are free of anatomical or surgical graft survival outcomes among adult LDLT recipients
comorbidities, who have not had prior significant right are excellent.34 As depicted in Table 58-4 and Figure
upper quadrant surgery, and who do not have significant 58-3, patient and graft survival among living donor recip-
portal hypertensive disease. Although these are perfect ients in the United States at 5 years exceeds 80% and
conditions, many patients who do not fit these criteria are 70%, respectively. Moreover, there appears to be no sig-
transplanted with living donors. nificant difference in the incidence or severity of acute
Although regeneration of the liver unique to LDLT cellular rejection between LDLT and DDLT recipients,
recipients was initially feared to diminish outcomes in with similar rates of graft loss caused by rejection.38 Such
specific patient populations, the majority of these fears
have not been supported by empirical data. Patients with
hepatitis C virus have similar outcomes after LDLT or 100
deceased donor liver transplantation (DDLT), and rates
of recurrent hepatitis C virus do not appear to differ sig- Domino whole liver
80
nificantly as well.22,23 Although there is no disease cause Right lobe
that serves as a contraindication to LDLT, patients with
severe cholestatic disease and hepatocellular carcinoma Left lobe
60
Percent

(HCC) patients are frequently thought of as superior Left lateral lobe segment (Peds)
candidates for LDLT.24 Although HCC recurrence has
been modeled to be slightly higher in LDLT recipients 40
than in DDLT recipients,25 and the survival benefit of
LDLT over DDLT in HCC patients is not as pro- 20
nounced as in non-HCC patients given their level of
MELD priority,26 these patients are often selected to be
LDLT recipients given their lower biological MELD 0
2005 2006 2007 2008 2009
scores and fear of tumor progression on the waiting list.
In addition, there is the sense that some of the HCC Year
patients are “fast-tracked” with LDLT, not allowing the FIGURE 58-2 n Living donor liver transplants by graft type. Peds,
biological character of the tumor to be recognized on the Pediatrics.
waiting list.
A potentially more important determinant of post-
transplant outcome among LDLT recipients than dis- TABLE 58-4 G
 raft and Patient Survival Among
ease cause is liver disease severity. Although LDLT has LDLT Recipients (United States)
fallen out of favor as an option for high-MELD recipi-
ents given published series reporting poor outcomes No. of
among high-MELD and status1 recipients,27,28 LDLT in Study Patients Patient Survival Graft Survival
higher-MELD candidates has been performed success- UNOS33 764 79% (2 yr) 64% (2 yr)
fully in certain high-volume centers in North America UNOS40 731 87% (1 yr) 79% (1 yr)
with ­comparable short-and long-term outcomes.29 The A2ALL23 385 89% (1 yr) 81% (1 yr)
Toronto data and results from Asia suggest that although SRTR*34 1664 80% (5 yr) 75% (5 yr)
the more limited graft mass provided by LDLT may be
inadequate in patients with high physiological demand, *In the late experience of transplant centers (>15 prior LDLTs).
A2ALL, Adult-to-Adult Living Donor Liver Transplantation Study
MELD score alone does not reliably identify recipients Group; LDLT, living donor liver transplantation; SRTR, Scientific
too sick for LDLT, but that it is a multifactorial Registry of Transplant Recipients; UNOS, United Network for
process. Organ Sharing.
 58 Outcomes of Living Donor Transplantation: The Western Perspective 747

outcomes that compare favorably with DDLT, as well as environment of organ scarcity. A2ALL has not only
broad patient applicability, should ultimately promote shown that LDLT provides survival benefit for patients
the use of LDLT throughout the United States. with lower MELD (<15) scores26 but has also revealed
Although recipient outcomes early in the U.S. experi- the negative impact of prolonged waiting list time on
ence were voluntarily self-reported primarily by single overall transplant outcome. Specifically, overall mortality
center institutions with significant experience in deceased is significantly diminished among patients who undergo
donor liver transplantation39, contemporary, detailed LDLT compared to patients waiting for deceased donor
data regarding outcomes of LDLT in the United States liver transplantation (Fig. 58-4), and this survival benefit
are now available thanks to the Adult-to-Adult Living can be attributed to expeditious transplantation and
Donor Liver Transplantation (A2ALL) cohort study.23,34 avoidance of prolonged waiting times.26
This consortium has provided detailed information on
both donor and recipient outcomes of adult LDLT in the Recipient Complications. Although available data dem-
United States over a 10-year period (1998-2008) among onstrate the overall safety and efficacy of LDLT for
nine experienced transplant centers. Both retrospective appropriately selected adult recipients, data from both
and prospective data from A2ALL have provided defini- the Scientific Registry of Transplant Recipients (SRTR)
tive evidence for the utility and safety of LDLT in the and the A2ALL cohort demonstrate that the surgical
United States. Most notably, A2ALL has clearly demon- complexity of LDLT can negatively affect recipient out-
strated the survival benefit of LDLT in the current come. When compared to whole-organ DDLT, living
donor recipients have historically shown a higher early
graft failure rate (graft survival at 2 years: 64% versus
100 73%, LDLT versus DDLT),33 a higher retransplantation
6 month
rate (12% versus 6.6%, LDLT versus DDLT),40 and a
90 higher rate of biliary complications (42% versus 24%,
Percent graft survival

LDLT versus DDLT)41 (Table 58-5). However, these

1 year early analyses did not account for the improved outcomes
80 observed as center experience increases; it is important to
3 years
recognize that surgical complications drop dramatically
70 5 years with center experience and often approximate DDLT
outcomes in centers that have performed over 20
60
LDLTs.41 More recent data show improved posttrans-
plant survival that is equivalent to and perhaps better
than DDLT, and decreasing surgical complications with
50 increased experience.34 Moreover, the importance of
98 01 03 05 07 09 shortening waiting list time with LDLT should not be
Year underestimated, because the benefit of expeditious trans-
FIGURE 58-3 n Graft failure among adult living donor recipients. plantation with LDLT may outweigh the increased

0.4
LDLT vs. No LDLT:
MELD <15: HR = 0.39, P < .001
MELD 15+: HR = 0.42, P < .001
0.3
Probability of death

No LDLT - MELD <15

No LDLT - MELD 15+
0.2

LDLT - MELD 15+

0.1
LDLT - MELD <15

0.0
0 1 2 3 4 5
Patients at Risk (N)
Years from donor evaluation
No LDLT-MELD 15+ 378 303 251 212 177 131
No LDLT-MELD <15 360 297 246 208 160 114
LDLT-MELD 15+ 165 146 116 99 83 62
LDLT-MELD <15 192 168 144 131 103 73
FIGURE 58-4 n Transplant candidate mortality following initial potential donor evaluation (no hepatocellular carcinoma). HR, Hazard
ratio; LDLT, living donor liver transplantation; MELD, Model for End-Stage Liver Disease. (Reprinted with permission from Berg CL,
Merion RM, Shearon TH, et al. Liver transplant recipient survival benefit with living donation in the Model for Endstage Liver Disease
allocation era. Hepatology. 2011;54:1317.)
748 PART VI Split and Living Donor Transplantation

complication risk for any given recipient.26,42 Finally, syndrome and a relatively low frequency because of
recent OPTN data unequivocally demonstrate compara- avoidance of low-hepatic-volume allografts. There is also
ble 5-year patient survival among LDLT and DDLT the empirical use of potential therapeutic interventions
recipients (approximately 70%) and show that early graft such as splenic artery embolization and portocaval shunt-
failure among both DDLT and LDLT recipients has ing in presumed at-risk patient groups such as left lobe
decreased precipitously in recent years (in 2000, 15% grafts and small-volume right grafts and in recipients
[LDLT] versus 8% [DDLT]; in 2008, 5% [LDLT and with very high portal pressures.35-37 As a result of these
DDLT]).43 confounders, even prospective cohort studies of LDLT
Without question, biliary complications are more fre- recipients in the United States fail to provide detailed
quent in recipients of LDLT than in recipients of DDLT data on the incidence or outcomes of SFSS.23
given the tenuous nature of the bile duct blood supply, Despite the variable definitions of this entity and
the size mismatch of the bile duct between the donor and unclear prevalence, the specter of SFSS has inspired
the recipient, and the frequent necessity for multiple duct numerous investigators to attempt to calculate recipient
anastomoses. Both large-volume centers44,45 and the parenchymal requirements to avoid graft dysfunction
A2ALL data41 report the frequency of biliary complica- caused by insufficient hepatic mass—the graft-to-recipient
tions to be approximately 25% to 35% in right lobe weight ratio (GRWR) and the percentage of standard
recipients. This complication rate is comparable to the liver volume (SLV) are among the most popular. Inter-
incidence of biliary complications in Asian centers46,47 estingly, the decision to proceed with LDLT between
and left lobe recipients.48 Biliary leaks are more frequent any individual donor and recipient will often hinge on
than stricture,41 present earlier,49 and are often associated the outcome of these volumetric calculations, although
with stricture development.44 Although there is contro- significant controversy remains regarding the utility of
versy surrounding the optimal management of biliary these methods in predicting SFSS or graft dysfunction.
complications, the high complication rate after endo- Although seminal work by Kiuchi et al54 demonstrated
scopic or surgical treatment49 adds to the complexity and poor graft survival among LDLT recipients with a
challenge of biliary complications after LDLT and has GRWR of less than 0.8%, other investigators have found
motivated all centers to consider refinements in surgical that neither the GRWR nor the percentage of SLV cal-
technique to decrease this rate. Evolving techniques in culations reliably predict either the development or out-
hilar plate dissection that avoid skeletonization of the come of SFSS,52,53 because these calculations do not
biliary ducts hold some promise to decrease biliary com- account for other factors that contribute to the patho-
plication rates.50 genesis of SFSS—namely, the degree of portal hyperper-
A unique complication of LDLT that significantly fusion of the allograft, as well as the liver disease severity
contributes to the complexity of patient selection and and metabolic demand of the recipient. In the absence of
recipient morbidity and mortality is the small-for-size more predictive tools, however, GRWR and percentage
syndrome (SFSS). Although there is considerable hetero- of SLV estimates are frequently employed by U.S. trans-
geneity in the definition of SFSS, this syndrome is gener- plant centers to determine donor and recipient suitabil-
ally ascribed to patients who develop cholestasis, ity before transplant and graft type.23,39 The fear of
hypercoagulability, and ascites within 1 week of LDLT in transplantation of an inadequate hepatic mass likely
the absence of technical or immunological reasons for explains the reluctance of North American centers to
graft dysfunction.51 In sum, SFSS is thought to be the routinely use left lobe allografts. This overall reluctance
result of the transplantation of insufficient hepatic mass of North American centers to transplant left lobe
and reportedly leads to mortality or retransplantation in allografts contrasts significantly with LDLT practices in
50% of recipients in North American centers.36,52,53 Sin- Asian centers, where the use of left lobe allografts and
gle centers have published that SFSS affects 3% to 19% small right hepatic lobe allografts (i.e., GRWR < 0.8%;
of LDLT recipients,36,52,53 but the true incidence of this percentage of SLV < 40%) is being expanded.55-57
entity among LDLT recipients in North America remains Although insufficient hepatic mass may indeed con-
unknown because of a lack of consistent definition of the tribute to the development of SFSS, there are data that
suggest that hepatic hyperperfusion or vascular conges-
tion may also be responsible for this phenomenon.31,58
TABLE 58-5 C
 omplication Rates Among Inflow modification of the graft may be performed to
Recipients of LDLT Versus DDLT attenuate the degree of portal hyperperfusion; techniques
that are widely described include splenic artery ligation,
Complication LDLT (%) DDLT (%) splenectomy, and portomesenteric shunting, and a num-
Retransplantation40 12 6.5 ber of both Eastern and Western centers have used these
Complications leading to 15.9 9.3 techniques either to prevent SFSS in recipients of small
retransplantation or death41 grafts or to treat the process after transplantation.36,59-62
Biliary leak41 27 10 Ensuring adequate venous outflow of the graft is also
Bile duct bacterial infection41 8 3 critical to avoiding SFSS, and hepatic venous reconstruc-
Vascular41 6.5 2.3 tion or a posterior cavoplasty has been described to avoid
Hepatic artery thrombosis 2.9 0 outflow congestion of the transplanted lobe.63,64 Although
Portal vein thrombosis
modification of graft vascular inflow and outflow may
DDLT, Deceased donor liver transplantation; LDLT, living donor liver indeed prevent or treat SFSS and even permit the wider
transplantation. use of left lobe allografts,36,61 objective criteria that will
 58 Outcomes of Living Donor Transplantation: The Western Perspective 749

allow standardization and the development of protocols to receive LDLT in Europe greatly resembles LDLT
for these techniques are lacking. Although measurement recipients in the United States and Canada in terms of
of hepatic arterial and portal inflow via manometry, ultra- graft type, transplant indication, and degree of liver dis-
sonography, or transonic flowmetry has been described ease severity.
by single centers,59,65 the widespread use of these tech- Patient and graft survival outcomes for adult recipients
niques to identify recipients who would benefit from vas- of LDLT in Europe are shown in Table 58-6. As pub-
cular modification awaits multicenter validation. Such a lished in the referenced single-center and multicenter
study of discrete measurement of hepatic hemodynamics reports, 1-year patient and graft survival is consistently
is currently being conducted by the A2ALL consortium. on the order of 80%, and 3-yr survival is approximately
70%. The European Liver Transplant Registry reports a
Europe comprehensive 80% 1-year, 73% 3-year, and 69% 5-year
graft survival among 4196 living donor recipients that
The experience with LDLT in European countries over were transplanted between January 1988 and December
the last 15 years has mirrored the North American expe- 2010, but these data do not fractionate pediatric from
rience in many ways. The first adult LDLT in Europe adult recipients (http://www.eltr.org). Nevertheless,
was performed in Essen, Germany, in 1998,8 and LDLT there is ample evidence that survival outcomes in Europe
subsequently expanded to numerous European centers reproduce those in the United States, as would be
throughout the 1990s. By 2001, 46 of 118 registered expected in experienced transplant centers performing
European transplant centers had performed this type of similar procedures on comparable patient populations.
transplant.9 However, the adoption of LDLT through- Likewise, all of these reports state that biliary complica-
out Europe was not homogenous; whereas Great Britain tions are the most frequent type of complication in
used LDLT infrequently and primarily for foreign LDLT recipients, affecting approximately 15% to
patients who did not have ready access to cadaveric trans- 45%.8,9,68 Although fear of the SFSS is mentioned in
plantation,66 German transplant centers embraced these series of patients, there are few reports of its
LDLT to a much greater degree.67 At its peak in 2000 occurrence.
and 2001, 11% of the liver transplants in Germany were
performed from living donors.9 However, the enthusiasm
for this technique has waned substantially in Germany in DONOR OUTCOMES OF LIVING DONOR
recent years because of several well-publicized donor LIVER TRANSPLANTATION IN THE WEST
deaths in the United States and Europe, as well as the
recent adoption of MELD allocation in Germany. Adult- The reluctance of many Western centers to aggressively
to-adult LDLT represented only approximately 3% of expand living donor programs can be attributed primarily
German transplants performed between 2006 and 2009.68 to access to deceased donors and valid concerns regarding
As is commonly practiced in North America, ­European donor safety. Although rates of donor complications have
centers have primarily performed right lobe transplants decreased, the rate remains significant, and severe donor
in adult recipients because of concerns regarding the complications, including deaths, have nonetheless been
matching of recipient metabolic demand with adequate observed, even in the most experienced centers. Although
hepatic mass. According to the European Liver Trans- many complications are minor in this healthy population,
plant Registry, 93% of the 359 adult recipients of LDLT any complication that afflicts an altruistic patient that did
from 1991 to 2001 received a right lobe transplant.67 not need an operation is cause for concern. Even though
Similarly, LDLT is generally avoided in European recip- donor safety is of utmost priority, and protocols are put in
ients who possess MELD scores over 25,69 and published place to minimize complications, it must be recognized
data indicate that European recipients of LDLT fre- that it is impossible to make the risk negligible for an
quently have MELD scores in the range of 15 to 23 and operation of such magnitude. Counseling a potential
are more frequently transplanted for cholestatic liver dis- donor with respect to the risks involved in donor hepa-
ease and HCC.68 Hence the patient population selected tectomy is ethically mandated before undertaking LDLT,
but until recently there have been few registry data to
allow estimation of true risk.
TABLE 58-6 G
 raft and Patient Survival Among As of 2010 there had been 20 deaths reported globally
LDLT Recipients (Europe) among living hepatic donors, and one additional donor
remains in a persistent vegetative state.10,70 Fourteen of
No. of Patient Graft these deaths have been attributed directly to donation,
Study Patients Survival Survival
whereas the other deaths that occurred were not necessar-
Broelsch et al 123 86% 83% ily a consequence of the surgical procedure.10 Most of
(11 centers)8 these deaths (n = 9) occurred in right hepatic lobe donors,
ELTR67 359 66% (3 yr) 66% (3 yr) but the data set is incomplete because of a lack of manda-
UK66 16 75% 75% tory global reporting. Deaths have been due primarily to
Settmacher et al 408 82% (1 yr) NR sepsis, myocardial infarction, cerebral hemorrhage, and
(25 centers)9
pulmonary emboli.10 Available data suggest that overall
Germany68 84 81% (1 yr) NR
donor mortality after liver donation in the United States
ELTR, European Liver Transplant Registry; LDLT, living donor liver and Europe is on the order of 0.2%; this frequency is cal-
transplantation; NR, not reported; UK, United Kingdom. culated based on the known deaths of seven donors among
750 PART VI Split and Living Donor Transplantation

TABLE 58-7 C
 lavien System for Classification TABLE 58-8 D
 onor Complications Reported by
of Negative Surgical Outcomes the A2ALL Cohort Study (n = 740)
Clavien Grade Complication Description Clavien Grade (%)
Frequency
Grade 1 Any deviation from routine Complication (%) 1 2 3 4
­postoperative course
Biliary leak 8.1 3.3 4.7
Grade 2 Potentially life threatening
Biliary stricture 0.6 0.1 0.5
Results in ICU stay > 5 days or
hospitalization > 4 weeks Incisional hernia 6.6 1.3 5 0.1
No permanent disability Unplanned 2.7 0.1 2.6 0.1
reexploration
Grade 3 Residual lasting disability or the
Bowel obstruction 1.6 0.4 1.1
development of malignant disease
DVT 0.8 0 0.8
Grade 4 Retransplantation or death
Pulmonary 0.9 0.2 0.7
embolism
ICU, Intensive care unit.
Liver failure 0
HAT/PVT 0.5 0.2 0.2
4,598 donor hepatectomies.10 Although these compiled Infection 13.2 3.3 9.7 0.1
Psychological 5.6 3.1 2.3 0.3
data suggest that mortality is higher among donors of the difficulties
right hepatic lobe versus the left hepatic lobe, this finding
has not been consistently reported among the limited Modified from Abecassis MM, Fisher RA, Olthoff KM, et al.
number of Western centers that have retrospectively eval- Complications of living donor hepatic lobectomy—a comprehen-
uated this issue.70 The United Network for Organ Shar- sive report. Am J Transplant. 2012;12:1208.
A2ALL, Adult-to-Adult Living Donor Liver Transplantation Study
ing (UNOS)/OPTN mandates reporting of donor death Group; DVT, deep venous thrombosis; HAT, hepatic artery
in the United States and should be a reliable data source. thrombosis; PVT, portal vein thrombosis.
Data regarding donor morbidity in Western centers
have been published by a number of centers as well as the
A2ALL cohort. In studies that include donors of either complications, and two from psychological difficulties that
the right or left hepatic lobe, the overall complication occurred later. Most of these complications occurred
rate has been on the order of 21%.70 However, in studies within the first 3 months of surgery, but psychological dif-
including only right hepatic lobe donors, complication ficulties and hernias tended to develop later after donation
rates are higher and have ranged between 38% and but within the first 2 to 3 years. Overall, the complication
47%.11,71 The most recent publication from the A2ALL rates and severity reported by the A2ALL71,72 consortium
consortium reports an overall donor complication rate of reflect other single-center experiences throughout the
40%, ranging from minor to life-threatening complica- United States and Europe11,70, 75-77 (Table 58-9).
tions.72 These data from Western centers are congruent
with the widely held belief that morbidity is higher among
donors of right hepatic lobes, owing to the more exten- CONCLUSIONS
sive operative dissection.
Reported complications in donors of hepatic lobes have LDLT has successfully allowed the transplantation of
ranged in diversity and severity from pleural effusions to thousands of patients in the United States, Canada, and
suicide. Most laboratory abnormalities that occur in Europe with excellent recipient outcomes over the last
donors after lobectomy (i.e., mild elevations of transami- decade. Children in particular benefit greatly from LDLT
nase and bilirubin levels) resolve quickly, although 20% of given their limited access to cadaveric grafts of appropri-
donors may have persistently lower platelet counts 2 to 3 ate size, and outcomes among pediatric recipients of
years after donation, though the clinical significance of this LDLT are comparable if not superior to those of cadav-
finding is unknown.73 Liver failure requiring rescue trans- eric recipients. Unfortunately, the use of LDLT among
plantation is extremely rare but ­frequently fatal; only five adult recipients in the West is currently much more lim-
cases have been reported in the global literature, and four ited. Following a brief surge in 2000 and 2001, LDLT has
of these cases were reported in donors of the right lobe.74 decreased in frequency and now constitutes approximately
Data from the A2ALL consortium indicate that approxi- only 3% to 5% of all liver transplants performed in West-
mately 50% of donor complications are minor, defined as ern transplant centers, except for a few unique centers.
grade 1 by the Clavien system (Table 58-7).72 Although The expansion of LDLT beyond this frequency has been
Clavien grade 3 or 4 complications were rare (1.1%), these limited in the West by both recipient and donor consider-
complications led to death of the donor or permanent dis- ations. Although contemporary data from UNOS indicate
ability. Of all donor complications reported by the consor- comparable patient survival between living donor and
tium, infections, pleural effusion, bile leak, and incisional cadaveric donor recipients, biliary and vascular complica-
hernia were most common (Table 58-8).72 Clavien grade 3 tions are clearly more numerous in living donor recipients
complications included one intra-abdominal abscess,
­ and contribute to diminished graft survival in this popula-
one bowel obstruction, and three wound complications tion. In addition, enthusiasm for LDLT in the West has
(two hernias, one dehiscence).72 There were three donor been tempered by concerns over donor safety. Although
deaths in the A2ALL retrospective cohort, one early serious complications such as donor mortality or need for
because of infection that could be attributed to surgical transplantation are extremely uncommon throughout the
 58 Outcomes of Living Donor Transplantation: The Western Perspective 751

TABLE 58-9 Donor Complications (Single-Center Studies) (North America and Europe)
Complications
Liver
Study No. of Patients Death (%) Biliary (%) Infection (%) PE/DVT (%) Hernia (%) ­Dysfunction (%)
Italy77 75 0 9.3 2.6 1.3 0 4
(right lobe)
Pittsburgh76 121 0 6 5 2 3 0.8
(right lobe)
Toronto75 202 0 3.5 4.5 2 4 0
(right lobe)
Germany70 87 (right or left 0 4.6 8 0 4.6 0
lobe)
France11 91 0 14 14 0 0 2.2
(right lobe)

DVT, Deep venous thrombosis; PE, pulmonary embolism.

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the rate of biliary complications is comparable between 15. Abt PL, Rapaport-Kelz R, Desai NM, et al. Survival among pedi-
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752 PART VI Split and Living Donor Transplantation

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