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Liver Transplantation: Clinical Assessment and Management [2nd Edition]
 1119633982, 9781119633983, 9781119633990, 9781119634010

Table of contents :
List of Contributors

Foreword to the first edition

See PDF for foreword to reuse

Foreword to the second edition

Preface

Abbreviations

Copyeditor please collate from chapters into one list

PART 1 When to Refer a Patient for Liver Transplantation

1 Overview on organ donation and liver transplantation

Michael Ronan Lucey

2 Predicting Outcomes and Use and Abuse of Prognostic Models

Moira B. Hilscher and Patrick S. Kamath

PART 2 Selection, Assessment and Management on the List

3 Assessment of the potential transplant recipient

Michael Volk

4 Frailty and pre-habilitation

Armstrong MJ, Lai JC

5 Alcohol use (excluding alcohol related liver disease), Tobacco, Marijuana and Illicit Drugs

John P. Rice

6 The Role of the Psychiatric Consultant in the Selection, Assessment and Management of Liver Transplant Patients

RM Weinrieb

7 When Liver Transplant Patients do not Adhere to Therapeutic Plans

Kerry Webb and Rowena Jones

8 Liver transplant assessment for young people : addressing the needs of young people with liver disease

M Samyn, J Day

9 Assessment and Management of the patient with Hepatitis C

Emma L. Hathorn and David J. Mutimer

10 MANAGEMENT OF HBV INFECTION PRE-TRANSPLANTATION

Bruno ROCHE, Didier SAMUEL

11 Transplantation For The Management Of Malignancy

Adiba I. Azad, Julie K. Heimbach and Gregory J. Gores

12 Assessment and management of the liver transplant candidate with acute-on-chronic liver failure

Giovanni Perricone and Rajiv Jalan

13 Assessment and Management of the transplant candidate with alcohol-associated liver disease

Stéphanie Faure, Magda Meszaros, Lucy Meunier, Hélène Donnadieu-Rigole, Georges-Philippe Pageaux

14 NAFLD as an indication for liver transplantation

P. Horn, P.N. Newsome

15 Consent

Christopher J.E. Watso

16 Prehabilitation and General Management

Matt Armstrong and F. Williams

17 Removal of Patients from the Liver Transplant Waiting List

John O’Grady

18 Palliative Care and Liver Transplantation

Mina Rakoski and Puneeta Tandon

PART 3 Transplantation for Acute Liver Failure

19 Assessment of the Patient with Acute Liver Failure

Ashley Barnabas and John O’Grady

20 Management of the Patient with Fulminant Hepatic Failure Awaiting Liver Transplantation

Robert J. Fontana

PART 4 Donation and Allocation

21 Ethical and Legal Aspects of Organ Donation

Jessica Mellinger

22 Liver allocation, including Principles of organ allocation

Parita Patel and Michael Charlton

23 Living Donor Liver Transplant (LDLT) in Children

Adebowale A. Adeyemi, Elizabeth B. Rand, Kim M Olthoff

24 Living liver donation in adults

Mohamed Rela and Ashwin Rammohan

25 Deceased Liver Donors: Standard and Expanded Criteria

Shareef Syed and Sandy Feng

26 Donor Transmitted Disease

James Neuberger

27 LIVER DONATION AND PRESERVATION

Navneet Tiwari, Hynek Mergental

28 Liver Retrieval and Preservation

Carlo DL Ceresa, Brian R Davidson, Peter J Friend and Rutger J Ploeg

29 Alternatives to Whole Graft Liver Transplantation

Paolo Muiesan, Alessandro Parente, Hector Vilca-Melendez

30 Surgical aspects of deceased donor transplantation

Amit Nair, K.V Narayanan Menon, Cristiano Quintini and Charles Miller

PART 5 Care of the Liver Transplant Recipient

31 Outcomes after liver transplantation

James Neuberger

32 Out-patient follow-up of liver transplant recipients

Amardeep Khanna & James Ferguson

33 Medication adherence

Maureen Whitsett, Josh Levitsky

34 Transitional Care

Fiona Thompson

35 Managing the liver transplant recipient with abnormal liver blood tests

Joanna A Leithead

36 The Immune System in Liver Transplantation: Rejection vs. Tolerance

Palak J. Trivedi and Nick D. Jones

37 Immunosuppressive Medications – Liver Transplantation

Mitchell T, MacQuillan G

38 Immunosuppression in Liver Transplantation

Nicholas Lim and John R. Lake

39 : Patterns of Liver Allograft Rejection

G. W. McCaughan, K. Liu, A. Majumdar, P. Bertolino, D.G. Bowen, S. I. Strasser

40 De novo autoimmune hepatitis

James Neuberger

41 Managing rejection

Neil Halliday & Douglas Thorburn

42 Withdrawal of Immunosuppression after liver transplantation

Luca Toti, Tommaso Maria Manzia, Francesca Blasi, Giuseppe Tisone.

43 Liver Transplant Pathology

Owen L Cain and Stefan G Hübscher

44 Care of the Liver Transplant Recipient: Management of Renal Function

Andres F. Carrion, Paul Martin

45 Managing Cardiovascular Risk in the Liver Transplant Recipient

Manhal Izzy and Kymberly D. Watt

46 Bone Disease in Liver Transplantation

John Ayuk

47 Diagnosis and Management of Recurrent Autoimmune Liver Disease

Fernanda Q Onofrio, Nazia Selzner, Gideon M Hirschfield

48 NAFLD and NASH in the patient after liver transplantation

P. Horn, P.N. Newsome

49 Recurrent Metabolic Diseases

James Neuberge

50 Treatment of Hepatitis C in the Transplant Setting

Jeffrey Kahn and Norah A. Terrault

51 MANAGEMENT OF HBV INFECTION POST-TRANSPLANTATION

Bruno ROCHE, Didier SAMUEL

52 Antimicrobial prophylaxis following liver transplantation

Michael J Williams, Peter C Hayes

53 Cytomegalovirus and the liver transplant recipient

James Ferguson

54 Post-liver transplant infections

Miruna David, Ahmed El-Sharkawi

55 De novo malignancies after liver transplantation

Simone I Strasser, Ken Liu, Avik Majumdar, Geoffrey W McCaughan

56 Post-transplant lymphoproliferative disorders (PTLD).

Jose I. Herrero

57 Quality of life and Employment after liver transplantation

Santiago Tome, Esteban Otero, and Michael Lucey

58 Sexual function, fertility and pregnancy in liver disease and after liver transplantation

Patrizia Burra, Salvatore Stefano Sciarrone, Patrizio Bo

59 Common Drug Interactions

Amanda Smith

60 Immunization and Liver Transplantation

Erin Spengler

Postscript

Index

Citation preview

Liver Transplantation

Liver Transplantation Clinical Assessment and Management

Second Edition

Edited by

James Neuberger, DM, FRCP

Honorary Consultant Physician, Queen Elizabeth Hospital, Birmingham, UK

James Ferguson, MD, FRCPE

Consultant Hepatologist, Queen Elizabeth Hospital and Hon Reader in Medicine, University of Birmingham, Birmingham, UK

Philip N. Newsome, PhD, FRCPE

Professor of Experimental Hepatology and Director of the Centre for Liver and Gastrointestinal Research, University of Birmingham and Consultant Transplant Hepatologist, Queen Elizabeth Hospital, Birmingham, UK

Michael Ronan Lucey, MD, FRCPI

Professor of Medicine and Chief, Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

This edition first published 2021 © 2021 John Wiley & Sons Ltd Edition History John Wiley & Sons, Ltd.(1e, 2014) All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions. The right of James Neuberger, James Ferguson, Philip N. Newsome and Michael Ronan Lucey to be identified as the authors of the editorial material in this work has been asserted in accordance with law. Registered Office(s) John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial Office 9600 Garsington Road, Oxford, OX4 2DQ, UK For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com. Wiley also publishes its books in a variety of electronic formats and by print-on-demand. Some content that appears in standard print versions of this book may not be available in other formats. Limit of Liability/Disclaimer of Warranty The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting scientific method, diagnosis, or treatment by physicians for any particular patient. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. Library of Congress Cataloging-in-Publication Data Names: Neuberger, James, editor. | Ferguson, James, 1975- editor. | Newsome, Philip N., editor. | Lucey, Michael R., editor. Title: Liver transplantation : clinical assessment and management / edited by James Neuberger, James Ferguson, Philip N. Newsome, Michael Ronan Lucey. Other titles: Liver trasplantation (2014) Description: Second edition. | Hoboken, NJ : John Wiley & Sons, Inc., 2021. | Includes bibliographical references and index. Identifiers: LCCN 2020030504 (print) | LCCN 2020030505 (ebook) | ISBN 9781119633983 (cloth) | ISBN 9781119634027 (adobe pdf) | ISBN 9781119633990 (epub) Subjects: MESH: Liver Transplantation | Liver Diseases–surgery Classification: LCC RD546 (print) | LCC RD546 (ebook) | NLM WI 770 | DDC 617.5/5620592–dc23 LC record available at https://lccn.loc.gov/2020030504 LC ebook record available at https://lccn.loc.gov/2020030505 Cover Design: Wiley Cover Image: © SEBASTIAN KAULITZKI/SCIENCE PHOTO LIBRARY/Getty Images Set in 9.5/12.5pt STIXTwoText by SPi Global, Pondicherry, India 10  9  8  7  6  5  4  3  2  1

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Contents List of Contributors  x Foreword to the Second Edition  xx Foreword to the First Edition  xxi Preface  xxii Abbreviations  xxiii Part 1  When to Refer a Patient for Liver Transplantation  1 1 Overview on Organ Donation and Liver Transplantation  3 Michael Ronan Lucey 2 Predicting Outcomes and Use and Abuse of Prognostic Models  11 Moira B. Hilscher and Patrick S. Kamath Part 2  Selection, Assessment, and Management on the List  19 3 Assessment of the Potential Transplant Recipient  21 Michael L. Volk 4 Frailty and the Potential Liver Transplant Candidate  27 Matthew J. Armstrong and Jennifer C. Lai 5 Alcohol Use (excluding Alcohol-Related Liver Disease), Tobacco, Marijuana, and Illicit Drugs  33 John P. Rice 6 The Role of the Psychiatric Consultant in the Selection, Assessment, and Management of Liver Transplant Patients  39 Robert M. Weinrieb and Arpita Goswami-Banerjee

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Contents

7 When Liver Transplant Patients Do Not Adhere to Therapeutic Plans  48 Kerry Webb and Rowena Jones 8 Liver Transplant Assessment for Young People: Addressing the Needs of Young People with Liver Disease  55 Marianne Samyn and Jemma Marie Day 9 Assessment and Management of the Patient with Hepatitis C  64 Emma L. Hathorn and David J. Mutimer  10 Management of Hepatitis B Virus Infection Pre Transplantation  68 Bruno Roche and Didier Samuel 11 Transplantation for the Management of Malignancy  74 Adiba I. Azad, Julie K. Heimbach, and Gregory J. Gores 12 Assessment and Management of the Liver Transplant Candidate with Acute-on-Chronic Liver Failure  82 Giovanni Perricone and Rajiv Jalan 13 Assessment and Management of the Transplant Candidate with Alcohol-Associated Liver Disease  96 Stéphanie Faure, Magdalena Meszaros, Lucy Meunier, Hélène Donnadieu-Rigole, and Georges-Philippe Pageaux 14 Non-alcoholic Fatty Liver Disease as an Indication for Liver Transplantation  104 Paul Horn and Philip N. Newsome 15 Consent 109 Christopher J.E. Watson 16 Prehabilitation and General Management  116 Matthew J. Armstrong and Felicity R. Williams 17 Removal of Patients from the Liver Transplant Waiting List  123 John O’Grady 18 Palliative Care and Liver Transplantation  126 Mina Rakoski and Puneeta Tandon Part 3  Transplantation for Acute Liver Failure  135 19 Assessment of the Patient with Acute Liver Failure  137 Ashley Barnabas and John O’Grady 20 Management of the Patient with Fulminant Hepatic Failure Awaiting Liver Transplantation  143 Robert J. Fontana

Contents

Part 4  Donation and Allocation  153 21 Ethical and Legal Aspects of Organ Donation  155 Jessica Mellinger 22 Liver Allocation, Including Principles of Organ Allocation  161 Parita Patel and Michael Charlton 23 Living Donor Liver Transplant in Children  168 Adebowale A. Adeyemi, Elizabeth B. Rand, and Kim M. Olthoff  24 Living Liver Donation in Adults  180 Mohamed Rela and Ashwin Rammohan 25 Deceased Liver Donors: Standard and Expanded Criteria  190 Shareef Syed and Sandy Feng 26 Donor-Transmitted Disease  203 James Neuberger 27 Liver Donation and Preservation  209 Navneet Tiwari and Hynek Mergental 28 Liver Retrieval and Preservation  223 Carlo D.L. Ceresa, Brian R. Davidson, Peter J. Friend, and Rutger J. Ploeg 29 Alternatives to Whole Graft Liver Transplantation  236 Paolo Muiesan, Alessandro Parente, and Hector Vilca-Melendez 30 Surgical Aspects of Deceased Donor Transplantation  252 Amit Nair, K.V. Narayanan Menon, Cristiano Quintini, and Charles Miller Part 5  Care of the Liver Transplant Recipient  265 31 Outcomes after Liver Transplantation  267 James Neuberger 32 Outpatient Follow-Up of Liver Transplant Recipients  276 Amardeep Khanna and James Ferguson 33 Medication Adherence  285 Maureen Whitsett and Josh Levitsky 34 Transitional Care  299 Fiona Thompson

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35 Managing the Liver Transplant Recipient with Abnormal Liver Blood Tests  303 Joanna A. Leithead 36 The Immune System in Liver Transplantation: Rejection versus Tolerance  317 Palak J. Trivedi and Nick D. Jones 37 Immunosuppressive Medications: Liver Transplantation  334 Tim Mitchell and Gerry MacQuillan 38 Immunosuppression in Liver Transplantation  344 Nicholas Lim and John R. Lake 39 Patterns of Liver Allograft Rejection  353 Geoffrey W. McCaughan, Ken Liu, Avik Majumdar, Patrick Bertolino, David G. Bowen, and Simone I. Strasser 40 De Novo Autoimmune Hepatitis  360 James Neuberger 41 Managing Rejection  364 Neil Halliday and Douglas Thorburn 42 Withdrawal of Immunosuppression after Liver Transplantation  386 Luca Toti, Tommaso Maria Manzia, Francesca Blasi, and Giuseppe Tisone 43 Liver Transplant Pathology  393 Owen L. Cain and Stefan G. Hübscher 44 Care of the Liver Transplant Recipient: Management of Renal Function  403 Andres F. Carrion and Paul Martin 45 Managing Cardiovascular Risk in the Liver Transplant Recipient  409 Manhal Izzy and Kymberly D. Watt 46 Bone Disease in Liver Transplantation  418 John Ayuk 47 Diagnosis and Management of Recurrent Autoimmune Liver Disease  424 Fernanda Q. Onofrio, Nazia Selzner, and Gideon M. Hirschfield 48 NAFLD and NASH in the Patient after Liver Transplantation  438 Paul Horn and Philip N. Newsome 49 Recurrent Metabolic Diseases  445 James Neuberger 50 Treatment of Hepatitis C in the Transplant Setting  449 Jeffrey Kahn and Norah A. Terrault

Contents

51 Management of Hepatitis B Virus Infection Post Transplantation  458 Bruno Roche and Didier Samuel 52 Antimicrobial Prophylaxis Following Liver Transplantation  469 Michael J. Williams and Peter C. Hayes 53 Cytomegalovirus and the Liver Transplant Recipient  475 James Ferguson 54 Post-Liver Transplant Infections  481 Miruna David and Ahmed Elsharkawy 55 De Novo Malignancies after Liver Transplantation  493 Simone I. Strasser, Ken Liu, Avik Majumdar, and Geoffrey W. McCaughan 56 Post-Transplant Lymphoproliferative Disorders  500 Jose Ignacio Herrero 57 Quality of Life and Employment after Liver Transplantation  507 Santiago Tome, Esteban Otero, and Michael Ronan Lucey 58 Sexual Function, Fertility, and Pregnancy in Liver Disease and after Liver Transplantation  514 Patrizia Burra, Salvatore Stefano Sciarrone, and Patrizio Bo 59 Common Drug Interactions  519 Amanda Smith 60 Immunization and Liver Transplantation  525 Jessica Hause and Erin Spengler Postscript  529 James Neuberger Index  531

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­List of Contributors Adebowale A. Adeyemi, MD Medical Director, Liver Transplant Program Nemours/Alfred I. duPont Hospital for Children Wilmington, DE USA Matthew J. Armstrong, PhD, MRCP Consultant in Liver and Transplant Medicine Queen Elizabeth University Hospital Honorary Lecturer National Institute for Health Research Biomedical Research Centre University of Birmingham Birmingham, UK John Ayuk, MD Consultant Endocrinologist Queen Elizabeth Hospital Honorary Senior Lecturer University of Birmingham Birmingham UK Adiba I. Azad, MD, PhD Gastroenterology Fellowship Mayo Clinic Rochester, MN USA Ashley Barnabas, MRCP Clinical Research Fellow Institute of Liver Studies King’s College Hospital London UK

Patrick Bertolino, MD Associate Professor Centenary Institute of Cancer Medicine and Cell Biology AW Morrow Gastroenterology & Liver Centre Royal Prince Alfred Hospital University of Sydney Camperdown Australia Francesca Blasi, MD PhD student Transplant and HepatobiliaryUnit Department of Surgery University of Rome Tor Vergata Rome Italy Patrizio Bo, MD Gynecologist Obstetrics and Gynecology Unit Cittadella Hospital Cittadella Padua Italy David G. Bowen, MD Associate Professor of Medicine Centenary Institute of Cancer Medicine and Cell Biology AW Morrow Gastroenterology & Liver Centre Australian National Liver Transplant Unit Royal Prince Alfred Hospital University of Sydney Camperdown Australia

­List of Contributor

Patrizia Burra, MD, PhD Professor and Head of Multivisceral Transplant Unit Department of Surgery, Oncology and Gastroenterology Padua University Hospital Padua Italy

Brian R. Davidson, MB, ChB, MD, FRCS (Glasg), FRCSEng Professor of Surgery University College London Consultant HPB and Liver Transplant Surgeon Wellington Hospital and Royal Free Hospital NHS Foundation Trust London UK

Owen L. Cain, MD, FRCPath Consultant Histopathologist Queen Elizabeth Hospital Birmingham UK

Jemma Marie Day, DClinPsy Clinical Psychologist Department of Child Health King’s College Hospital Foundation NHS Trust London UK

Andres F. Carrion, MD Assistant Professor of Clinical Medicine Division of Gastroenterology and Hepatology University of Miami Miller School of Medicine Miami, FL USA

Hélène Donnadieu-Rigole, MD, PhD Consultant and Head of Department Addiction Unit, CHU Saint Eloi Montpellier University Montpellier France

Carlo D.L. Ceresa, MB, ChB, MRCS, DPhil MRC Clinical Research Fellow Nuffield Department of Surgical Sciences, University of Oxford Oxford University Hospitals NHS Foundation Trust Oxford UK Michael Charlton, MD, FRCP Professor of Medicine Director, Center for Liver Diseases University of Chicago Biological Sciences Chicago, IL USA Miruna David, MRCP, FRCPath Consultant Microbiologist Department of Microbiology Queen Elizabeth Hospital Birmingham UK

Ahmed Elsharkawy, MD Consultant Hepatologist Liver Unit Queen Elizabeth Hospital Birmingham UK Stéphanie Faure, MD Consultant Hepatology and Liver Transplantation Unit, CHU Saint Eloi Montpellier University Montpellier France Sandy Feng, MD, PhD Professor of Surgery Director of the Abdominal Transplant Fellowship Program Division of Transplantation, Department of Surgery University of California–San Francisco San Francisco, CA USA

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James Ferguson, MD Consultant Physician and Honorary Reader Liver Unit Queen Elizabeth Hospital Birmingham UK Robert J. Fontana, MD Professor of Medicine and Medical Director of Liver Transplantation University of Michigan Medical School Ann Arbor, MI USA Peter J. Friend, MD, FRCS Professor of Transplantation Nuffield Department of Surgical Sciences, University of Oxford Consultant HPB and Transplant Surgeon Oxford University Hospitals NHS Foundation Trust Oxford UK Gregory J. Gores, MD Consultant Division of Gastroenterology and Hepatology, Department of Internal Medicine Executive Dean for Research Mayo Foundation for Medical Education and Research Mayo Clinic Rochester, MN USA Arpita Goswami-Banerjee Penn Transplant Institute University of Pennsylvania Health Systems Perelman School of Medicine Philadelphia, PA USA Neil Halliday, MB BS, BSc Speciality Registrar Institute for Liver and Digestive Health University College London The Sheila Sherlock Liver Centre Royal Free Hospital London UK

Emma L. Hathorn, MD Fellow Queen Elizabeth Hospital Birmingham UK Jessica Hause Fellow Gastroenterology & Hepatology Faculty University of Wisconsin Madison, WI USA Peter C. Hayes, MD, PhD Professor of Hepatology and Consultant Physician Scottish Liver Transplant Unit Royal Infirmary of Edinburgh Edinburgh UK Julie K. Heimbach, MD Professor of Surgery Consultant and Chair Division of Transplantation Surgery, Department of Surgery Mayo Clinic Rochester, MN USA Jose Ignacio Herrero, MD Consultant, Liver Unit Clinica Universidad de Navarra Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) Instituto de Investigación Sanitaria de Navarra (IdiSNA) Pamplona Spain Moira B. Hilscher, MD Consultant Gastroenterologist Division of Gastroenterology and Hepatology Mayo Clinic Rochester, MN USA

­List of Contributor

Gideon M. Hirschfield, MRCP, PhD Lily and Terry Horner Chair in Autoimmune Liver Disease Research Toronto Centre for Liver Disease, Toronto General Hospital University Health Network Toronto Canada Paul Horn, MSc, MD Research Fellow Centre for Liver and Gastrointestinal Research Birmingham UK Stefan G. Hübscher, MC, ChB, FRCPath Leith Professor and Professor of Hepatic Pathology Institute of Immunology and Immunotherapy University of Birmingham Consultant Histopathologist Queen Elizabeth Hospital Birmingham UK Manhal Izzy, MD Assistant Professor of Medicine Department of Gastroenterology and Hepatology Vanderbilt University Medical Center Nashville, TN USA Rajiv Jalan, MD, FRCP Professor of Hepatology and Head, Liver Failure Group UCL Institute for Liver and Digestive Health UCL Medical School, Royal Free Hospital London UK Nick D. Jones, BSc, DPhil Senior Lecturer Institute of Immunology and Immunotherapy University of Birmingham Birmingham UK Rowena Jones, MD Liver Unit, Queen Elizabeth Hospital Birmingham UK

Jeffrey Kahn, MD Assistant Professor of Clinical Medicine Division of Gastrointestinal and Liver Diseases University of Southern California Los Angeles, CA USA Patrick S. Kamath, MD Consultant, Division of Gastroenterology and Hepatology Department of Internal Medicine Mayo Clinic Rochester, MN USA Amardeep Khanna, MRCP Specialist Registrar Liver Unit Queen Elizabeth Hospital Birmingham UK Jennifer C. Lai, MD Gastroenterologist Division of Gastroenterology and Hepatology Department of Medicine University of California–San Francisco San Francisco, CA USA John R. Lake, MD, BCh, BAO Assistant Professor of Medicine Division of Gastroenterology, Hepatology and Nutrition University of Minnesota Minneapolis, MN USA Joanna A. Leithead, MBChB, MRCP Consultant Hepatologist Addenbrookes Hospital Cambridge UK Josh Levitsky, MD, MS Professor of Medicine (Gastroenterology and Hepatology), Medical Education and Surgery (Organ Transplantation) Northwestern Memorial Hospital Chicago, IL, USA

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Nicholas Lim, MD Professor of Surgery and Medicine Executive Medical Director for Solid Organ Transplantation University of Minnesota Medical Center Minneapolis, MN USA

Tommaso Maria Manzia, MD, PhD, FEBS Professor in Liver and Kidney Transplantation Transplant and Hepatobiliary Unit Department of Surgery University of Rome Tor Vergata Rome Italy

Ken Liu, MD Senior Clinical Lecturer Centenary Institute of Cancer Medicine and Cell Biology; AW Morrow Gastroenterology and Liver Centre; Australian National Liver Transplant Unit Royal Prince Alfred Hospital University of Sydney Camperdown Australia

Paul Martin, MD, FRCP, FRCPI Chief, Division of Digestive and Liver Diseases Professor of Medicine University of Miami Miller School of Medicine Miami, FL USA

Michael Ronan Lucey, MD Professor of Medicine Chief, Division of Gastroenterology and Hepatology University of Wisconsin School of Medicine and Public Health Madison, WI USA Gerry MacQuillan, PhD, FRACP, FRCP Consultant Transplant Hepatologist/ Gastroenterologist WA Liver Transplantation Service Hepatology Department and Liver Transplant Service Sir Charles Gairdner Hospital Nedlands, WA Australia Avik Majumdar, MD Senior Clinical Lecturer AW Morrow Gastroenterology and Liver Centre; Australian National Liver Transplant Unit Royal Prince Alfred Hospital University of Sydney Camperdown Australia

Geoffrey W. McCaughan, MD Professor of Medicine Faculty and Program Head, Liver Injury and Cancer Program Centenary Institute of Cancer Medicine and Cell Biology Director, AW Morrow Gastroenterology and Liver Centre Co-Director, Australian National Liver Transplant Unit Royal Prince Alfred Hospital University of Sydney Camperdown Australia Jessica Mellinger, MD, MSc Assistant Professor Department of Medicine University of Michigan Taubman Center Ann Arbor, MI USA K.V. Narayanan Menon, MD Staff Hepatologist/Medical Director of Liver Transplantation Cleveland Clinic Cleveland, OH USA

­List of Contributor

Hynek Mergental, MD Consultant Liver Transplant and Multi-Organ Retrieval Surgeon Queen Elizabeth Hospital Birmingham UK

Amit Nair, MD, FRCS Assistant Professor of Surgery Division of Transplantation/Hepatobiliary Surgery University of Rochester Rochester, NY, USA

Magdalena Meszaros, MD Fellow Hepatology and Liver Transplantation Unit, CHU Saint Eloi Montpellier University Montpellier France

James Neuberger, DM, FRCP Honorary Consultant Physician Queen Elizabeth Hospital Birmingham UK

Lucy Meunier, MD Chief of Clinic Hepatology and Liver Transplantation Unit, CHU Saint Eloi Montpellier University Montpellier France Charles Miller, MD Enterprise Director of Transplantation Cleveland Clinic Cleveland, OH USA Tim Mitchell, FRACP Fellow Hepatology Department and Liver Transplant Service Sir Charles Gairdner Hospital Nedlands, WA Australia Paolo Muiesan, MD, FRCS, FEBS Consultant Surgeon Liver Unit Queen Elizabeth Hospital and Birmingham Childrens’ Hospital Birmingham UK David J. Mutimer, MD, FRACP Consultant Physician University of Birmingham Birmingham UK

Philip N. Newsome, PhD, FRCPE Professor of Experimental Hepatology and Hon Consultant Hepatologist Institute of Immunology and Immunotherapy Director of the Centre for Liver and Gastrointestinal Research Director of the Midlands & Wales Advanced Therapy Treatment Centre Deputy Director of the NIHR Birmingham Biomedical Research Centre University of Birmingham Birmingham UK John O’Grady, MD, FRCPI Consultant Hepatologist Liver Unit King’s College Hospital London UK Kim M. Olthoff, MD Surgical Director, Liver Transplant Program The Children’s Hospital of Philadelphia Donald Guthrie Professor of Surgery and Chief, Division of Transplant Surgery The Perelman School of Medicine at the University of Pennsylvania Philadelphia, PA USA Fernanda Q. Onofrio, MD Hepatology Fellow Toronto Centre for Liver Disease, Toronto General Hospital

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University Health Network Toronto Canada Esteban Otero, PhD Liver Transplantation Unit University Hospital Santiago de Compostela, Spain Georges-Philippe Pageaux, MD, PhD Professor Hepatology and Liver Transplantation Unit, CHU Saint Eloi Montpellier University Montpellier France Alessandro Parente, MD Surgical Fellow Liver Unit Queen Elizabeth Hospital Birmingham UK Parita Patel, MD Gastroenterology and Hepatology Fellow Division of Gastroenterology and Hepatology University of Chicago Chicago, IL USA Giovanni Perricone, MD Consultant in Hepatology and Gastroenterology Liver Failure Group, UCL Institute for Liver and Digestive Health UCL Medical School, Royal Free Hospital London, UK Hepatology and Gastroenterology Unit Azienda Socio-Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda Milan Italy Rutger J. Ploeg, MD, PhD, FRCS, FEBS (Hon) Professor of Transplant Biology Nuffield Department of Surgical Sciences, University of Oxford

Consultant Transplant Surgeon Oxford University Hospitals NHS Foundation Trust Oxford, UK Professor of Transplant Surgery and Research University of Groningen Groningen, Netherlands Leiden University Leiden, Netherlands Cristiano Quintini, MD Director of Liver Transplantation Cleveland Clinic Cleveland, OH USA Mina Rakoski, MD Gastroenterologist Division of Gastroenterology and Hepatology Loma Linda University Health Loma Linda, CA USA Ashwin Rammohan, MCh, FRCS Director, Academics and Research Consultant, Abdominal Trauma, HPB Surgery and Liver Transplantation Institute of Liver Disease & Transplantation Dr. Rela Institute & Medical Centre Chennai India Elizabeth B. Rand, MD Medical Director, Liver Transplant Program The Children’s Hospital of Philadelphia Philadelphia, PA USA Mohamed Rela, MS, FRCS, DSc Chairman and Director Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre Chennai India Institute of Liver Studies King’s College Hospital London UK

­List of Contributor

John P. Rice, MD Section Chief of Hepatology Division of Gastroenterology and Hepatology Department of Medicine Medical Director, Liver and Pancreas Center UW Health Digestive Health Center University of Wisconsin Madison, WI USA

Nazia Selzner, MD, PhD Assistant Professor of Medicine University of Toronto Medical Director, Live Donor Transplant Multi-organ Transplant Program, Toronto General Hospital University Health Network Toronto Canada

Bruno Roche, PH, MD Practicien hospitalier Centre Hépato-Biliaire AP-HP, Hôpital Paul-Brousse Villejuif France

Amanda Smith, BParm(Hons), MRPharmS, DipClinPharm Lead Pharmacist Liver and Solid Organ Transplantation Queen Elizabeth Hospital Birmingham UK

Didier Samuel, MD, PhD Professor of Hepatology and Gastroenterology Université Paris-Sud Medical Director, Liver Transplant Program Head of Liver and Intensive Care Units Centre Hépato-Biliaire AP-HP, Hôpital Paul-Brousse Villejuif France

Erin Spengler, MD Assistant Professor (CHS) Gastroenterology & Hepatology Faculty University of Wisconsin Madison, WI USA

Marianne Samyn, MD Consultant Paediatric Hepatologist Clinical Lead for Liver Transition Service Paediatric Liver, GI and Nutrition Centre King’s College Hospital NHS Foundation Trust London UK Salvatore Stefano Sciarrone, MD Digestive Specialist Multivisceral Transplant Unit Department of Surgery, Oncology and Gastroenterology Padua University Hospital Padua Italy

Simone I. Strasser, MD Associate Professor AW Morrow Gastroenterology and Liver Centre; Australian National Liver Transplant Unit Royal Prince Alfred Hospital University of Sydney Camperdown Australia Shareef Syed, MD, ChB, MRCS Transplant Surgeon Division of Transplantation, Department of Surgery University of California–San Francisco San Francisco, CA USA Santiago Tome, PhD Liver Transplantation Unit University Hospital Santiago de Compostela, Spain

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­List of Contributor

Puneeta Tandon, MD Assistant Professor, Department of Medicine Division of Gastroenterology (Liver Unit) University of Alberta Edmonton, Alberta Canada Norah A. Terrault, MD, MPH Professor Emeritus, Medicine Division of Gastrointestinal and Liver Diseases University of Southern California Los Angeles, CA USA Fiona Thompson, DM Consultant Physician Liver Unit Queen Elizabeth Hospital Birmingham UK Douglas Thorburn, MD, FRCP Consultant Hepatologist Clinical Director for Liver Transplantation, HPB & Hepatology Royal Free Hospital Professor of Hepatology Institute for Liver & Digestive Health University College London Royal Free London NHS Foundation Trust Royal Free Hospital London UK Giuseppe Tisone, MD Professor of Medicine and Director of Transplant Centre Transplant and Hepatobiliary Unit Department of Surgery University of Rome Tor Vergata Rome, Italy Navneet Tiwari, MD Senior Clinical Fellow Queen Elizabeth Hospital Birmingham UK

Luca Toti, MD, PhD Consultant Surgeon Transplant and Hepatobiliary Unit Department of Surgery University of Rome Tor Vergata Rome, Italy Palak J. Trivedi, PhD, MRCP Consultant Physician and Clinical Scientist Honorary Consultant Hepatologist Liver Unit University Hospitals Birmingham Birmingham UK; Clinician Scientist NIHR Birmingham BRC Institute of Immunology and Immunotherapy University of Birmingham Birmingham UK Hector Vilca-Melendez, MD Consultant Surgeon Liver Unit King’s College Hospital London UK Michael L. Volk, MD Medical Director of Liver Transplantation Chief of Gastroenterology and Hepatology Associate Professor of Medicine Loma Linda University Health Loma Linda, CA USA Christopher J.E. Watson, MA, MD BChir, FRCS Professor of Transplantation and Hon Consultant Surgeon University of Cambridge and Cambridge University Hospitals NHS Foundation Trust Addenbrooke’s Hospital Cambridge UK

­List of Contributor

Kymberly D. Watt, MD Medical Director, Liver Transplant Program Consultant in Gastroenterology and Hepatology Mayo Clinic and Foundation Rochester, MN USA Kerry Webb, MSc Nurse Consultant Birmingham and Solihull Mental Health Trust Birmingham UK; Liver Unit, Queen Elizabeth Hospital Birmingham UK Robert M. Weinrieb, MD, FACLP Professor of Psychiatry Chief Psychiatric Consultant, Penn Transplant Institute Program Director, Penn/VA Consultation-Liaison Psychiatry Fellowship University of Pennsylvania Health Systems Perelman School of Medicine Philadelphia, PA USA

Maureen Whitsett, MD Gastroenterology Fellow NYU Langone Health New York USA Felicity R. Williams, BSc NIHR Clinical Research Fellow Biomedical Research Centre, Institute of Inflammation and Ageing University of Birmingham Birmingham UK Michael J. Williams, PhD Consultant Hepatologist Scottish Liver Transplant Unit Royal Infirmary of Edinburgh Edinburgh UK

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­Foreword to the Second Edition Without doubt, liver transplantation is one of the greatest success stories in medicine and I never cease to be amazed when I see in follow-up patients who I remember as having terminal illness, 20–30 years after transplantation, living happily in good health and on minimum immunosuppression. Many more people are going to have this opportunity with the greater number of donor organs that advances in machine preservation are making possible. Donor livers that would not have been considered because of fatty change or ischemic damage can be restored with a period of preservation to a healthy functioning state. The move to an “opt-out” plan of deemed consent in England in May will also significantly increase the number of consents to donation, as has been proven by the experience in Wales. The scenario of patients suitable for transplant being on the waiting list for months and with a mortality of about 20% should become a matter of the past. But there are important ongoing issues that need to be addressed, for instance the impairment of cognitive ability and educational attainment that has been demonstrated in children after transplantation for biliary atresia or autoimmune hepatitis, detracting from the otherwise remarkable survival figures. Also in the pediatric area are the difficulties that can occur in the transition period to adult life. The biggest challenge, though, is the emergence of non-alcoholic fatty liver disease (NAFLD) taking over as the leading cause for liver transplantation, supplanting viral hepatitis cases now that there are effective drugs, particularly against hepatitis B and C. Cardiovascular and metabolic complications of obesity can add up to a considerable co-morbidity affecting NAFLD patients coming to transplantation, in both immediate and long-term outcomes. The long timeframe of NAFLD disease causes difficulties in assessing prognosis and need for transplantation. There can also be problems in the diagnosis of primary hepatocellular carcinoma (HCC) in patients who are likely to be obese. The steadily rising prevalence of HCC poses additional challenges to transplant programs with the burgeoning number of effective medical agents as well as ablative techniques used in conjunction with transplantation, making close collaboration between Hepatology and Oncology even more necessary. Finally, the unmet need for transplantation in instances of severe liver failure consequent on decompensated cirrhosis or on acute alcohol hepatitis will need to be addressed, and here there have been reports of successful transplantation even at the stage of multiorgan failure. Even at 50 years since transplantation got underway, there are unsolved issues to be solved and new challenges – in other words, much to do, but with continuing great outcomes for the patients.  Professor Roger Williams, CBE  Director, Institute of Hepatology London  Professor of Hepatology, King’s College London (Roger Williams sadly died on 25 July 2020; see https://bts.org.uk/passing-of-prof-roger-williams/)

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Foreword to the First Edition Liver transplantation in humans has come a very long way in a short period of time. My first studies of liver transplantation in animals began in 1958 when I showed that such a procedure was technically possible. I identified three key challenges: the need to preserve the liver between retrieval and implantation, the need to preserve the recipient in hemodynamic stability, and the need to prevent rejection. The first human liver transplant was performed in 1963 and identified a number of issues that needed resolution, so the program was put on hold, but restarted with the first successful transplant in 1967. The program, initially in Denver and subsequently in Pittsburgh, grew rapidly and was followed by the successful program in Cambridge, UK, in 1968, led by Sir Roy Calne and Roger Williams. Those early pioneering days were exciting but stressful, physically and emotionally. Outcomes improved slowly but surely. In 1983, the procedure came of age when liver transplantation was recognized by the NIH as an effective treatment. Other programs developed around the world and liver transplantation is now routine, with many recipients surviving 20 and more years with an excellent quality of life. The progression from a high-risk and resource-intensive procedure, where blood use of less than 100 units was considered a success and outcomes were measured in 1-year survival, to a low-risk, routine, and usually bloodfree procedure has been achieved as a result of the dedication, hard work, enthusiasm, imagination, and sheer persistence of a large number of people: surgeons, physicians, scientists, intensivists, microbiologists, and many others have all made huge contributions to the success of the procedure. The contribution of both donors and recipients must also be acknowledged for, without their support, these advances could never have occurred. Yet many challenges remain. Despite advances in medical care, the need for liver transplantation is increasing and the availability of donor livers inadequate. Liver preservation is still a concern: new perfusion fluids and machine perfusion may mitigate some of the problems. While immunosuppression has improved enormously, with the introduction initially of ciclosporin and tacrolimus and, more recently, mycophenolate, sirolimus, and biologic agents, most recipients require long-term treatment, with its associated side effects; tolerance remains an elusive goal. Selection and allocation policies are attracting, quite appropriately, public scrutiny. Regulation is increasing: indeed, it is doubtful whether liver transplantation could have developed as quickly as it did under the current risk-averse climate. Liver transplantation is expanding and outcomes are better than ever, so more clinicians will be touched by the procedure, whether for referral or for follow-up. It is hoped that this volume will provide a useful and practical guide to the successful management of these patients.  Thomas E. Starzl, MD, PhD  Professor of Surgery  University of Pittsburgh School of Medicine  Pennsylvania, PA, USA

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Preface Welcome to the second edition of Liver Transplantation. Since the first edition, there have been many changes in the management of patients with liver disease, both before and after transplantation, and this new edition reflects this. As with the first edition, the aim of the volume is to provide a concise, practical, and authoritative guide for junior medical staff and other health professionals working in liver transplant units, for healthcare professionals looking after those patients with liver disease who are or may become liver transplant candidates, and for patients following liver transplantation. We have expanded both the number and the reach of authors, with a consequent increase in chapters. We have sought to represent the breadth of liver transplant medicine across Europe and North America, while recognizing also the role of liver transplantation in the rest of the world. We appreciate that this means some duplication and occasional divergence of views. We have intentionally retained these so that each chapter is entire in and of itself and the reader understands where there is uncertainty. We are very grateful to the authors who have written and revised their contributions during the height of the Covid-19 pandemic. We are grateful to those at Wiley-Blackwell, especially Jennifer Seward, Pri Gibbons, Bhavya Boopathi and Sally Osborn, for their help and patience and, most importantly, to our partners and children who have been patient with us during the preparation of this second edition. Finally, we would like to acknowledge the work of Professor Roger Williams, who died in July 2020 and who contributed so much to hepatology worldwide; he was one of the first to recognize the importance of liver transplantation and helped ensure that it rapidly transitioned from an experimental, high-risk procedure to a routine operation that has benefited so many people. We are delighted and honored to include his Foreword to this second edition. James Neuberger James Ferguson Philip N. Newsome Michael Ronan Lucey

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Abbreviations 6MWD/6MWT AA AASLD ABC ABOi LT ABP ACE ACLF ACP ACR AD ADH ADL ADV AH AICD AIH AILD AKI ALD ALDLT ALF ALP ALPPS ALT AMA AMR ANA APA APAP APC

6-minute walk distance/time amino acids American Association for the Study of Liver Diseases adenosine triphosphate-binding cassette ABO-incompatible liver transplant arterial blood pressure angiotensin-converting enzyme acute-on-chronic liver failure advance care planning albumin creatinine ratio/acute cellular rejection acute decompensation antidiuretic hormone activity of daily living adefovir alcoholic hepatitis activation-induced cell death autoimmune hepatitis autoimmune liver disease acute kidney injury alcohol-related liver disease adult living donor liver transplantation acute liver failure alkaline phosphatase associating liver partition and portal vein ligation for staged hepatectomy alanine aminotransferase American Medical Association/antimitochondrial antibody antibody-mediated rejection antinuclear antibody American Psychiatric Association N-acetyl-para-aminophenol (acetaminophen) antigen-presenting cell

xxiv

Abbreviations

APOLT aPTT ARB ASCVD ASMA AST AT ATG ATP AUC AUD AUDIT AZA BCAA BCC BCG Bcl6 BCLC BD BEC BIA BMD BMI BP BSEP CA CAD CAM CANONIC CBC CBD CBT CCA CCM CCR cccDNA CDC CDR CHA CHOP CI CIA CIT CKD CKD-EPI CLEVER-1 CLIF-SOFA

auxiliary partial orthoptic liver transplantation activated partial thromboplastin time angiotensin II receptor blocker atherosclerotic cardiovascular disease anti-smooth muscle antibody aspartate transaminase anaerobic threshold anti-thymocyte globulin adenosine triphosphate area under the curve alcohol use disorder Alcohol Use Disorder Identification Test azathioprine branched chain amino acid basal cell carcinoma Bacille Calmette–Guerin B-cell lymphoma 6 Barcelona Clinic Liver Cancer twice daily biliary epithelial cell bioelectric impedance analysis bone mineral density body mass index blood pressure bile salt export pump cancer antigen/carbohydrate antigen coronary artery disease cell adhesion molecule CLIF Acute-oN-ChrONic LIver Failure in Cirrhosis complete blood count common bile duct cognitive behavioral therapy cholangiocarcinoma cirrhotic cardiomyopathy CC chemokine receptor covalently closed circular DNA complement detection cytotoxicity crude death rate common hepatic artery cyclophosphamide, doxorubicin, vincristine, and prednisone confidence interval common iliac artery cold ischemia time chronic kidney disease CKD-Epidemiology Collaboration common lymphatic endothelial and vascular endothelial receptor-1 Chronic Liver Failure-Sequential Organ Failure Assessment

Abbreviations

CLIF-C ACLF CMA CMV CNI CNS CoA COPD COT CPET CPP CR CsA CT CTP CUSA CV CVD CVVH CXCR CXR DAA DAMP DASI DBD DC DCD DCDD DD DDC DDLT DEXA D-HOPE DILI dnAIH DNR DPP-4 DR DRI dsDNA DSA DT DTC DTD DTI EAD EASL EASL–CLIF

CLIF Consortium Acute on Chronic Liver Failure chaperone-mediated autophagy cytomegalovirus calcineurin inhibitor central nervous system coenzyme A chronic obstructive pulmonary disease clinical operational tolerance cardiopulmonary exercise test cerebral perfusion pressure chronic rejection cyclosporine computed tomography Child-Turcotte-Pugh score cavitron ultrasonic aspirator cardiovascular cardiovascular disease continuous veno-venous hemofiltration CXC receptor chest X-ray direct-acting antiviral agent damage-associated molecular pattern Duke Activity Status Index deceased from brain death dendritic cell/decompensated cirrhosis deceased after circulatory death donation after circulatory determination of death deceased donor donor-derived cancer deceased donor liver transplantation dual-energy X-ray absorptiometry dual hypothermic oxygenated machine perfusion drug-induced liver injury de novo autoimmune hepatitis do not resuscitate dipeptidyl peptidase 4 donor–recipient donor risk index double-stranded DNA Donation Service Area/donor-specific antibody domino transplant donor-transmitted cancer donor-transmitted disease donor-transmitted infection early allograft dysfunction European Association for the Study of the Liver European Association for the Study of the Liver–Chronic Liver Failure

xxv

xxvi

Abbreviations

EBV ECD ECG ECMO EEG EEM eFLR eGFR ERCP ESLD ESRD ETV EU EUS EVR FAP FasL FBC FDA fDWIT FEV FFP FFQ FHF FIC FiO2 FSH FTC fWIT GCS GDA GFR GGT GLP-1 GRWR GSD 1 GSST1 GVHD HA HAART HADS HAdV HALT HAT hATTR HAV HBA1c

Epstein–Barr virus extended-criteria donor electrocardiogram extracorporeal membrane oxygenation electroencephalogram electronic event monitoring estimated future liver remnant estimated glomerular filtration rate endoscopic retrograde cholangiopancreatography end-stage liver disease end-stage renal disease entecavir European Union endoscopic ultrasonography everolimus familial amyloid polyneuropathy Fas ligand full blood count Food and Drug Administration functional donor warm ischemia time forced expiratory volume fresh frozen plasma Food Frequency Questionnaire fulminant hepatic failure familial intrahepatic cholestasis fraction of inspired oxygen follicle-stimulating hormone emtricitabine functional warm ischemia time Glasgow Coma Score gastroduodenal artery glomerular filtration rate gamma-glutamyl transferase glucagon-like peptide 1 graft-to-recipient body weight ratio glycogen storage disease type 1 glutathione S-transferase graft versus host disease hepatic artery highly active antiretroviral therapy Hospital Anxiety and Depression Score human adenovirus heterotopic auxiliary liver transplantation hepatic artery thrombosis hereditary transthyretin-mediated amyloidosis hepatitis A virus hemoglobin A1c

Abbreviations

HBeAg HBIG HBsAb HBsAg HBV HCB HCV HCC HCG HD HDL HDU HDV HE HEHE HELLP HEV HGS HH HHS HHV HiB HIDA HIV HLA HMG HMP HOPE HPS HPV HR HRQOL HRS HRV HSEC HSV HTK HTLV HU HV IA IADL IAIHG IBD IC ICAM ICP

hepatitis B e antigen hepatitis B immune globulin hepatitis B surface antibody hepatitis B surface antigen hepatitis B virus hexachlorobenzene hepatitis C virus hepatocellular carcinoma human chorionic gonadotropin hemodialysis high-density lipoprotein high dependency unit hepatitis D virus hepatic encephalopathy hepatic epithelioid hemangioendotheliomatosis hemolysis, elevated liver enzymes, low platelets syndrome hepatitis E virus/high endothelial venule hand grip strength hereditary hemochromatosis Department of Health and Human Services human herpesvirus Haemophilus influenzae type B hepatobiliary iminodiacetic acid human immunodeficiency virus human leucocyte antigen 3-hydroxy-3-methylglutaryl hypothermic machine perfusion hypothermic oxygenated machine perfusion hepatopulmonary syndrome human papilloma virus heart rate/hazard ratio health-related quality of life hepatorenal syndrome heart rate variability hepatic sinusoidal endothelial cell herpes simplex virus histidine-tryptophan-ketoglutarate solution human T-lymphotropic virus Hounsfield units hepatic vein invasive aspergillosis instrumental activity of daily living International Auto-immune Hepatitis Group inflammatory bowel disease ischemic cholangiopathy intercellular cell adhesion molecule intracranial pressure

xxvii

xxviii

Abbreviations

ICU IDO IFN Ig IGF-1 IGL-1 IgSf IL IL-2R IM IMPDH IMV INH INR IPAA IPI IRI IS ISWT ITBL ITP IV IVC IVR JV JVP KDIGO KPS LAI LAL-D LAM LAM-R LCMV LD LDL LDLT LFI LFT LH LHV LI-RADS LKMA LLS LPS LSD LT LTBI

intensive care unit indoleamine interferon immunoglobulin insulin-like growth factor-1 Institute Georges Lopez solution immunoglobulin superfamily interleukin interleukin-2 receptor intramuscular inosine monophosphate dehydrogenase inferior mesenteric vein isoniazid international normalized ratio ileal pouch–anal anastomosis International Prognostic Index ischemia/reperfusion injury immunosuppression incremental shuffle walk test ischemic-type biliary lesion immune thrombocytopenia intravenous inferior vena cava interactive voice response jugular venous jugular venous pressure Kidney Disease Improving Global Outcomes Karnofsky performance status Liver Attenuation Index lysosomal acid lipase deficiency lamivudine resistance mutation(s) to lamivudine lymphocytic choriomeningitis virus living donor living donor liver; low-density lipoprotein living donor liver transplantation Liver Frailty Index liver function test luteinizing hormone left hepatic vein Liver Imaging Reporting and Data System liver–kidney microsomal antibody left lateral segment lipopolysaccharide lysergic acid diethylamide liver transplantation latent tuberculosis infection

Abbreviations

MAC MAESTRO-Tx MAGIC MAMC MAP MAQ MARS MaS MayoPSCr MDRD MDT MELD MFI MHC mHealth MHV MI MINI miRNA MLVI MMaT MMF MMR MMT MNa MPA MPAP MPaT MRA MRCP MRI MS MSM MSUD mTOR NA NAFLD NASH NAT NCMLD NCV NET NFAT NHS NHSBT NIAAA NICE

mid-arm circumference Medication Adherence Enhancing Strategies in Solid Organ Transplantation Medication Adherence Given Individual SystemCHANGE mid-arm muscle circumference mean arterial pressure Multidimensional Adherence Questionnaire molecular adsorption recirculation; Medication Adherence Report Scale macrovesicular steatosis Mayo primary sclerosing cholangitis risk score Modification of Diet in Renal Disease multidisciplinary team Model for End-Stage Liver Disease mean fluorescence intensity major histocompatibility complex mobile health middle hepatic vein motivational interviewing Mini-International Neuropsychiatric Interview microRNA medication level variability index median MELD score at transplant mycophenolate mofetil measles, mumps, and rubella methadone maintenance therapy mycophenolate sodium mycophenolic acid mean pulmonary arterial pressure median PELD score at transplant magnetic resonance angiography magnetic resonance cholangiopancreatography magnetic resonance imaging metabolic syndrome men who have sex with men maple syrup urine disease mammalian target of rapamycin nucleos(t)ide analogue non-alcoholic fatty liver disease non-alcoholic steatohepatitis nucleic acid testing/technology non-cirrhotic metabolic liver disease nerve conduction velocity neuroendocrine tumor nuclear transcription factor of activated T-cells National Health Service NHS Blood and Transplant National Institute for Alcohol Abuse and Alcoholism National Institute for Health and Care Excellence

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xxx

Abbreviations

NIDDK NIH NK NLR NLRB NMP NRCLM NRP NSAID nvCJD OCA OD OF OGTT OKT3 OLT OPO OPTN PA PAIS PAMP PaO2 PBC PBG PBMC PC PCP PCR PCV-13 PDS PEEP PELD PERT PET PFIC-2 pmp PNF POCD POPH PPARG PPI PPSV-23 PR PRI PSC PT PTC

National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health natural killer native liver regeneration National Liver Review Board normothermic machine perfusion non-resectable colorectal liver metastases normothermic regional perfusion non-steroidal anti-inflammatory drug new variant Creutzfeld–Jakob disease obeticholic acid once daily organ failure oral glucose tolerance test orthoclone-muromonab-CD3 orthotopic liver transplantation Organ Procurement Organization Organ Procurement and Transplant Network posterior–anterior; pulmonary artery Psychosocial Adjustment to Illness Scale pathogen-associated molecular pattern partial pressure of oxygen primary biliary cholangitis porphobilinogen peripheral blood mononuclear cell palliative care Pneumocystis pneumonia polymerase chain reaction/plasma cell-rich rejection 13-valent pneumococcal conjugate vaccine polydioxanone positive end-expiratory pressure Pediatric End-Stage Liver Disease model pancreatic enzyme replacement therapy positron emission tomography progressive familial intrahepatic cholestasis type 2 per million population primary non-function postoperative cognitive dysfunction portopulmonary hypertension peroxisome proliferator-activated receptor gamma proton pump inhibitor 23-valent pneumococcal polysaccharide vaccine prolonged release preservation/reperfusion injury primary sclerosing cholangitis prothrombin time percutaneous transhepatic cholangiography

Abbreviations

PTDM PTH PTLD PTSD PV PVT QALY QOL RAI rAIH RANKL RANTES RAPID RAS rATG RBV RFA RHV ROR ROTEM rPBC RPR rPSC RR RRT RV SaBTO SALT SCC SCS SFSS SGLT2 SHBG SIPAT SIR SMA SMI SMV SNOD SOFA SOT SPPB SpO2 SRR SRTR SSRI STAT

post-transplant diabetes mellitus parathyroid hormone post-transplant lymphoproliferative disorder post-traumatic stress disorder portal vein; pulmonary vein portal vein thrombosis quality-adjusted life-year quality of life Rejection Activity Index recurrent autoimmune hepatitis receptor activator of nuclear factor kappa-Β ligand regulated on activation, normal T-cells expressed and secreted resection and partial liver segment II/III transplantation with delayed total hepatectomy resistance-associated substitution rabbit anti-thymocyte globulin ribavirin radiofrequency ablation right hepatic vein retinoic acid-related orphan receptor rotational thromboelastography recurrent primary biliary cholangitis rapid plasma reagin recurrent primary sclerosing cholangitis relative risk renal replacement therapy right ventricular Advisory Committee for the Safety of Blood Tissues and Organs Sustained Alcohol Use Post-LT squamous cell carcinoma static cold storage small-for-size syndrome sodium glucose co-transporter 2 sex hormone-binding protein Stanford Integrated Psychosocial Assessment for Transplant standardized incidence ratio superior mesenteric artery/smooth muscle antibody skeletal muscle index superior mesenteric vein Specialist Nurse – Organ Donation Sequential Organ Failure Assessment spontaneous operational tolerance short physical performance battery pulse oximetric saturation steroid-resistant rejection Scientific Registry for Transplant Recipients selective serotonin reuptake inhibitor signal transducer and activator of transcription

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Abbreviations

SVR TACE TAKE-IT TB TBS TCMR TCR Td Tdap TDF TDM TDV TEG TGF TIPS TLR TMC TNF TNFR TOL TRAQ Treg TSF TTR TTV TZD UAGA UC UCSF UDCA UDDA UE ULN UNOS UKELD UW VAP-1 VCAM VE-cadherin VEGF VL VLDL VO2Max VQ VZIG VZV WGALT WHO

sustained virologic response transarterial chemo-embolization Teen Adherence in Kidney Transplant Effectiveness of Intervention tuberculosis Transplant Benefit Score T-cell–mediated rejection T-cell receptor tetanus and diphtheria tetanus, diphtheria, and acellular pertussis tenofovir disoproxil fumarate therapeutic drug monitoring tenofovir thromboelastography transforming growth factor transjugular intrahepatic portosystemic shunt toll-like receptor tacrolimus versus microemulsified cyclosporin tumor necrosis factor tumor necrosis factor receptor operational tolerance Transition Readiness Assessment Questionnaire regulatory T-cell triceps skin fold transthyretin total tumor volume thiazolidinedione Uniform Anatomical Gift Act ulcerative colitis University of California San Francisco ursodeoxycholic acid Uniform Determination of Death Act urea and electrolytes upper limit of normal United Network for Organ Sharing United Kingdom Model for End-Stage Liver Disease University of Wisconsin vascular adhesion protein-1 vascular cell adhesion molecule vascular endothelial cell cadherin vascular endothelial growth factor vital load very low-density lipoprotein maximal oxygen uptake ventilation-perfusion varicella zoster immunoglobulin varicella zoster virus whole graft auxiliary liver transplantation World Health Organization

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Part 1 When to Refer a Patient for Liver Transplantation

3

1 Overview on Organ Donation and Liver Transplantation Michael Ronan Lucey Division of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

Key points ●● ●● ●●

●●

●●

●●

Liver disease and its consequences are a major cause of death globally. Many patients with cirrhosis die from non-hepatic causes. The causes of liver failure vary between countries, but alcohol and NAFLD are the major causes of cirrhosis and liver failure in the developed world. ALD and non-specific cirrhosis have the worst prognosis, with the outcome of the former being dependent on whether the patient continues to drink alcohol. Only a small proportion of those dying from liver failure are suitable for consideration for liver transplantation. Rates of deceased and living organ donation vary between countries.

­The global burden of liver disease Liver disease is a major cause of illness and death throughout the world. Recent estimates indicate that cirrhosis, with or without hepatocellular carcinoma (HCC), is the cause of around 2 million deaths annually (Asrani et al. 2019). As shown in Table 1.1, the relative contribution of liver disease to total annual mortality varies geographically. These variances reflect the causes of liver injury that predominate in different parts of the world. For example, alcohol-related liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are the predominant causes of chronic liver disease in North America and Europe, whereas chronic viral hepatitis plays a greater role in Africa and Asia. The data are limited by concerns about the accuracy of information in some countries of South America, Asia and Africa. The picture is also in flux because of social changes in the use of alcohol in different countries (for example, declining alcohol consumption in France and Spain, and rising consumption in the US) and changing dietary habits leading to an increase in mean body mass in parts of the world that are adopting a Western lifestyle. In turn, the relative impact of these forces is apt to be influenced by public health efforts to reduce the risk of liver disease.

Liver Transplantation: Clinical Assessment and Management, Second Edition. Edited by James Neuberger, James Ferguson, Philip N. Newsome and Michael Ronan Lucey. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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Part 1  When to Refer a Patient for Liver Transplantation

Table 1.1  Global mortality related to liver disease and liver cancer, 2015. Cirrhosis and the liver

World

HCC

Global rank

Deaths (000s)

% of total deaths

CDR (per 100,000 population)

Deaths (000s)

11

1162

2.1

15.8

788

East Asia and Pacific

13

328

2.0

14.4

547

Europe and Central Asia

17

115

1.2

12.7

78

Latin America and Caribbean

 9

98

2.7

15.6

33

Middle East and North Africa

 8

77

3.5

18.2

24

North America

12

50

1.7

14.0

27

South Asia

10

314

2.5

18.0

38

Sub-Saharan Africa

16

179

1.9

17.9

42

Note: This is likely to be an underestimate and does not account for deaths due to acute hepatitis. Data available from Global Health Estimates 2015: Deaths by Cause, Age, Sex, by Country and by Region, 2000–2015. Geneva: World Health Organization, 2016. CDR, crude death rate; HCC, hepatocellular carcinoma. Source: Asrani et al. (2019).

­What causes death in patients with liver disease? In a recent study of national statistics from Great Britain, in which the causes of death in more than 5000 patients with cirrhosis were contrasted with a contemporaneous cohort of more than 150,000 persons who died without cirrhosis, and a similar nationwide cohort study from Denmark, 50% of deaths in the liver cohorts were attributed to causes related to cirrhosis (Ratib et al. 2017). In the British study, patients with alcohol-related cirrhosis, chronic viral hepatitis, or autoimmune/metabolic disease were at a higher risk of liver-related death than of any other cause of death, and this risk was greatest for patients with ALD, whereas patients with compensated cirrhosis of unspecified etiology were at a higher risk of non-liver or neoplastic death, when compared with the general population, up to 5 years post diagnosis. This distinction is most likely a consequence of the co-morbid cardiovascular mortal risks associated with NAFLD arising in the setting of metabolic syndrome. In a separate study, Orntoft et al. (2014) analyzed a cohort of 1951 Danish patients with a first-time hospital discharge diagnosis of alcoholic hepatitis (AH) between 1999 and 2008, of whom 1001 patients (364 women, 637 men) died. The authors stratified this subgroup according to interval from admission to death: 401 before and 600 after the first 85 days In the early death group; the causes of death were liver failure (40%), infection (20%), or hepato-renal failure (11%). In the patients dying later in their clinical course, 326 did not have features of cirrhosis and their causes of death were mostly related to resumption of alcohol use, whereas among the 675 with cirrhosis, 34% died of liver failure, 16% of infection, and 11% of variceal bleeding. The onset of a decompensating event is often recognized as the turning point in the clinical course of patients with cirrhosis. Jepsen et al. (2010) described the clinical course from the moment of decompensation in a cohort of 466 with a hospital-based diagnosis of alcohol-related cirrhosis (see also Orntoft et al. 2014). At diagnosis 24% were compensated, 55% had ascites, 6% had variceal bleeding, 4% had bleeding plus ascites, and 11% had hepatic encephalopathy. During the follow-up interval of 1611 patient years, 36% remained abstinent, 43% were intermittent drinkers, and 21% drank alcohol persistently. Figure  1.1 shows mortality according to the patient’s initial

Chapter 1  Overview on Organ Donation and Liver Transplantation 1 0.9

Relative survival

0.8 Chronic hepatitis

0.7 0.6

Primary biliary cholangitis

0.5

Alcoholic liver cirrhosis

0.4 0.3

Non-specified cirrhosis

0.2 0.1 0

0

1

2

3

4 5 6 Years of follow-up

7

8

9

10

Figure 1.1  Relative survival curves for 10,154 patients with liver cirrhosis, grouped in four subcohorts during a 10-year follow-up period. Source: Sorensen et al. (2003).

presentation. The study demonstrates that the majority of subjects already had decompensated at the point of recruitment. Second, there was no characteristic pattern of decompensating events at presentation. Third, mortality was high after decompensation. Moreover, even patients who had well-compensated liver function at recruitment had a poor prognosis, with > 50% dead at 5 years. Unfortunately, the authors did not analyze the outcome comparing abstinence with continued drinking. Recent studies from Spain and France suggest that late deaths in patients who survive an episode of AH are most affected by drinking (Altamirano et al. 2017; Louvet et al. 2017). Furthermore, the ubiquity of alcohol in Western society means that it may contribute to deterioration in patients with liver disease not characterized as alcohol related. A different approach to looking at ante-mortem events in patients with liver disease was adopted by Moreau et al. (2013), who developed the concept of acute-on-chronic liver failure, defined as patients with chronic liver disease who have been admitted to hospital with organ failure. They constructed 28- and 90-day mortality in 1343 patients who were hospitalized. These studies have shown that multiorgan failure, often accompanied by infection, is the mechanism by which most of cirrhotic patients die. The onset of renal failure is a critical development and the accumulation of failing systems increases the mortality risk.

­A global perspective on liver transplantation When viewed against the scale of liver disease just described, we can assert with confidence that liver transplantation (LT) will never be the sole, or even the most significant, response to the global problem of serious liver disease. Major advances in reducing the burden of liver disease will require action to improve public health: public health efforts to limit alcohol consumption, improve nutrition, provide clean water and disposal of sewage; and programs to vaccinate against and/or treat viral hepatitis. These actions include efforts to reduce excessive consumption of alcohol, such as the introduction in Scotland and Ireland of minimum pricing units for alcohol. The global scourge of chronic viral hepatitis B will be best overcome by the adoption of vaccination. The introduction of effective curative therapy for hepatitis C virus (HCV) is changing the landscape of this disease in the developed world, resulting in dramatic declines in the proportion of HCV-infected persons coming for LT in the US, Europe, and Australia/New Zealand. LT requires the sourcing of a partial or complete liver allograft for use in the recipient. In many countries in the developed world, deceased donation after declaration of brain death is the most important source of donor livers.

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Part 1  When to Refer a Patient for Liver Transplantation

These countries have sophisticated medical systems that enable maintenance of patients on life support after the loss of brain function. As shown in Table 1.2, there are marked country to country variances in rates of successful donation after declared brain death. The same holds true in the US, where there are marked state to state variations. Spain has been most successful in converting declared brain-dead patients into effective donors. It has reached a successful conversion rate of almost 40 deceased donors per million population (pmp). Some states in the US (Minnesota and Wisconsin) have achieved rates of 30% or higher. This success in donation requires a concerted effort at the level of local care of patients on life support, awareness of the importance of donation by professionals in community intensive care units, and specially trained personnel in those units to interview the families of potential donors. In contrast, in countries where the prevailing mores do not favor donation after brain death such as Japan, or where, in addition, the medico-social infrastructure is inadequate to support widespread donation after death, such as India, LT with partial livers removed from healthy living donors, often called living donor liver transplantation (LDLT), is the norm.

­The donor organ In LT with a deceased donor, typically there is no personal connection between the donor and the recipient. Up to now, unlike in kidney transplantation where donor to recipient matching involves immune compatibility, in deceased donor liver transplantation (DDLT) matching has been relatively simple, based on body habitus and ABO blood type. Patients with liver failure on the waiting list are like passengers waiting for the next bus. The system works on the premise that all deceased donor allografts, just like the right bus, are equally good. In subsequent chapters, we have assembled experts to discuss the current state of donation, after brain death, after declared cardiovascular failure, from donors with recognized risk factors (so-called extended-use donors) and from living donors. Current research assesses new approaches, such as warm ex vivo perfusion, to improve outcome of use of liver allografts from declared cardiac death or extended-use donors. In reality, not all donor livers are equally good. Some livers may not function well or at all, and some may unintentionally transmit diseases. Excessive macrovesicular fat has long been identified as a risk factor for impaired liver function post transplant. However, how much fat is too much is a subjective assessment by the accepting transplanting surgeon. Feng et al. (2006) identified a set of additional factors that were strongly associated with graft failure in LTs in the US: donor age over 40 years (and particularly over 60 years), deceased after circulatory death (DCD) donation, and split/partial grafts. In addition, African-American ethnicity, lower height, cerebrovascular accident, and “other” causes of brain death were more modestly but still significantly associated with graft failure. Since there is not an absolute, objective method to identify the “hopeless” graft, it remains a subjective judgment whether or not to accept a donor offer. Data from the US nationwide transplant system show that deceased donor organs that are successful have often been declined by another center with a higher-priority patient, and that patients who die on the list or have been withdrawn from the waiting list with the expectation of death have frequently been offered a donor organ that was successfully transplanted elsewhere (Lai et al. 2012). Finally, a center’s level of comfort with a challenging donor offer is associated with that center’s rate of death on or withdrawal from the transplant waiting list, with the highest likelihood of death on the waiting list at centers with the greatest “turn-down” rate (Goldberg et al. 2016). This last point speaks to the dynamics of success or failure at an individual center and how they might influence acceptance of less than perfect donor offers. Matters are different when considering LDLT. Typically, in living donation, the donor and the recipient are a dyad. Occasionally, a putative donor will have no personal connection to the recipient. In subsequent chapters (see Part 4: Donation and allocation), we will discuss the ethics of donation, including living donation, and the troubling issues surrounding payment for donation and its potential for abuse, including transplant tourism. We have not seen a chain of linked unrelated donations in LT, as has been successful in kidney transplantation.

Table 1.2  Worldwide comparison of liver transplantation practices. Germany

UK

India

Ireland

Aust/NZ

Brazil

Spain

Japan

US

Population (million)

82

64

1.19**

4.59

27.7

202

47.8

127

318.9

No of LTs annually (2015)

846

882

~1000

50–60

270

1,700

> 1000

450–500

7127

LT centers

23

7

30

1

5 Au,1 N

56

24

67

136

Prioritization

MELD

UKELD*



MELD

MELD

MELD

MELD

MELD

MELD

Living donation

 6 years; see Box 39.4). Withdrawal of immunosuppression may occur in the context of a deliberate tolerance strategy or be forced by malignancy or complications of immunosuppression. If this is done in a proactive manner, then it is highly recommended that liver biopsy be performed. Successful operational tolerance patients should have a normal liver biopsy, with only minor portal tract immune infiltrates, no interface hepatitis, no bile duct or endothelial changes,

Chapter 39  Patterns of Liver Allograft Rejection

Box 39.4  Operational tolerance ●● ●● ●● ●● ●●

Occurs in only 1 : 40) Antinuclear antibodies or anti-smooth muscle antibodies, anti-liver–kidney microsomal antibodies Characteristic histology Dense lymphocytic portal-tract infiltrate Plasma cells Interface hepatitis

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Table 40.2  Risk factors for de novo autoimmune hepatitis Recipient pre-transplant Co-existing autoimmune disorders Higher titers of autoantibodies Human leucocyte antigen (HLA) Donor and/or recipient HLA-DR3 and/or HLA-DR4 donor/recipient mismatch Rejection Episodes of acute rejection Immunosuppression Use of antilymphocyte antibodies Withdrawal of corticosteroids (early or late) Monotherapy Inadequate immunosuppression secondary to non-adherence Histology Severe necro-inflammatory activity Other Antiviral therapy with pegylated interferon and ribavarin Glutathione S-transferase donor/recipient mismatch

­Pathogenesis As the name suggests, dnAIH is considered an autoimmune disease occurring in the graft, with the autoimmunity possibly triggered by a virus, medication, or xenobiotic, possibly related to molecular or structural mimicry, epitope spreading, or uncovering of cryptic antigens. The varying proposed risk factors suggest that, at least in some cases, the human leucocyte antigen (HLA) phenotype of the donor or recipient may be important factors, although a closer match between donor and recipient is not associated with a greater risk. The association between dnAIH and hepatitis C virus (HCV), and the treatment with interferon and ribavirin, are both compatible with a drug- or virus-triggered autoimmunity. Whether the greater use of effective direct-acting antiviral therapy will reduce the incidence of dnAIH remains to be seen. Other researchers have suggested that dnAIH is a form of late cellular rejection, with the immune response being directed against a donor antigen. In support of this hypothesis is the observation that acute cellular rejection is associated with the appearance of autoantibodies and is one of the suggested risk factors. One potential target for the alloimmune response is glutathione S-transferase (GSST1); about 1 in 5 Caucasians does not have GSST1 and anti-GSST1 antibodies have been reported in some of those with dnAIH, particularly in recipients who are GSST1 negative and receive a liver from a GSST1-positive donor. These findings remain controversial.

­Treatment Most cases can be treated effectively with increased doses of immunosuppressive agents, especially with an increase or reintroduction of corticosteroids, but may progress to graft failure and require re-transplantation.

Chapter 40  De Novo Autoimmune Hepatitis

­Further reading Aguilera I, Aguado-Dominguez E, Sousa JM, Nuñez-Roldan A. Rethinking de novo immune hepatitis, an old concept for liver allograft rejection: relevance of glutathione S-transferase T1 mismatch. World J Gastroenterol. 2018;24(29):3239–3249. Castillo-Rama M, Sebagh M, Sasatomi E, Randhawa P, Isse K, Salgarkar AD, et al. Plasma cell hepatitis in liver allografts: identification and characterization of an IgG4-rich cohort. Am J Transpl. 2013;13:2966–2977. Kerkar N, Hadzić N, Davies ET, Portmann B, Donaldson PT, Rela M, et al. De-novo autoimmune hepatitis after liver transplantation. Lancet. 1998;351(9100):409–413. Stirnimann G, Ebadi M, Czaja AJ, Montano-Loza AJ. Recurrent and de novo autoimmune hepatitis. Liver Transpl. 2019;25:152–166. Vukotic R, Vitale G, D’Errico-Grigioni A, Muratori L, Andreone P. De novo autoimmune hepatitis in liver transplant: state-of-the-art review. World J Gastroenterol. 2016;22:2906–2914.

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41 Managing Rejection Neil Halliday1,2 and Douglas Thorburn1,3 1

 Institute for Liver and Digestive Health, University College London, UK  The Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK 3 Royal Free London NHS Foundation Trust, Royal Free Hospital, London, UK 2

Key points ●●

●●

●●

●●

●●

●●

●●

●●

Organ allograft rejection is defined as an immunologic reaction to an alloantigen that results in damage to the graft. There are three recognized dominant mechanisms of allograft rejection: T-cell–mediated rejection, antibody-mediated rejection, and chronic rejection. T-cell–mediated rejection occurs in 15–40% of liver transplant recipients, usually in the first few weeks, but may occur late (after 90 days) and is characterized by the triad of bile duct inflammation, portal tract infiltration, and portal (or sometimes hepatic) vein endotheliitis. Early T-cell–mediated rejection is managed with high-dose corticosteroids, with little adverse impact on long-term graft function. Mild rejection may require little change in immunosuppression; however, late acute rejection responds less well and may lead to chronic rejection and graft loss. Acute antibody-mediated rejection is rare (1%) following liver transplantation. It most commonly occurs in recipients with anti-HLA donor-specific antibodies. Hyperacute rejection occurs predominantly in those with ABO-incompatible allografts, leading to acute liver failure, and usually requires emergency re-grafting. Chronic rejection occurs in  15 hours)

Low trough CNI levels

Ethnicity: black patients > white patients

Female donor (in male recipients)

Rapid weaning of steroids

Younger age (although not in  177 µmol/L) AIH, autoimmune hepatitis; CMV, cytomegalovirus; CNI, calcineurin inhibitor; CTLA4, cytotoxic T lymphocyte antigen-4; DR, donor–recipient; HLA, human leucocyte antigen; IL, interleukin; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis.

Chapter 41  Managing Rejection

Clinical presentation TCMR may be asymptomatic and is often detected incidentally due to worsening laboratory parameters, which illustrates the necessity for a high index of suspicion and pre-emptive monitoring. When symptoms and signs of TCMR occur, they can be indistinguishable from those due to other common complications after liver transplant, such as vascular thromboses, infection, and bile leaks, which should be excluded. These include: ●● ●● ●● ●●

fever ± rigors; malaise; abdominal pain; and anorexia and asthenia.

Patients with late TCMR are frequently asymptomatic in the early stages, but develop similar features to early TCMR as the disease progresses. On clinical examination tender hepatomegaly is described (but is clinically rarely useful). In those patients with external biliary drainage (T-tube), the bile color becomes lighter.

Diagnosis Histologic assessment is the gold standard and currently the only way of diagnosing TCMR due its non-specific clinical presentation. However biochemical, microbiologic, and radiologic assessments are essential to exclude co-existent pathology or other causes of graft dysfunction. A typical investigation algorithm is shown in Figure 41.1.

Laboratory investigations Graft dysfunction is typically detected by the presence of elevated liver enzymes, including alanine aminotransferase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP), and climbing bilirubin levels. Early TCMR is characterized by a cholestatic profile, with a hepatitic picture emerging later.

Abnormal or non-improving liver function tests Clinical suspicion of graft rejection

Exclude other causes of graft dysfunction: Low tacrolimus/cyclosporine level Non-compliance Sepsis Drug-induced liver injury CMV/EBV/HSV/HEV

Urgent Doppler ultrasound to exclude vascular cause

Consider contrast enhanced CT or MRI Urgent liver biopsy

Figure 41.1  Suggested investigation algorithm in suspected acute graft rejection. CMV, cytomegalovirus; CT, computed tomography; EBV, Epstein–Barr virus; HEV, hepatitis E virus; HSV, herpes simplex virus; MRI, magnetic resonance imaging.

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Patients presenting with graft dysfunction need to be assessed rapidly to identify TCMR and exclude other important causes of graft dysfunction. As biochemical indicators are neither sensitive nor specific for TCMR or its histologic severity, liver biopsy and imaging studies are required. Investigation of other causes of graft dysfunction such as hepatitis E, CMV, Epstein–Barr virus (EBV), or herpes simplex virus (HSV) hepatitis by quantification of viremia in peripheral blood, sepsis by assessment of C-reactive protein, fever, leucocytosis, and blood culture is important, although elevated inflammatory markers may be seen in the setting of TCMR. Peripheral eosinophilia has been demonstrated to predict the evolution of TCMR: an elevated eosinophil count is associated with more severe histologic appearances, and a fall is associated with resolution of TCMR. DSAs are identified in up to 50% of patients with TCMR and the presence of DSAs is associated with a greater frequency of TCMR, worse prognosis, and higher rates of steroid-resistant and chronic rejection.

Radiology Radiologic investigations are not required for a diagnosis of TCMR; however, prompt assessment of the graft vasculature is essential in patients presenting with graft dysfunction to rule out arterial or venous thrombosis and other complications of transplantation. Doppler ultrasound examination of the hepatic artery is typically a firstline test, and reduced portal blood flow velocity and an increase in splenic pulsatility index are recognized features of TCMR (accuracy 88%).

Histology Histologic assessment remains the gold standard for the diagnosis and grading of severity of TCMR. The updated Banff Working Group on Liver Allograft Pathology 2016 retains the core histological triad (see Figures  41.2 and 41.3): ●● ●● ●●

portal inflammation with a mixed inflammatory infiltrate; bile duct damage; and vascular endotheliitis.

The degree of activity can be scored using the rejection activity index (RAI), with a score of up to 3 for each domain (see Table 41.2) and the composite assessment of indeterminate, mild, moderate, and severe TCMR (see Table  41.3) is routinely used to guide therapy and assess treatment responses. However, the severity of TCMR scored by the RAI does not predict treatment response and, importantly, abnormalities observed in each domain are not equivalent, as the prominence of histologic features changes over the course of an episode of TCMR, hence the composite descriptive assessment (see Table 41.3) is often favored.

Specific features Early T-cell–mediated rejection ●●

●●

Portal inflammatory response: mixed cellular infiltrate consisting of eosinophils, monocytes, neutrophils, and CD4+ and CD8+ lymphocytes. Interface hepatitis is rarely more than mild. Vascular endotheliitis: –– inflammation primarily affects the venules of the portal tract; –– hepatic veins are occasionally affected; –– hepatic arteritis is observed in severe cases; –– lobular inflammation in the form of a variable central perivenulitis is occasionally associated with hepatic vein endotheliitis.

(a)

(b)

(c)

Figure 41.2  Early acute cellular rejection. (a) Portal inflammation (mixed population). (b) Bile duct inflammation ­ (non-suppurative destructive cholangitis). (c) Venous endothelial inflammation (endotheliitis).

(a)

(b)

Figure 41.3  Late acute rejection with severe central perivenulitis. (a) Severe central perivenulitis with bridging necrosis. (b) Mild portal inflammation without typical features of acute rejection.

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Table 41.2  Histopathologic criteria and scoring of Rejection Activity Index (RAI) for T-cell–mediated rejection of liver allografts. Site of inflammation

RAI score

Histologic criteria

Portal tracts

1

Mostly lymphocytic inflammation involving, but not noticeably expanding, a minority of the triads

2

Expansion of most/all triads, by a mixed infiltrate containing lymphocytes with occasional blasts, neutrophils, and eosinophils. If eosinophils are conspicuous and accompanied by edema and microvascular endothelial cell hypertrophy is prominent, consider AMR

3

Marked expansion of most/all triads by a mixed infiltrate containing blasts and eosinophils with inflammatory spillover into periportal parenchyma

1

Minority of ducts cuffed and infiltrated by inflammatory cells with mild reactive changes such as increased nuclear : cytoplasmic ratio of the epithelial cells

2

Most/all ducts infiltrated by inflammatory cells. More than an occasional duct shows degenerative changes such as nuclear pleomorphism, disordered polarity, and cytoplasmic vacuolization of the epithelium

3

As for 2, with most or all of the ducts showing degenerative changes or focal luminal disruption

1

Subendothelial lymphocytic infiltration involving some, but not a majority of the portal and/or hepatic venules

2

Subendothelial infiltration involving most/all portal and/or hepatic venules with or without confluent hepatocyte necrosis/drop-out involving a minority of perivenular regions

3

As for 2, with moderate or severe perivenular inflammation that extends into the perivenular parenchyma and is associated with perivenular hepatocyte necrosis involving a majority of perivenular regions

Bile ducts

Venous endothelium

Total score and grading of rejection severity Total

0–2

No rejection

3–5

Mild rejection

6–7

Moderate rejection

8–9

Severe rejection

AMR, antibody-mediated rejection; RAI, Rejection Activity Index. Source: Adapted from Demetris AJ, Bellamy C, Hübscher SG, O’Leary J, Randhawa PS, Feng S, et al. Comprehensive update of the Banff Working Group on Liver Allograft Pathology. Am J Transpl. 2016;16:2816–2835.

●●

●●

●●

Biliary infiltration: predominantly a CD8+ lymphocytic infiltrate. A ductular reaction may be present, the extent of which correlates with the severity of bile duct injury and cholestasis. Centrilobular hepatocyte damage: ballooning and bilirubinostasis are common features in the first few weeks post transplant and are related to preservation–reperfusion injury. Centrilobular hepatocyte loss is observed in cases with central perivenulitis. Fibrosis is not a feature of early acute cellular rejection (ACR).

Late T-cell–mediated rejection ●●

Portal inflammatory response: predominantly a mononuclear cell infiltrate consisting of lymphocytes, monocytes, and plasma cells, with a variable degree of interface hepatitis.

Chapter 41  Managing Rejection

Table 41.3  Histopathologic criteria for the global assessment of T-cell–mediated rejection of liver allografts. Severity of rejection

Histologic criteria

Indeterminate

Portal and/or perivenular inflammatory infiltrate that is related to an alloreaction, but shows insufficient tissue damage to meet criteria for a diagnosis of mild acute rejection

Mild

Rejection-type infiltrate in a minority of the triads or perivenular areas, which is generally mild, and mostly confined within the portal spaces for portal-based rejection, and an absence of confluent necrosis/hepatocyte drop-out for those presenting with isolated perivenular infiltrates

Moderate

Rejection-type infiltrate, expanding most or all of portal tracts and/or perivenular areas, with confluent necrosis/hepatocyte drop-out limited to a minority of perivenular areas

Severe

As above for moderate, with spillover into periportal areas and/or moderate to severe perivenular inflammation that extends into the hepatic parenchyma and is associated with perivenular hepatocyte necrosis involving a majority of perivenular areas

Source: Adapted from Demetris AJ, Bellamy C, Hübscher SG, O’Leary J, Randhawa PS, Feng S, et al. Comprehensive update of the Banff Working Group on Liver Allograft Pathology. Am J Transpl. 2016;16:2816–2835. ●●

●● ●● ●●

Vascular endotheliitis: –– portal vein and hepatic vein inflammation is rarely more than mild; –– arterial lesions are not readily seen on needle biopsies; –– central perivenulitis is more frequent than in early ACR and typically occurs without hepatic vein endotheliitis. Biliary infiltration: bile duct inflammation is rarely more than mild. Centrilobular hepatocyte damage: hepatocyte ballooning and bilirubinostasis are uncommon. Fibrosis: mild degrees of fibrosis (periportal or centrilobular) may be present and can progress with time.

Management The management of TCMR is complex and needs to be tailored to the individual patient’s clinical history, the risks of treatment, histologic severity, and degree of graft dysfunction. Broadly, treatment relies on augmenting the underlying immunosuppressive regimen and adding high-dose corticosteroids to induce remission of TCMR (see Figure 41.4). Caution is required in the presence of infections (e.g., viral hepatitis, postoperative infections, or competing diagnoses such as primary infection with HSV, CMV, or EBV), as corticosteroids could worsen outcomes for patients, especially if TCMR is mild. Conversely, patients with multiple risk factors for TCMR should be treated promptly and aggressively when TCMR is suspected, optimally after histologic confirmation. Management decisions are based on the histologic severity of TCMR (mild TCMR compared to those with moderate–severe TCMR), and secondly the response to treatment. Histologically mild disease

When a patient experiences mild TCMR with evidence of graft dysfunction, the approach is to augment the maintenance immunosuppression regimen: ●● ●● ●● ●●

Optimize trough tacrolimus whole blood levels to 8–12 μg/L. Add an additional agent such as mycophenolate mofetil (MMF). Change azathioprine to MMF. Add or increase corticosteroids.

If histologically mild TCMR is identified without graft dysfunction or the liver tests are near normal, no change in treatment is necessarily required following assessment of the risk of rejection, as discussed above, as only a small proportion evolve to more significant TCMR. Therefore, the value of so-called protocol liver biopsy in the absence of graft dysfunction is low and the practice is not encouraged.

371

Mild (Banff score 3–5)

Moderate (Banff score 6–7)

Severe (Banff score 8–9)

ALT, AST, ALP >2XULN Yes

No Transplanted with HBV/HCV viremia

No

Yes

Observe and reassess in one week Non-response Treat as per non-viral pathway

PO prednisolone 200 mg/day or IV methylprednisolone 10 mg/kg/day (max 1g/day)

Aim trough tacrolimus levels 8–12 µg/L Reassess in 1–2 weeks Non-response/ Tacrolimus optimised

Improvement in liver biochemistry after 3 days? Yes

Substitute azathioprine for mycophenolate mofetil; reassess in 1–2 weeks Non-response Treat as moderate/severe pathway

Gradual wean of corticosteroids

No Consider repeat biopsy to confirm ongoing TCMR and repeat steroid pulse or Alternate therapy - ATG - Muromonab-CD3 - Basiliximab

Figure 41.4  Typical treatment strategy for patients with T-cell–mediated rejection, with decisions being made based on histologic severity and treatment response. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate transaminase; ATG, anti-thymocyte globulin; HBV, hepatitis B virus; HCV, hepatitis C virus; IV, intravenous; PO, per os (oral); TCMR, T-cell–mediated rejection; ULN, upper limit of normal.

Chapter 41  Managing Rejection

In the now uncommon setting of patients transplanted with HCV viremia, for those with near-normal liver biochemistry and mild histologic features of rejection, a “watch and wait” approach is reasonable, as HCV recurrence can be hard to distinguish from TCMR and can be aggravated by corticosteroids. Early treatment of HCV recurrence with direct-acting antivirals should be considered. First episode of moderate/severe T-cell–mediated rejection

High-dose corticosteroids are required: methylprednisolone 10  mg/kg/day, maximum 1  g/day intravenously (IV) for 3 days, or prednisolone 200  mg/day orally for 3 days. The dose of steroids is tapered gradually once a favorable response is observed, which typically occurs at between 3 and 5 days. Recurrent and non-responsive (steroid-resistant) rejection

Generally 75–80% of cases of acute rejection respond to initial treatment as outlined above, and histologically confirmed recurrent TCMR or initially corticosteroid non-responsive TCMR can be successfully treated with further cycles of corticosteroid therapy. However, repeated rejection is associated with an increased risk of developing chronic graft dysfunction. An isolated episode of early ACR becomes a threat to the graft when it fails to respond to pulsed high-dose corticosteroids, termed steroid-resistant rejection (SRR). Although tacrolimus-based regimens have reduced the incidence of SRR in the first year of transplantation by 50%, approximately 10% of TCMR still fails to respond to high-dose corticosteroids. In this situation, several approaches using anti-T-cell targeted therapies have been used and lead to positive outcomes in 60–70% of patients. ●●

●●

●●

Rabbit anti-thymocyte globulin (rATG): 60% of SRR patients respond (dosage 1.5 mg/kg/day IV for 3–7 days). Side effects include thrombocytopenia, leucopenia, and sepsis. –– rATG is a polyclonal antibody preparation that includes antibodies targeting a range of T-cell surface markers. It acts to deplete T-cells via activation-induced cell death, complement-dependent cytotoxicity, and antibody-dependent cell-mediated cytotoxicity. Additionally, depletion of B-cell lineages and modulation of lymphocyte trafficking and natural killer and dendritic cell function have been described. The half-life of ATG in human plasma is 30 days, hence it provides protracted immunosuppressive activity. Monoclonal antibodies (e.g., muromonab-anti-CD3): up to 77% of patients with SRR respond (dosage 5 mg/day IV for 5–10 days). However, this treatment is associated with an increased risk of sepsis, and prophylactic antibiotics may be required. It is most effective when used early after transplantation and when the liver function test derangement is not so pronounced, but is ineffective when graft function is severely compromised. –– CD3 is a component of the T-cell receptor complex and targeting by anti-CD3 antibody results in T-cell depletion by Fc receptor–mediated killing, blockade of T-cell receptor–antigen interactions, and downregulation of CD3 preventing T-cell receptor signaling. The effect of anti-CD3 antibodies is short-lived, with restitution of normal T-cell markers and populations within 48 hours to 1 week of stopping treatment. Anti-IL-2 receptor antibodies (basiliximab; dosage 20 mg with a further dose 3–5 days later): this is effective (response rate 48–75%) in those with SRR and no evidence of CR. However, the median time to respond may be 25–30 days and infective complications occur in up to 20% of patients. –– Basiliximab is a monoclonal antibody targeting CD25, a constituent of the high-affinity interleukin (IL)2 receptor complex, which is expressed on activated T-cells. IL2 signaling is essential for T-cell proliferation and function, hence its blockade impairs T-cell function and the alloimmune response. Consistent blockade is persistent for at least 4–6 weeks following treatment.

Prognosis TCMR is rarely associated with graft loss ( 50% of the circumference of portal microvascular endothelia (portal veins and capillaries), affecting  50% of the circumference of portal microvascular endothelia (portal veins and capillaries) – usually without extension into periportal sinusoids, affecting 10–50% of portal tracts

3 Diffuse

C4d deposition in > 50% of the circumference of portal microvascular endothelia (portal veins and capillaries) – often with extension into inlet venules or periportal sinusoids, affecting > 50% of portal tracts

1

Portal microvascular endothelial cell enlargement (portal veins, capillaries, and inlet venules) involving a majority of portal tracts, with sparse microvasculitis defined as 3–4 marginated and/or intraluminal monocytes, neutrophils, or eosinophils in the maximally involved capillary with generally mild dilation

2

Monocytic, eosinophilic, or neutrophilic microvasculitis/capillaritis, defined as at least 5–10 leukocytes marginated and/or intraluminal in the maximally involved capillary prominent portal and/or sinusoidal microvascular endothelial cell enlargement involving a majority of portal tracts or sinusoids, with variable but noticeable portal capillary and inlet venule dilatation and variable portal edema

3

As above, with marked capillary dilatation, marked microvascular inflammation (10 or more marginated and/or intraluminal leukocytes in the most severely affected vessels), at least focal microvascular disruption with fibrin deposition, and extravasation of red blood cells into the portal stroma and/or space of Disse

Source: Adapted from Demetris AJ, Bellamy C, Hübscher SG, O’Leary J, Randhawa PS, Feng S, et al. Comprehensive update of the Banff Working Group on Liver Allograft Pathology. Am J Transpl. 2016;16:2816–2835.

Scoring and diagnosis of acute antibody-mediated rejection The 2016 Banff criteria recommend scoring C4d deposition as (1) minimal; (2) focal; or (3) diffuse, and histopathologic scoring criteria are outlined in Table  41.5. Determination of acute AMR as definite, suspicious, or indeterminate is made following the schema in Table 41.6. Due to the relative rarity of AMR, the frequent presence of DSAs without damage, the overlap of histologic features with other pathology (e.g., ischemia–reperfusion), and the potential toxicity of treatment, cautious interpretation of histologic changes is important to avoid overdiagnosis.

Chronic antibody-mediated rejection The clinical syndrome and histopathologic features of chronic AMR remain poorly defined. The most strongly associated lesions observed with persistent DSAs are: ●● ●●

portal, periportal, and perivenular lymphoplasmacytic inflammation; interface and perivenular necro-inflammation;

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Part 5  Care of the Liver Transplant Recipient ●● ●● ●● ●● ●●

non-inflammatory fibrosis; biliary strictures; nodular regenerative hyperplasia; obliterative arteriopathy; microvascular C4d deposition.

Endotheliitis is much less pronounced in chronic compared to acute AMR. The Banff 2016 diagnostic criteria for chronic AMR are shown in Table 41.7.

Management of antibody-mediated rejection The management of AMR is challenging and most evidence is from uncontrolled case series. Prevention of AMR by avoiding ABO-incompatible grafts is common practice in most transplant programs. Avoidance of sensitization by minimizing blood product exposure of patients with liver disease is important. Pre- and perioperative reduction of pre-formed DSAs and suppression of (hyper)acute rejection in highly sensitized individuals, or when ABO-incompatible grafting is undertaken, can be achieved with combinations of: ●● ●● ●● ●● ●● ●● ●● ●●

plasmapheresis/plasma exchange; B-cell depletion (rituximab); high-dose methylprednisolone; IV immunoglobulin; cyclophosphamide; gabexate mesilate (proteasome inhibitor) infusion via the portal vein; prostaglandin E1 infusion via the hepatic artery or portal vein; or splenectomy.

Table 41.6  Diagnostic criteria for acute antibody-mediated rejection of liver allografts. Grade

Criteria

Definitive (all 4 required)

Histopathologic pattern of injury consistent with acute AMR Histopathology score = 2–3 Positive serum DSA Diffuse microvascular C4d deposition in ABO-compatible or portal stromal C4d deposition in ABO-incompatible allografts C4d deposition score = 3 Exclusion of other insults that might cause a similar pattern of injury

Suspicious (both required)

Positive serum DSA

Indeterminate (requires 1st AND 2nd criteria plus 3rd OR 4th)

Total C4d deposition and histopathology score  2

Histopathology score  1 and total C4d deposition score + histopathology score = 3–4 DSA not available, equivocal, or negative C4d staining not available, equivocal, or negative Co-existing insult might be contributing to the injury

AMR, antibody-mediated rejection; DSA, donor-specific antibody. Source: Adapted from Demetris AJ, Bellamy C, Hübscher SG, O’Leary J, Randhawa PS, Feng S, et al. Comprehensive update of the Banff Working Group on Liver Allograft Pathology. Am J Transpl. 2016;16:2816–2835.

Chapter 41  Managing Rejection

Table 41.7  Diagnostic criteria for chronic antibody-mediated rejection of liver allografts. Grade

Criteria

Probable (all 4 criteria required)

Histopathologic pattern of injury consistent with chronic antibody-mediated rejection: both required: (a) Otherwise unexplained and at least mild mononuclear portal and/or perivenular inflammation with interface and/or perivenular necro-inflammatory activity (b) At least moderate portal/periportal, sinusoidal and/or perivenular fibrosis Recent circulating HLA donor-specific antibody At least focal C4d-positive (> 10% portal tract microvascular endothelia) Exclusion of other insults that might cause a similar pattern of injury

Possible

As above, but C4d staining is minimal or absent

Source: Adapted from Demetris AJ, Bellamy C, Hübscher SG, O’Leary J, Randhawa PS, Feng S, et al. Comprehensive update of the Banff Working Group on Liver Allograft Pathology. Am J Transpl. 2016;16:2816–2835.

DSA titers of  1:8 are desired pre transplantation and treatment of postoperative AMR is based on the above modalities if DSA titers rise. This approach is limited to rare and highly specific clinical circumstances. Hyperacute AMR typically requires emergency re-transplantation despite appropriate escalation of immunosuppression and is associated with high mortality. Listing for re-transplantation is advised according to existing criteria for primary non-function and severe early graft dysfunction. Patients with established ABO-compatible acute AMR have been managed with a variety of approaches. There is no consensus strategy, but general approaches for mild acute AMR include: ●● ●● ●●

corticosteroids; optimization of tacrolimus trough levels; and rATG. For moderate to severe acute AMR the approaches include:

●● ●● ●● ●●

rituximab (often favored in early AMR); proteasome inhibitors, e.g., bortezomib (favored in late AMR); IV immunoglobulin; and plasmapheresis/plasma exchange.

There is a significant risk of sepsis with these treatment approaches and, due to overlap in features of TCMR and AMR, patients may have received additional immunosuppression, therefore careful evaluation for the presence of AMR and the risk of sepsis is required. Chronic AMR is difficult to manage, but encouragement of compliance with immunosuppressive regimens, optimization of tacrolimus trough levels, and additional corticosteroid treatment are the mainstay of management.

Prognosis The presence of pre-formed high-titer HLA class I DSAs significantly reduces early survival following transplantation, especially in the setting of a high Model for End-Stage Liver Disease (MELD) score and high donor risk index. Evidence for an impact of pre-formed HLA class II DSAs is conflicting and frequently from small retrospective studies, with short follow-up and older immunosuppression regimens. Many pre-formed class I or class II DSAs, especially those of low titer, disappear following transplantation, but high-titer class II and combined class I and class II DSA can lead to acute AMR and graft loss. Consequently, DSA measurements alone rarely influence the decision to

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offer a specific organ, but may influence the immunosuppressive regimens used and degree of suspicion of AMR if graft dysfunction is observed. Similarly, acute AMR is observed in only 5% of patients who had a positive cross-match at transplantation, but a positive cross-match itself is not associated with an increased risk of adverse outcomes, so should not preclude transplantation. However, a history of positive cross-match would increase the suspicion of AMR if graft dysfunction occurred. De novo DSA formation following liver transplantation occurs in approximately 8% of recipients by 1 year and is associated with accelerated allograft fibrosis and reduced patient and graft 5-year survival (de novo DSA associated HR of death = 1.99). However, the incidences of late acute AMR and chronic AMR are poorly defined and there is no consensus for routine assessment of DSAs following transplantation.

­Chronic rejection CR is a distinct pathologic process, not simply an end stage of TCMR and AMR, although the occurrence and chronicity of TCMR are associated with increased risk of CR. Late TCMR in particular is associated with CR; up to 27% of patients treated for late TCMR develop CR, whereas only 5-10% of patients treated for early TCMR develop CR. CR is mediated via a combination of cell-mediated and antibody-mediated pathways and results in chronic arterial occlusion and direct immune-mediated damage of bile ducts, leading to duct loss (hence the previous name of vanishing bile duct syndrome), cholestasis, and graft fibrosis.

Incidence and onset of chronic rejection The incidence of CR has fallen over the last few decades from 15–20% to 2–5% in adult recipients, probably as a consequence of more effective immunosuppression regimens (tacrolimus replacing cyclosporine) and early detection, although it remains more frequent in pediatric recipients and is one of the common causes of late graft failure (> 1 year after transplantation). The proportion of re-transplantation that occurs for CR has fallen from 35% in the late 1980s–mid 1990s to 11.6% in the period 2002–2014 in adults, with a similar pattern seen for pediatric recipients. 20-year follow-up of pediatric recipients revealed the occurrence of CR in up to a third of recipients. Most cases occur late (>  12 months) post transplant, with insidious presentation and indolent course, in some cases running for several years, although it is possible for onset to be within months of transplantation and lead to graft loss within the first year. The likelihood of recurrence of CR after re-transplantation is high.

Risk factors The most important risk for development of CR is re-transplantation for previous CR. Other risk factors are: ●● ●● ●● ●● ●● ●● ●● ●● ●●

underlying immune-mediated liver disease: PSC, PBC, and AIH; late, recurrent, or severe TCMR episodes; poor compliance with immunosuppression regimen; recipient of non-European descent (13% vs. 6%); donor–recipient sex mismatch (e.g., male donor and female recipient); donor age > 40 years; prolonged cold ischemia time; CMV infection; and genetically unrelated donor (in living donor transplantation programs).

Chapter 41  Managing Rejection

Clinical presentation CR may be asymptomatic, with graft dysfunction detected on routine blood tests characterized by elevated bilirubin, and elevated ALP and GGT. With progressive hyperbilirubinemia patients may report symptoms of cholestasis, including pruritus, fatigue, and jaundice. With progressive graft fibrosis and veno-occlusive disease, features of decompensated liver disease such as ascites and encephalopathy may be present. Patients may have had recurrent, severe, or unresolved TCMR that evolves into CR, or CR may less commonly present without preceding TCMR, with or without inadequate immunosuppression.

Diagnosis Laboratory investigations

The biochemical features are of progressive cholestasis, with bilirubin rising in the later stages and decline in liver synthetic function. Anti-tissue antibodies (anti-nuclear antibody (ANA) and anti-smooth muscle antibody (ASMA)) can be detected in > 70% of patients, but are neither specific nor sensitive for the diagnosis. Radiology

Doppler ultrasonography, contrast-enhanced CT, or hepatic artery angiography is indicated to exclude hepatic artery thrombosis or stenosis, since the differential diagnosis for cholestasis in liver transplantation includes ischemic cholangiopathy. Hepatic angiography, if performed, may show pruning of the distal branches of the hepatic artery with poor peripheral filling, but is not recommended as a diagnostic evaluation. Magnetic resonance cholangiopancreatography (MRCP) is required to exclude disease recurrence in those transplanted for PSC and for other causes of duct obstruction. Histology

The cardinal features of CR are: ●● ●● ●●

loss of bile ducts with no ductular reaction; obliterative foam cell arteriopathy; and zone 3 and terminal hepatic venule inflammation and fibrosis.

The arteriopathy typically affects large and medium-sized arteries, which are rarely represented in liver biopsies, hence these changes are better observed in explants. Therefore other causes of bile duct loss need to be carefully excluded (see management). Arterial lesions are mainly inflammatory and include lymphocytes (mainly T-cells) and lipid-laden macrophages, increasing numbers of myofibroblasts, and intimal fibrosis. Early CR demonstrates: ●● ●● ●● ●●

inflammatory and degenerative changes in bile ducts; ductopenia without ductular reaction (Figure 41.6), although this is seen in some later-presenting cases; subendothelial and perivenular mononuclear infiltrate; hepatocyte drop-out and fibrosis around terminal hepatic venules. Progression or CR results in:

●● ●● ●● ●● ●● ●● ●●

acidophilic necrosis of hepatocytes (“transition” necrosis); bridging fibrosis; hepatic venule proliferation; hepatocyte ballooning and drop-out; hepatocanalicular cholestasis; foam cell clusters; and loss of bile ducts from  50% of sampled portal tracts.

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Figure 41.6  Chronic liver allograft rejection – bile duct loss, no ductular reaction.

Despite the clear classification outlined in the Banff criteria (Table 41.8), histologic interpretation can be challenging; obliterative arteriopathy is rarely seen due to larger vessels not being sampled, bile duct loss can be heterogeneous leading to misleading sampling error in small biopsy samples, the features of CR overlap with many other causes of ductopenia, and the progression from early to late CR is not uniform. For example, arteriopathy can occur without bile duct loss and vice versa. Similarly, bridging perivenular fibrosis may be present without significant bile duct loss or obliterative arteriopathy. An important practical point is that, although the biopsy findings and severity graded by Banff criteria provide useful information about the likelihood of reversal (those with > 50% of portal tracts with well-preserved biliary architecture being more likely to have reversible disease), these findings should be combined with the clinical and biochemical phenotype before any decision to alter medical therapy or proceed with re-transplantation is made.

Management CR may be reversible in some patients, especially in those with   33%) may be considered as a relative contraindication. Focal lesions (both hepatic and non-hepatic) in the donor may also be biopsied for frozen section prior to commencement of the transplantation procedure. Typically the purpose of these biopsies is to exclude malignant disease such as melanoma, which has the potential for transfer to the recipient.

­Assessment of post-implantation liver: the “time zero” allograft biopsy The “time zero” liver biopsy is taken intraoperatively, immediately after reperfusion of the allograft. Such biopsies are performed for two reasons: to assess the degree of liver damage that has occurred from the time of organ harvesting or donor death (preservation/reperfusion injury, PRI) and to assess for any evidence of pre-existing donorrelated chronic liver disease. PRI is caused by ischemia. Cold ischemia primarily causes injury to hepatic sinusoidal endothelium and warm ischemia mainly damages hepatocytes, with both resulting in adenosine triphosphate (ATP) depletion and cell death. On reperfusion these changes induce an inflammatory cascade with activation of Kupffer cells, formation of reactive oxygen species, and neutrophil recruitment. On biopsy PRI manifests as glycogen depletion, swelling and ballooning of hepatocyte cytoplasm, single-cell apoptosis, and, in severe cases, confluent necrosis. These changes tend to be most pronounced in centrilobular regions, because hepatocytes in these regions receive the lowest concentrations of oxygenated blood that flows from the portal tracts, and are thus most susceptible to ischemia. Biopsy may also show clusters of neutrophils and accumulation of bile in centrilobular regions (bilirubinostasis). The features of PRI will usually resolve within the first few weeks after transplantation. Severe PRI is, however, predictive of an increased risk of primary non-function and death within the first 90 days of transplant. Occasionally the “time zero” biopsy may detect significant pre-existing donor-related chronic liver disease. Documenting even relatively mild pathologic changes may be of relevance when interpreting subsequent biopsies of the allograft.

Chapter 43  Liver Transplant Pathology

­Liver allograft biopsy Liver allograft biopsy remains a key element in the workup of post-transplant patients with clinical evidence of liver dysfunction. It remains the gold standard test for diagnosing acute cellular rejection (T-cell–mediated rejection, TCMR), and may also provide clues to other causes of graft dysfunction requiring further investigation with other modalities, such as infection or vascular problems. Historically it was common practice to obtain protocol biopsies at various pre-defined time points post transplant. However, many institutions have now stopped obtaining protocol biopsies because of the risk of biopsy-related complications and the frequent finding of histologic abnormalities in patients with normal liver function tests. In the following sections the pathologic changes occurring in various causes of liver ­dysfunction will be discussed, focusing on areas where histologic assessments are most relevant for diagnosis and clinical management. The cause of liver allograft dysfunction is often multifactorial, resulting in a mixed histologic picture. Interpretation of these changes can be complex, requiring specialist expert assessment and regular clinico-pathologic ­correlation at multidisciplinary team meetings.

Acute cellular rejection (T-cell–mediated rejection) Acute cellular rejection is the commonest manifestation of alloimmune damage to the liver allograft, which is mediated by T-cells and is therefore also now referred to as T-cell–­mediated rejection. Alloantigens are presented to host T-cells in lymph nodes. The a­ ctivated T-cells then migrate to the liver, where a number of effector mechanisms are initiated, including direct T-cell–mediated cell lysis of the allograft tissue and recruitment of cells of innate immunity, including neutrophils, eosinophils, and macrophages, which cause non-antigen-specific tissue damage. All cell types in the allograft liver may be injured, including hepatocytes, biliary epithelial cells, and endothelial cells. Histologically TCMR is characterized by three main features: (1) a mixed inflammatory cell infiltrate in portal tracts comprising lymphocytes, neutrophils, eosinophils, plasma cells, macrophages, and large “blast-like” cells (Figure 43.1); (2) inflammatory cell infiltration of the bile duct epithelium; and (3) endothelial inflammation involving portal and/or hepatic veins. In more severe forms of rejection inflammation can expand the portal tracts and spill over into periportal regions. Lobular inflammatory changes are also commonly present, particularly in more severe cases, and typically involve centrilobular regions. The presence of hepatic vein endothelitis and inflammation of surrounding parenchyma is known as central perivenulitis. Acute cellular rejection may be associated with centrilobular ballooning, hepatocyte apoptosis, and cholestasis, features also seen in PRI (see above). The Banff scheme is used to grade the overall severity of the rejection infiltrate as mild, moderate, or severe and to score the individual components of the infiltrate to give a Rejection Activity Index (Tables 43.1 and 43.2). In the early post-transplant period, identification of the histologic features described above is highly specific for a diagnosis of TCMR. However, TCMR can occur many months or even years after transplantation, particularly if there is a change to the immunosuppressive regimen, and the diagnosis of late rejection may be more challenging. The portal infiltrate in late acute cellular rejection often shows a higher proportion of mononuclear cells and evidence of interface hepatitis, with less inflammation of bile ducts and blood vessels. Central perivenulitis is also frequently seen in this setting. The overall histologic appearance is similar to chronic hepatitis in the native liver, and depending on the clinical situation may raise the differential of recurrent hepatitis B/C virus (HBV/HCV) infection, recurrent autoimmune hepatitis, or a drug-induced liver injury. Close clinico-pathologic correlation is therefore needed to establish the correct diagnosis. Acute cellular rejection with histologic features of moderate or severe grade is usually treated with pulsed steroids, whereas mild rejection may require only optimization of the patient’s current immunosuppressive regimen.

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*

*

Figure 43.1  Acute cellular rejection. This biopsy is from a 56-year-old male 8 days post liver transplant with persistently deranged liver function tests and fever. This image shows a portal tract expanded by a mixed inflammatory cell infiltrate. There is inflammation of bile duct profiles that show degenerate epithelial changes (asterisk) and prominent endothelitis of the portal vein branch, with inflammatory cells undermining and lifting up the endothelium (arrows). The patient was successfully treated with pulsed steroids and had no further rejection episodes. Table 43.1  Updated Banff schema for grading acute cellular rejection (T-cell–mediated rejection): global assessment and overall rejection grade. Global assessment

Criteria

Indeterminate

Portal and/or perivenular inflammatory infiltrate that fails to meet the criteria for the diagnosis of mild acute rejection

Mild

Rejection-type infiltrate in a minority of portal tracts or perivenular areas that is generally mild and is confined within the portal spaces and is without confluent necrosis/drop-out

Moderate

Rejection-type infiltrate, expanding most or all of portal tracts and/or perivenular areas with confluent necrosis/drop-out limited to a minority of perivenular areas

Severe

As above for moderate, with spillover into periportal areas and moderate to severe perivenular inflammation that extends into the hepatic parenchyma and is associated with perivenular hepatocyte necrosis involving a majority of perivenular areas

Source: Adapted from Demitris et al. 2016.

Chronic rejection Chronic rejection is the end result of immune-mediated injury to the allograft, characterized by bile duct loss and occlusive foam cell arteriopathy. Most cases are preceded by clinically documented episodes of TCMR, which is often severe histologically. Antibody-mediated mechanisms have also been implicated in the pathogenesis of chronic rejection. Histologically chronic rejection is characterized by senescence/degenerative changes in biliary epithelium and progressive loss of bile ducts (Table 43.3). Loss of more than 50% of small bile ducts in a biopsy is regarded as characteristic of late chronic rejection. However, the assessment of ductopenia may be difficult due to problems with sampling variability, and a minimum of 20 portal tracts is recommended in order to provide a meaningful

Chapter 43  Liver Transplant Pathology

Table 43.2  Updated Banff schema for grading acute cellular rejection (T-cell–mediated rejection): Rejection Activity Index. Component

Portal inflammation

Bile duct inflammation/damage

Venous endothelial inflammation

Score

Criteria

P1

Mostly lymphocytic inflammation involving, but not noticeably expanding, a minority of the triads

P2

Expansion of most or all of the triads, by a mixed infiltrate containing lymphocytes with occasional blasts, neutrophils, and eosinophils

P3

Marked expansion of most or all of the triads by a mixed infiltrate containing blasts and eosinophils with inflammatory spillover into the periportal parenchyma

B1

A minority of the ducts are cuffed and infiltrated by inflammatory cells and show only mild reactive changes such as increased nuclear/cytoplasmic ratio of the epithelial cells

B2

Most or all of the ducts infiltrated by inflammatory cells. More than an occasional duct shows degenerative changes such as nuclear pleomorphism, disordered polarity, and cytoplasmic vacuolization of the epithelium

B3

As for B2, with most or all of the ducts showing degenerative changes or focal luminal disruption

E1

Subendothelial lymphocytic infiltration involving some, but not a majority, of the portal and/or hepatic venules

E2

Subendothelial infiltration involving most or all of the portal and/or hepatic venules with or without confluent necrosis involving a minority of perivenular regions

E3

As for E2, with moderate or severe perivenular inflammation that extends into the perivenular parenchyma and is associated with perivenular hepatocyte necrosis involving a majority of perivenular regions

Source: Adapted from Demitris et al. 2016.

Table 43.3  Histopathologic features of chronic rejection. Structure

Early chronic rejection

Late chronic rejection

Small bile ducts

Senescence changes involving a majority of ducts Bile duct loss in  20,000. The patient was successfully treated with further immunosuppression and plasma exchange.

time a pattern of chronic biliary disease with ductopenia and fibrosis may develop. Medium- and large-caliber bile ducts may be inflamed, ulcerated, and necrotic, although such ducts are rarely sampled in biopsy material. Examination of failed allografts with ITBLs frequently shows areas of necrosis and bile staining extending through the full thickness of the walls of large bile ducts and sometimes also into surrounding tissues, often with super-added infection.

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Table 43.4  Criteria for establishing a diagnosis of acute/active antibody-mediated rejection. Definite for acute/active antibody-mediated rejection (all four criteria required)

1

Histopathologic pattern of injury consistent with acute antibody-mediated rejection, usually including the following: portal microvascular endothelial cell hypertrophy; portal capillary and inlet venule dilatation; monocytic, eosinophilic, and neutrophilic portal micro-vasculitis; portal edema; ductular reaction; cholestasis is usually present but variable; edema and periportal hepatocyte necrosis are more common/prominent in ABO-incompatible allografts; variable active lymphocytic and/or necrotizing arteritis

2

Positive serum donor-specific antibodies

3

Diffuse microvascular C4d deposition on frozen or formalin-fixed, paraffin-embedded tissue in ABO-compatible tissues or portal stromal C4d deposition in ABO-incompatible allografts

4

Reasonable exclusion of other insults that might cause a similar pattern of injury

Source: Adapted from Demitris et al. 2016.

Table 43.5  Criteria for probable chronic active antibody-mediated rejection. Probable chronic active antibody-mediated rejection (all four criteria required)

1

Histopathologic pattern of injury consistent with chronic antibody-mediated rejection: a. Otherwise unexplained and at least mild mononuclear portal and/or perivenular inflammation with interface and/or perivenular necro-inflammatory activity b. At least moderate portal/periportal, sinusoidal, and/or perivenular fibrosis

2

Recent (for example, measured within 3 months of biopsy) circulating human leucocyte antigen donor-specific antibodies in serum samples

3

At least focal C4d positive (> 10% portal tract microvascular endothelia)

4

Reasonable exclusion of other insults that might cause a similar pattern of injury

Source: Adapted from Demitris et al. 2016.

Biliary features can been seen in biopsies with acute and chronic rejection. The presence of a significant inflammatory infiltrate would usually point more toward rejection, but the distinction between ITBL and chronic rejection can be particularly challenging. It is also difficult to distinguish biliary complications in the graft from recurrent primary sclerosing cholangitis, since they share many overlapping features. Close correlation with clinical and radiologic findings is needed.

Vascular complications Vascular complications are usually diagnosed radiologically and liver biopsy has a limited role in this setting. Hepatic artery thrombosis remains an important cause of post-transplant liver dysfunction. In the immediate/ early post-transplant period it is manifest as ischemic necrosis, which can be either geographic or perivenular. Later hepatic artery thrombosis is an important cause of ischemic cholangiopathy. Portal vein thrombosis is less common. In the immediate/early post-transplant period it may result in ischemic necrosis. Thrombosis or anastomotic strictures in the hepatic vein block the venous outflow of the liver and result in a morphologic picture similar to that seen in Budd–Chiari syndrome, with sinusoidal dilatation and congestion and translocation of erythrocytes to the space of Disse.

Chapter 43  Liver Transplant Pathology

As discussed above, perivenular necrosis can be seen in acute and chronic rejection and is sometimes associated with congestive changes resembling those seen in hepatic venous outflow obstruction. The presence of co-existent inflammatory changes (portal and/or centrilobular) may help to point to diagnosis of rejection. Correlation with imaging studies can be helpful in providing definitive evidence of a vascular problem.

Infection Long-term immunosuppression renders liver transplant recipients at increased risk of ­infection. However, liver biopsy has a limited role in the diagnosis of post-transplant ­infections, the majority of which are diagnosed via other modalities. Characteristic ­morphologic changes are occasionally seen in cytomegalovirus (CMV) hepatitis, in which neutrophil micro-abscesses and nuclear viral inclusions point toward the diagnosis. Immunohistochemical staining is helpful in confirming the diagnosis, and correlation should be made with serum CMV-DNA levels. Other viruses with nuclear inclusions detectable on light microscopy include herpes simplex virus and adenovirus; again, immunohistochemistry is helpful in confirming the diagnosis. Inflamed bile ducts containing biliary sludge, as seen in ITBL for example, may harbor fungal or bacterial elements occasionally detectable on biopsy material.

Recurrent disease Liver biopsy is helpful in detecting the presence and severity of recurrent disease in the liver allograft. Commonly recurring diseases include primary biliary cholangitis (typically asymptomatic and non-progressive), primary sclerosing cholangitis (more often symptomatic and, as mentioned above, difficult to distinguish from other causes of biliary pathology in the allograft), autoimmune hepatitis (which can have overlapping features with late acute cellular rejection), HBV and HCV (although rates have dramatically reduced due to improvements in antiviral therapies), and non-alcoholic fatty liver disease (NAFLD). Histologic findings are mostly similar to those seen with the original diseases occurring in the native liver, but may be modified by immunosuppressive therapy and by interactions with other graft complications. In cases where more than one cause for graft dysfunction is suspected (e.g., late TCMR and recurrent HCV), liver biopsy may help to identify the main cause of graft injury.

Other findings in late post-transplant biopsies The liver allograft may develop de novo disease, which is a different primary liver disease from the initial indication for transplant. Fatty liver disease, viral hepatitis, and hepatocellular carcinoma have all been reported in this context. Biopsies showing morphologic ­features of autoimmune hepatitis may be interpreted as de novo autoimmune hepatitis in the graft, although it is now felt that this is better regarded as a form of rejection (“plasma cellrich rejection”). Biopsies from long-term liver allografts commonly show features of chronic hepatitis (“idiopathic post-transplant hepatitis”) and /or fibrosis not related to other recognized complications in the graft. These changes have frequently been observed in protocol biopsies from asymptomatic patients with good graft function. There is increasing evidence to suggest that many of these cases represent a subclinical form of late rejection, possibly related to chronic AMR (as discussed above). Subtle architectural changes, of which nodular regenerative hyperplasia is the most frequent example, are also commonly seen in late protocol biopsies. Possible causes for these changes include antibody-mediated endothelial injury, drug toxicity (e.g., azathioprine), and disturbances in vascular microanatomy related to liver regeneration in reduced-size allografts. Most patients with these findings are asymptomatic, but some may develop features of portal hypertension.

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­Further reading Clouston AD, Hübscher SG. Transplantation pathology. In Burt AD, Ferrell LD, Hübscher SG, eds. MacSween’s pathology of the liver, 7th edn (pp. 880–965). Philadelphia, PA: Elsevier, 2017. Demetris AJ, Bellamy C, Hübscher SG, O’Leary J, Randhawa PS, Feng S, et al. Comprehensive update of the Banff Working Group on Liver Allograft Pathology: introduction of antibody-mediated rejection. Am J Transpl. 2016;16(10):2816–2835. de Vries Y, von Meijenfeldt FA, Porte RJ. Post-transplant cholangiopathy: classification, pathogenesis, and preventive strategies. Biochim Biophys Acta Mol Basis Dis. 2018;1864:1507–1515. Kelly D, Verkade HJ, Rajanayagam J, McKiernan P, Mazariegos G, Hübscher S. Late graft hepatitis and fibrosis in pediatric liver allograft recipients: current concepts and future developments. Liver Transpl. 2016;22:1593–1602. Linares I, Hamar M, Selzner N, Selzner M. Steatosis in liver transplantation: current limitations and future strategies. Transplantation. 2019;103:78–79. Taner T, Stegall MD, Heimbach JK. Antibody-mediated rejection in liver transplantation: current controversies and future directions. Liver Transpl. 2014;20:514–527. Voigtländer T, Alten TA, Kirstein MM. Clinical impact of liver biopsies in liver transplant recipients. Ann Transpl. 2017;22:108–114.

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44 Care of the Liver Transplant Recipient: Management of Renal Function Andres F. Carrion and Paul Martin University of Miami Miller School of Medicine, Miami, FL, USA

Key points ●●

●●

●●

●●

●●

●●

Pre-transplant renal impairment has many causes and is associated with an increased risk of renal failure post transplant and decreased graft and patient survival post-transplant. Renal replacement therapy for more than 6 weeks before transplantation may ­indicate the need for combined liver–kidney transplant. Those with pre-transplant renal dysfunction should be considered for modification of the standard immunosuppressive regimen, using either delayed introduction of CNI or a CNI-free regimen. Post-transplant renal impairment occurs in up to 50% of liver transplant recipients and is associated with an increased risk of renal failure, needing renal replacement therapy, and a fourfold increased risk of death. Causes of renal impairment include pre-transplant renal impairment, CNI use, other medications such as NSAIDs, hypertension, diabetes mellitus, and HCV infection. When renal impairment develops, clinicians should consider minimizing CNI dose or changing to a CNI-free regimen such as an mTOR inhibitor.

One consequence of improved survival following liver transplant (LT) is an aging cohort of recipients at risk of renal dysfunction due to nephrotoxic immunosuppressive agents. In addition, metabolic complications such as hypertension, diabetes mellitus, hyperlipidemia, and obesity are common and may contribute to renal disease. Although the causes of renal dysfunction in LT recipients are typically multifactorial, chronic immunosuppression with calcineurin inhibitors (CNIs), pre-transplant renal dysfunction, perioperative acute kidney injury (AKI), and metabolic co-morbidities such as diabetes mellitus and hypertension are important risk factors (Ojo et al. 2003). Hepatitis C virus (HCV) infection is also associated with renal disease in patients awaiting LT and LT recipients; however, the use of direct-acting antiviral agents will mitigate this. The reported incidence of AKI in the immediate perioperative period is highly imprecise because of the lack of a standardized definition. It has been estimated that the majority of LT recipients who survive past the first 6 months develop some degree of renal dysfunction with chronic kidney disease (CKD). Although the severity of CKD is highly variable, 5–8% of LT recipients develop end-stage renal disease requiring renal replacement therapy (RRT) during the first 10 years post transplant (Lucey et al. 2013).

Liver Transplantation: Clinical Assessment and Management, Second Edition. Edited by James Neuberger, James Ferguson, Philip N. Newsome and Michael Ronan Lucey. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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­Definitions of acute kidney injury and chronic kidney disease Several definitions of AKI have been proposed, the most recent one by the Kidney Disease Improving Global Outcomes (KDIGO) group: ●● ●● ●●

increase in serum creatinine by ≥ 0.3 mg/dL within 48 hours; or increase in serum creatinine to ≥ 1.5 times baseline within seven days; or urine output  130/85 mmHg); hypertriglyceridemia (> 8.3 mmol/L); low high-density lipoprotein (HDL) levels ( 85% at 1 year and > 70% at 5 years), it is essential to minimize cardiovascular events via controlling their risk factors (Figure 45.1).

­Management of cardiovascular risk factors in the liver transplant recipient Obesity Over one-third of patients with ESLD are now classified as obese, reflecting the rising prevalence of obesity in the general population. The proportion of LT recipients classified as obese increased from 15% in the early 1990s to 25% in the early 2000s. Most overweight or obese patients preoperatively will remain so post

Post-transplant cardiovascular care

Lifestyle changes Healthy diet (low salt, low fat) and exercise ≥ 150 mins/wk Abstinence from nicotine and alcohol

Minimizing immunosuppression

Testing for components of metabolic syndrome at 3, 6, 12 months then annually

Diabetes mellitus

Depending on status of glycemic control

Insulin Early post transplant with attempt to transition to oral agent

Metformin First-line oral agent in most patients

Hypertension

Calcium channel blockers such as amlodipine or felodipine as first line

ACE inhibiitors or ARBs if diabetic, proteinuria, CKD, or cardiac dysfunction

Echocardiographic testing at 6, 12, 24 months for patients with CCM

Dyslipidemia

Initiation of a statin if diabetic with LDL > 70 mg/dL, non-diabetic with LDL > 190 mg/dL, or nondiabetic with high atherovascular risk score

Addition of ezetimibe if target lipid level is not achieved on statin

Obesity (BMI > 30 kg/m2)

Treatment of hypertriglyceridemia

Initiation of fish oil if elevated triglycerides (>200 to < 500 mg/dL)

Initiation of Fibrates if triglycerides > 500 mg/dL

If worsening cardiac function, refer to cardiology and consider anti-remodeling medications

Multidisciplinary management (hepatology, endocrinology, and bariatric surgery)

Weight loss medications (e.g., liraglutide)

Weight loss surgery (BMI > 40 kg/m2)

GLP analogues or SGL2 in patients with CKD or heart failure

Figure 45.1  Algorithm for management of cardiovascular risk factors in the liver transplant recipient. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BMI, body mass index; CCM, cirrhotic cardiomyopathy; CKD, chronic kidney disease; GLP, glucagon-like peptide; LDL, low-density lipoprotein; SGL2, sodium–glucose co-transporter 2.

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Part 5  Care of the Liver Transplant Recipient 35 30 25 20 15 10 5 0 Pre LT

1 year post LT

2 years post LT

3 years post LT

Figure 45.2  Obesity rates after liver transplant (LT). Source: Data from Everhart et al. 1998.

transplant, with new-onset obesity, defined as a BMI >  30, reported to develop in 17–43% of patients post LT. The obesity trend after LT is illustrated in Figure 45.2. Weight gain post transplant is greater in patients over 50 years of age and those transplanted for chronic liver disease as compared with fulminant hepatic failure. As with other metabolic risk factors, obesity is particularly prevalent in patients undergoing transplantation for NASH, but is becoming more prevalent in other chronic liver diseases. Other pre-transplant predictors of subsequent obesity include both higher recipient and higher donor BMI, with the rate of post-transplant weight gain in patients with pre-existing obesity significantly greater and more sustained than in those with normal BMI pre transplant. Post-transplant obesity is multifactorial. In the LT literature, corticosteroids are not a significant contributor, whereas in the kidney transplant literature, prolonged and higher cumulative steroid dose has been associated with post-transplant obesity. There are limited data addressing weight gain and obesity relating to CNIs and mTOR inhibitors. Some animal data suggest that CNIs may be associated with increased weight gain. One study showed that everolimus may provide a relative weight loss advantage c­ ompared with tacrolimus alone. Post-transplant weight gain increases the risk of not only diabetes, cardiovascular disease, and NASH, but also other obesity-associated conditions such as sleep apnea and osteoarthritis, which can significantly impact on quality of life. Management of post-transplant obesity comprises dietary modifications, regular exercise, and pharmacotherapy or surgery when appropriate, and is ideally provided within the context of a multidisciplinary team. Physical activity is generally low in LT recipients and those who are physically active tend to have a lower BMI and less components of metabolic syndrome; therefore, strategies to increase exercise levels in LT recipients should be actively employed. There are five US Food and Drug Administration (FDA)-approved pharmacologic therapies for obesity (note that these may not be licensed in other countries). These medications should be prescribed in close collaboration with experts in medical weight loss and/or endocrinologists: ●●

●●

Orlistat, a pancreatic and gastric lipase inhibitor, may interact with cyclosporine by decreasing serum concentration, requiring dose adjustment. There have been case reports of liver injury in patients using Orlistat. Phentermine, in combination with topiramate (Qsymia®), is an appetite suppressant that is not known to interact with CNIs and not known to cause liver injury.

Chapter 45  Managing Cardiovascular Risk ●●

●●

●● ●●

Lorcaserin, a satiety-promoting agent, also has no significant drug interactions with CNIs or liver-related toxicity, but caution is advised in patients with renal dysfunction. Naltrexone combined with bupropion (Contrave®) is another FDA-approved medication for weight loss. Its mechanism of action is not well understood. The effect is believed to result from action on the appetite center in the hypothalamus. There have been no identified drug interactions with CNIs. This medication needs dose adjustment based on renal function and it is not advised in patients with end-stage renal disease. It is notable that elevation in liver enzymes has been reported in up to 1% of patients using naltrexone or bupropion. Liraglutide, a glucagon-like peptide 1 (GLP-1) analogue, was recently approved for weight loss. Additionally, it is shown to reduce cardiovascular events and provide better glycemic control. Importantly, it lacks hepatic metabolism; thus, its drug–drug interactions are limited, making it an obvious choice for management of postLT diabetes mellitus. Given its cost, use for weight loss purposes may be restricted.

Emerging data about sodium–glucose co-transporter-2 (SGLT2) inhibitors are promising with regard to weight loss benefits, but these medications have not yet been approved by the FDA for weight loss. Recent data demonstrated an important role for bariatric surgery at the time of LT and it may be considered in highly selected, morbidly obese patients to facilitate post-transplant weight loss. Sleeve gastrectomy at the time of transplant has been shown to result in sustained, significant weight loss and favorable impact on diabetes and hypertension. Post-transplant bariatric surgery is another feasible option in patients with morbid obesity, especially in those who failed medical therapy, though this approach has not become popular given concerns about surgical complexity in LT recipients. Preference for procedures that maintain access to the biliary tree is recommended. Endoscopic weight loss approaches are expanding and have shown promising results. However, the data are limited about their utility and safety in post-transplant patients. Conceptually, the risks should not be different than in the general population since this is purely a luminal intervention.

Dyslipidemia Dyslipidemia is very common in the post-transplant setting, affecting 66–85% of LT recipients. A mixed picture of elevated low-density lipoprotein (LDL) and triglycerides, often with low HDL, is usually present. Both corticosteroids and CNIs contribute to dyslipidemia, with cyclosporine associated with greater risk than tacrolimus. Sirolimus and everolimus have adverse effects on the lipid profile, particularly when used in combination with cyclosporine. Corticosteroids promote elevated cholesterol, very low-density lipoprotein (VLDL), and triglycerides, and reduced HDL via increased de novo lipogenesis and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity; CNIs lead to increased LDL and VLDL levels through reduction of lipoprotein lipase activity and cholesterol to bile salt conversion. Conversion from cyclosporine to tacrolimus has been shown to reduce cholesterol levels without increased rejection. In order to reduce the negative impact on both lipid profile and renal function, tacrolimus trough should be at the lowest level required to maintain the graft rejection free. Despite its hyperlipidemic effects, steroid-free immunosuppression post LT has not been shown to reduce hyperlipidemia. However, tapering corticosteroids, as is standard protocol, should be recommended in the absence of a specific reason for maintenance therapy. Although dietary modifications, specifically a Mediterranean diet rich in fruit, vegetables, omega-3 fatty acids, and fiber, are beneficial and usually recommended, many patients will eventually need pharmacologic therapy. Statins exert beneficial effects on both cholesterol and triglyceride levels, are generally well tolerated, and their efficacy in the post-transplant setting is well established. Pravastatin is often recommended, as it is the only statin that is not metabolized by the cytochrome P450 system, and therefore does not interact with other immunosuppressive medications, but it is also a weaker agent. Other agents like atorvastatin or rosuvastatin are well tolerated and just require immunosuppression monitoring and dose adjustment with initiation or dose changes of the statin. The combination of simvastatin and amlodipine or cyclosporine has been demonstrated to result in higher

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rates of myopathy, so these combinations should be avoided. Ezetemibe, which inhibits the enterohepatic circulation of lipids, has been shown to be well tolerated and effective in further reducing cholesterol levels, with no interaction with immunosuppressive regimens or other safety concerns in this patient population. The cardiology guidelines recommended in 2018 that certain groups get offered statin-based therapy (see Figure 45.1). Repeat levels are warranted to evaluate adherence and percentage-based response to LDL cholesterol-lowering medications. Addition of ezetimibe is suggested after inability to achieve target cholesterol using maximally dosed tolerated statin. Hypertriglyceridemia may be treated with fish oil (omega-3), which is well tolerated with few drug interactions. These agents may have additional beneficial anti-inflammatory and anti-proliferative effects. Data suggest an association of fish oil with improved post-LT survival in NASH patients. Fibrates (such as clofibrate and fenofibrate), the other main class of lipid-lowering agents, are generally well tolerated. Endocrine guidelines recommend initiation of this class of medications in patients with a triglyceride level of > 500 mg/dL. However, they may interact with CNI metabolism, and have been associated rarely with muscle injury, particularly when used in conjunction with statin therapy.

Hypertension Although common in the general population, the prevalence of hypertension is significantly higher in the posttransplant setting, affecting up to 70% of patients. Hypertension, defined as blood pressure greater than 130/80 mmHg, usually occurs early post transplant and is mostly sustained thereafter. Key precipitants and triggers of hypertension in LT recipients are renal dysfunction, obesity, and immunosuppressive agents, particularly corticosteroids and CNIs. As with dyslipidemia, tacrolimus is reported to have a lower impact on hypertension than cyclosporine, and an additive effect on blood pressure is seen when sirolimus is used in combination with CNIs. Similar to other components of MS, non-pharmacologic treatment of hypertension consists of a low sodium diet, regular exercise, and weight loss. However, pharmacologic therapy is often needed. The treatment aim is maintaining blood pressure less than 130/80 mmHg, and the ultimate goal is to reduce cardiovascular and renal complications of hypertension. Calcium channel blockers such as amlodipine and felodipine are often used as first-line agents, as they reduce the renal and systemic vasoconstriction that plays a significant role in post-transplant hypertension. Nifedipine, diltiazem, and verapamil are not preferred due to their interaction with CNIs. Beta blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) are also efficacious in this setting and represent the most commonly used second-line agents. In patients with hypertension and proteinuria, chronic kidney disease (CKD), or diabetes mellitus, ACE inhibitors or ARBs are used as first-line therapy. The most recent Cardiology Society guidelines suggest use of ACE inhibitors or ARBs in patients with hypertension and CKD (stage 3 or higher or stage 1 or 2 with albuminuria:  300 mg/day, or  300 mg/g albumin : creatinine ratio or the equivalent in the first morning void). It is notable that ACE inhibitors or ARBs might have a favorable impact on liver fibrosis, which may be relevant in settings of recurrent liver disease in the allograft. The main downside of these medications is that they exacerbate CNI-induced hyperkalemia.

Insulin resistance and diabetes Prevalence of post-transplant diabetes ranges from 13% to 61% depending on the criteria used, with a sixfold higher prevalence than in age- and sex-matched populations. Post-transplant diabetes is multifactorial; pretransplant diabetes, increased BMI, and high-dose steroids are risk factors. Both corticosteroids and CNIs promote insulin resistance and diabetes, with tacrolimus being more diabetogenic than cyclosporine. Conversion of immunosuppression from tacrolimus to cyclosporine may be considered in patients with poor glycemic

Chapter 45  Managing Cardiovascular Risk

control. Liver denervation during transplantation may also contribute to increased insulin resistance. As many as 80% of cases of new-onset post-transplant diabetes mellitus (PTDM) develop early within the first month, with only a minority of cases of sustained PTDM occurring after the first year. While diabetes mellitus resolves in some patients after discontinuation of corticosteroids, it may persist in others. Persistent post-transplant diabetes was recently found to be associated with increased incidence of cardiovascular events, up to 27% in 10 years post transplant. PTDM is also associated with increased incidence of hepatic artery thrombosis, acute and chronic rejection, and infectious and neurologic complications. The effects of hepatitis C virus (HCV) eradication may influence the prevalence of PTDM, as HCV was linked with an increased risk of diabetes mellitus. The likely reduction of this risk will probably be overshadowed by the increased prevalence of NASH in the transplant population. All individuals, regardless of their diabetic status, should receive regular monitoring of their plasma glucose profile post transplant to allow early diagnosis of diabetes mellitus. Patients should undergo HBA1c testing at 3, 6, and 12 months post transplant, and annually thereafter. Treatment with metformin should be considered in patients with pre-­diabetes whose hemoglobin A1c (HBA1c) is 5.7–6.4%, especially if their BMI is > 34 kg/m2 or their age is  200 mg/dL during an oral glucose tolerance test, which is the preferred test for PTDM. In the early post-transplant course when high-dose corticosteroids are used, insulin therapy is the first-line agent for optimum glycemic control; however, as the corticosteroid dose decreases, insulin requirements may decrease and oral anti-hyperglycemic agents should be utilized. While metformin remains the first-line oral agent advocated by most endocrine societies, a personalized approach considering co-morbidities such as atherosclerotic cardiovascular disease (ASCVD), heart failure, and CKD should be considered. Sodium–glucose cotransporter 2 inhibitors and GLP-1 receptor agonists have demonstrated cardiovascular and renal benefits in patients with ASCVD and patients with CKD, respectively, and may assist with weight loss. Sodium–glucose cotransporter 2 inhibitors are the preferred agents in patient with or at risk of heart failure. Longer-term management of PTDM should aim for glycemic control with HBA1c less than 7%. Dietary modification and physical activity should be encouraged, and screening for complications with foot checks, retinal examination, and proteinuria screening performed annually.

Undiagnosed pre-transplant cardiovascular disease The presence of CVD that had not been diagnosed on traditional pre-transplant testing is another risk factor for post-transplant cardiovascular events, given the probable CVD ­progression post transplant in the setting of concurrent development or worsening of MS. While stress testing is the standard of care for screening of CAD pre transplant, a recent study demonstrated that 12% of cardiovascular events in the first year post ­transplant were due to obstructive CAD requiring revascularization, which highlights the need for more effective screening strategies. Caution should be taken when evaluating patients with multiple risk factors (e.g., diabetes, hypertension, NASH, smoking history), where diagnostic coronary catheterization would be more appropriate. As the data evolve about the role of advanced cardiac imaging modalities (i.e., computer tomography [CT] and magnetic resonance imaging [MRI]), they might become of utility as non-invasive tests in improving the detection of CAD in this patient population. Cardiac muscle dysfunction reflecting cirrhotic cardiomyopathy is another CVD that can be overlooked pre transplant, since the echocardiographic testing is often focused on ejection fraction–related systolic assessment. Cirrhotic cardiomyopathy is defined as systolic and/or diastolic dysfunction in patients with ESLD without prior cardiac dysfunction (Table  45.1). Post-transplant heart failure was found to be associated with pre-transplant

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Table 45.1  Pre-transplant echocardiographic assessment for cirrhotic cardiomyopathya in liver transplant candidates. Systolic dysfunction

Any of the following: Left ventricular ejection fraction  50% b ●● Absolute global longitudinal strain  34 mL/m c ●● Tricuspid regurgitation velocity > 2.8 m/s ●●

a

 Presence of systolic and/or diastolic dysfunction in patients with end-stage liver disease without previously identified cardiac disease (e.g., ischemic heart disease) is diagnostic of cirrhotic cardiomyopathy. b  Global longitudinal strain (GLS) is noted in echocardiography reports as a negative value. Changes in GLS should be described as changes in the absolute value. c  In the absence of primary pulmonary hypertension or portopulmonary hypertension. e’, early diastolic mitral annular velocity; E/e’, ratio of mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (e’).

diastolic dysfunction. Recent recommendations by the Cirrhotic Cardiomyopathy Consortium suggested, in addition to measuring left ventricular ejection fraction, measuring myocardial strain and obtaining tissue Doppler imaging to assess for diastolic dysfunction. Patients with ejection fraction  50–100 IU/L thereafter. The use of IV HBIG has limitations, namely the high cost, parenteral administration, limited supply, need for frequent clinic visits, and laboratory monitoring. Alternative regimens have been studied, including the 1993

HBIG monoprophylaxis LAM monoprophylaxis HBIG + LAM HBIG + LAM/ADV HBIG + new NAs (ETV/TDV) New NAs monoprophylaxis

2015

(no or early discontinuation of HBIG)

Figure 51.1  Evolution of prophylaxis against post-transplant hepatitis B virus recurrence.

Chapter 51  Management of HBV Infection Post Transplantation

Table 51.1  Results of meta-analyses comparing combination prophylaxis to hepatitis B immune globulin or antiviral monoprophylaxis. Hepatitis B virus recurrence was defined as hepatitis B surface antigen positivity in the post-liver transplant recipient sera. Results: HBV recurrence (defined as reappearance of HBsAg ± HBV DNA), HBV-related mortality

Authors

Studies

Patients

Loomba et al. 2008

6 studies 1999–2003

HBIG + LAM n = 193 HBIG n = 124

HBIG + LAM vs. HBIG ●● Decreased risk of HBV recurrence 4.1% vs. 36.1% ●● Decreased HBV-related mortality: RR = 0.08; 95% CI (0.02, 0.33)

Rao et al. 2009

6 studies 2003–2007

HBIG + LAM n = 306 LAM n = 245

HBIG + LAM vs. LAM ●● Decreased risk of HBV recurrence: RR = 0.38; 95% CI (0.25, 0.58)

Katz et al. 2009

20 studies (3 RCTs) 1999–2007

LAM n = 249 HBIG n= 351 LAM + ADV = 23 HBIG + antiviral n = 712

HBIG + LAM vs. HBIG ●● Decreased risk of HBV recurrence: RR = 0.28; 95% CI (0.12, 0.66) ●● Decreased HBV-related mortality: RR = 0.12; 95% CI (0.05, 0.30) HBIG + LAM and/or ADV vs. LAM and/or ADV ●● Decreased risk of HBV recurrence: RR = 0.31; 95% CI (0.22, 0.44) ●● Decreased HBV-related mortality: RR = 0.31; 95% CI (0.09, 1.10) HBIG vs. LAM*: no statistically significant difference in HBV recurrence and HBV-related mortality

Cholongitas et al. 2011

46 studies (3 RCTs) 1998–2010

HBIG + LAM and/or ADV n = 2162 HBIG + ADV n = 154 HBIG n = 260 LAM and/or ADV n = 189

HBIG + LAM and/or ADV: HBV recurrence 6.6% HBIG + LAM and/or ADV vs. HBIG: HBV recurrence 6.6% vs. 26.2% HBIG + LAM and/or ADV vs. LAM and/or ADV: HBV recurrence 6.6% vs. 19% HBIG + LAM vs. HBIG + ADV and/ or LAM. HBV recurrence 6.1% vs. 2%

Cholongitas & Papatheodoridis 2013

17 studies (1 RCT) 2009–2012

ETV or TDV or TDV + FTC and HBIG n = 304 ETV or TDV or TDV + FTC and HBIG discontinuation n = 102 ETV or TDV or TDV + FTC without HBIG n = 112

ETV or TDV or TDV + FTC and HBIG: HBV recurrence 1.3% ETV or TDV or TDV + FTC and HBIG discontinuation: HBV recurrence 3.9%   ETV or TDV or TDV + FTC without HBIG: HBV recurrence - HBsAg + 26% ●● HBV DNA + 0.9%

* In 2 out of 3 studies, LAM was given after pre treatment with HBIG (one week or 6 months). ADV, adefovir; CI, confidence interval; ETV, entecavir; FTC, emtricitabine; HBIG, hepatitis B immune globulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; LAM, lamivudine; RCT, randomized control trial; RR, relative risk; TDV, tenofovir.

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use of low-dose intramuscular (IM) HBIG or subcutaneous HBIG. The most cost-effective combination prophylaxis regimen reported is a very low IM HBIG (400–800 IU monthly) plus LAM regimen, decreasing costs by more than 90% compared with an IV regimen, with a recurrence rate of 4% at 4 years (Gane et al. 2007). There are some contraindications for IM injections, such as coagulopathies or oral anticoagulation medication. More recently, subcutaneous HBIG has been shown to be effective, improving quality of life by offering greater independence and home self-administration, and this may contribute to decreasing costs by avoiding the need for day-case hospital stay (Di Costanzo et al. 2013). Safety of HBIG is generally good and adverse events reported are usually minor. Hypersensitivity reactions or even anaphylaxis rarely occur and can be controlled with antihistamines or steroids.

Newer prophylaxis protocols Hepatitis B immune globulin discontinuation

Indefinite combination therapy with HBIG plus an NA may not be required in all LT recipients. An alternative strategy to consider, especially in patients without detectable HBV DNA prior to transplantation, is the discontinuation of HBIG after a defined period of time and continuing treatment with antivirals alone (Table 51.2; Lenci et al. 2016; Buti et al. 2003, 2007; Wong et al. 2007; Angus et al. 2008; Gane et al. 2013; Saab et al. 2011; Teperman et al. 2013; Tanaka et al. 2014; Yi et al. 2013). The studies available to date highlight several key issues to consider prior to the discontinuation of HBIG post transplantation. Patients with high levels of HBV replication before transplantation have a high risk for recurrence when HBIG is discontinued. Several studies demonstrated cases of seroconversion to positive HBsAg associated with undetectable HBV DNA. Longer follow-up of these patients is necessary to determine whether they will clear HBsAg or whether they are at future risk of viral recurrence. Positivity of HBsAg may have a deleterious impact in case of delta co-infection. Duration of HBIG in HBIG withdrawal strategies is variable across centers and has not yet been established. In several studies, HBIG was stopped at 1 year post LT; however, some studies report shorter durations of HBIG (7 days or 1 month) with favorable results. Drug compliance to long-term antiviral therapy may be very important for transplant patients who have a life-long risk of HBV recurrence. Potential side effects could be observed using antiviral therapy in transplant patients: nephrotoxicity associated with tenofovir (TDV) may be enhanced in patients on calcineurin inhibitor therapy; there is a risk of decreased bone density with TDV; and mitochondrial toxicity is associated with entecavir (ETV). Hepatitis B immune globulin–free prophylaxis regimens

Studies of HBV prophylaxis using HBIG-free regimens reveal the following points (Fung et al. 2013; Gane et al. 2013; Schiff et al. 2007; Mutimer et al. 2000; Lo et al. 2001; Perrillo et al. 2001; Fung et al. 2011). First, ETV or TDV should be preferred to lamivudine to minimize the risk of drug resistance. In the HBIG era, HBsAg positivity was a good marker of HBV recurrence. In the HBIG-free era, HBsAg can persist or reappear in serum in around 20% of patients without detectable HBV DNA, and impact on the long-term patient and graft outcome. Withdrawal of all prophylaxis (both HBIG and NAs) is not recommended outside clinical trials, since it has been shown in low-risk patients that there are no tools to predict clearance of HBV and that, even in the long term, HBV reactivation is possible (Lenci et al. 2016). A proposed algorithm for prophylaxis against HBV recurrence after LT is shown in Figure 51.2.

­Use of liver grafts from anti-HBc-positive donors The growing organ shortage and the improved possibilities of HBV therapy favor the use of marginal grafts such as grafts from HBsAg-negative, anti-HBc-positive donors (Cholongitas et al. 2010; Huprikar et al. 2015). Anti-HBc is a marker of past HBV infection. However, after a resolved infection, the viral genome can persist as cccDNA in

Table 51.2  Prevention of hepatitis B virus recurrence after liver transplantation with hepatitis B immune globulin discontinuation and long-term antiviral therapy. Hepatitis B virus recurrence was defined as hepatitis B surface antigen positivity in the post-liver transplant recipient sera.

No. of Patients

HBV DNA positive at LT (%)

Buti et al. 2003, 2007

29

0

Wong et al. 2007

21

Angus et al. 2008

HBV recurrence n (%)

Duration of HBIG

Follow-up (months)

Randomized trial HBIG + LAM then LAM (n = 20) vs. LAM + HBIG IM 2000 IU/month (n = 9)

1 month

83

1/9 (11%) in the LAM + HBIG group 3/20 (15%) in the LAM group (poor compliance with LAM) Transient detection of HBV DNA n = 6

20% HBV DNA > 5 log cop/mL

HBIG ± LAM then LAM or ADV

median 26 months

40

HBV DNA+, HBsAg+ (LAM-R) n = 1, (5%) (poor compliance with LAM) HBV DNA+, HBsAg– (LAM-R) n = 1 Transient detection of HBV DNA n = 3 Transient detection of HBsAg n = 1

34

20%

Randomized trial IM HBIG + LAM then HBIG + LAM (n = 18) vs. ADV + LAM (n = 16)

> 12 months

21

0/18 in HBIG + LAM group 1/16 (6%) in ADV + LAM group (HBsAg+, HBV DNA–)

Saab et al. 2011

61

21%

IM HBIG + LAM then LAM or ETV + ADV or TDV (3 months of overlap therapy)

> 12 months

15

2/61 (3.3%) (HBsAg+, HBV DNA–)

Teperman et al. 2013

37

47%

Randomized trial At a median of 3.4 years post LT, HBIG + TDV–emtricitabine 24 weeks then HBIG + TDV–emtricitabine vs. TDV–emtricitabine

Median 3.4 years + 24 weeks

22

0

Gane et al. 2013

20 + 10

65%

IM HBIG + LAM + ADV then LAM + ADV

7 days

57

0 Transient detection of HBsAg in a patient with concomitant HCC recurrence

Lenci et al. 2016

30

0

HBIG + LAM ± ADV were withdrawn after liver biopsy specimens were negative for total and cccDNA

N/A

29

5/30 (17%) HBV DNA+, HBsAg+ n = 1 Transient detection of HBsAg n = 4

Yi et al. 2013

29

15 (52%)

IV HBIG + ETV then ETV

12 months

31

0 (0%) during the first year 1 (0.03%) during the second year

Tanaka et al. 2014

24

12 (50%)

IV/IM HBIG + TDF ± LAM then TDF ± LAM

12 months

29.1

0

Authors

Prevention of HBV recurrence

ADV, adefovir; cccDNA, covalently closed circular DNA; ETV, entecavir; HBIG: hepatitis B immune globulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; IM, intramuscular; IV, intravenous; LAM: lamivudine; LAM-R, resistance mutation(s) to lamivudine; LT, liver transplantation; N/A, not available; TDF, tenofovir disoproxil fumarate; TDV, tenofovir.

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Time of LT

Anhepatic phase and first postoperative week

Post LT

Low-risk patients • Undetectable HBV DNA levels • HBeAg negative • Fulminant hepatitis B

High-risk patients • Detectable HBV DNA levels • HBeAg positive • Presence of drug-resistant HBV • HDV coinfectiona • HIV coinfection • High risk of HCC recurrence • Poor compliance to antiviral therapy

HBIG IVb

Combination prophylaxis with lowdose IV, IM or subcutaneous HBIG and antiviral(s) to maintain anti-HBs levels > 50–100 IU/L

Combination prophylaxis with low-dose IV, IM or subcutaneous HBIG and antiviral(s) to maintain anti-HBs levels >50–100 IU/L

Discontinuation of HBIG is possible and maintain only long term antiviral(s). Duration of combination prophylaxis not determined (one year or less)

Cessation of HBIG is not recommended

Figure 51.2  Prophylaxis for prevention of hepatitis B virus graft recurrence following liver transplant: proposal for guideline. HBeAg, hepatitis B e antigen; HBIG, hepatitis B immune globulin; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HDV, hepatitis D virus; HIV, human immunodeficiency virus; IM, intramuscular; IV, intravenous; LT, liver transplantation. a  Shortening the duration of HBIG administration in HDV/HBV patients could have detrimental consequences, as reinfection in the case of HDV latency may lead to chronic hepatitis B and delta. b  High-dose IV HBIG during the first postoperative week could be associated with a lower frequency of HBV recurrence.

the liver and may reactivate during immunosuppressive therapy post transplant. The prevalence of anti-HBc is low in developed countries, ranging from 3% to 15%, but it may exceed 50% in highly endemic aeras. In the absence of HBV prophylaxis, the probability of de novo HBV infection after LT with grafts from anti-HBc-positive donors is around 50% in HBV-naive recipients. This risk is reduced to 15% in recipients with serologic markers of past HBV infection. Anti-HBV prophylaxis reduced de novo infection rates in both anti-HBc/anti-HBs-positive (15% to 3%) and HBV-naive recipients (50% to 12%). Conversely, the risk of HBV recurrence was not reported to be higher in HBsAg-positive recipients of anti-HBc-positive grafts using post-transplant prophylaxis, compared to those of anti-HBc-negative grafts. Before transplantation, HBV vaccination is recommended for HBV-naive transplant candidates. Anti-HBcpositive liver grafts should be first offered to patients transplanted for HBV-related liver disease, as they require life-long HBV prophylaxis, then to anti-HBc- and/or HBs-positive recipients, and only in the end should they be allocated to HBV-naive recipients (Figure 51.3; EASL 2009; Terrault et al. 2018; Cholongitas et al. 2010). Both antiHBc- and anti-HBs-positive recipients seem to represent a group that can safely receive anti-HBc-positive liver grafts even without any post-transplant HBV prophylaxis (probability of de novo HBV infection  95% of transplant recipients. Some form of HBV prophylaxis needs be continued indefinitely post transplant. However, in patients with low HBV DNA levels pre transplantation, discontinuation of HBIG, with continued long-term NA treatment, is possible. Depending on previous prophylaxis of HBV recurrence, new NAs seem to be the most attractive options for post-transplant HBV infection therapy. Anti-HBc-positive liver grafts should be first offered to HBsAg-positive recipients, then to anti-HBc- and/or anti-HBs-positive recipients, and only in the end should they be allocated to HBV-naive recipients. HBV-naive recipients should receive life-long antiviral prophylaxis.

­Further reading Angus PW, Patterson SJ, Strasser SI, McCaughan GW, Gane E. A randomized study of adefovir dipivoxil in place of HBIG in combination with lamivudine as post-liver transplantation hepatitis B prophylaxis. Hepatology. 2008;48:1460–1466. Buti M, Mas A, Prieto M, Casafont F, Gonzalez A, Miras M, et al. A randomized study comparing lamivudine monotherapy after a short course of hepatitis B immune globulin (HBIg) and lamivudine with long-term lamivudine plus HBIg in the prevention of hepatitis B virus recurrence after liver transplantation. J Hepatol. 2003;38:811–817. Buti M, Mas A, Prieto M, Casafont F, Gonzalez A, Miras M, et al. Adherence to lamivudine after an early withdrawal of hepatitis B immune globulin plays an important role in the long-term prevention of hepatitis B virus recurrence. Transplantation. 2007;84:650–654. Cholongitas E, Goulis J, Akriviadis E, Papatheodoridis GV. Hepatitis B immunoglobulin and/or nucleos(t)ide analogues for prophylaxis against hepatitis B virus recurrence after liver transplantation: a systematic review. Liver Transpl. 2011;17:1176–1190. Cholongitas E, Papatheodoridis GV. High genetic barrier nucleos(t)ide analogue(s) for prophylaxis from hepatitis B virus recurrence after liver transplantation: a systematic review. Am J Transpl. 2013;13:353–362. Cholongitas E, Papatheodoridis GV, Burroughs AK. Liver grafts from anti-hepatitis B core positive donors: a systematic review. J Hepatol. 2010;52:272–279. Di Costanzo GG, Lanza AG, Picciotto FP, Imparato M, Migliaccio C, De Luca M, et al. Safety and efficacy of subcutaneous hepatitis B immunoglobulin after liver transplantation: an open single-arm prospective study. Am J Transpl. 2013;13:348–352. European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370–398. Faria LC, Gigou M, Roque-Afonso AM, Sebagh M, Roche B, Fallot G, et al. Hepatocellular carcinoma is associated with an increased risk of hepatitis B virus recurrence after liver transplantation. Gastroenterology. 2008;134:1890–1899.

Chapter 51  Management of HBV Infection Post Transplantation

Fox AN, Terrault NA. The option of HBIG-free prophylaxis against recurrent HBV. J Hepatol. 2012;56:1189–1197. Fung J, Chan SC, Cheung C, Yuen MF, Chok KS, Sharr W, et al. Oral nucleoside/nucleotide analogs without hepatitis B immune globulin after liver transplantation for hepatitis B. American J Gastroenterol. 2013;108:942–948. Fung J, Cheung C, Chan SC, Yuen MF, Chok KS, Sharr W, et al. Entecavir monotherapy is effective in suppressing hepatitis B virus after liver transplantation. Gastroenterology. 2011;141:1212–1219. Gane EJ, Angus PW, Strasser S, Crawford DH, Ring J, Jeffrey GP, et al. Lamivudine plus low-dose hepatitis B immunoglobulin to prevent recurrent hepatitis B following liver transplantation. Gastroenterology. 2007;132:931–937. Gane E, Patterson S, Strasser S, McCaughan G, Angus P. Combination lamivudine plus adefovir without HBIG is safe and effective prophylaxis against HBV recurrence in HBsAg+ liver transplant candidates. Liver Transpl. 2013;19:268–274. Huprikar S, Danziger-Isakov L, Ahn J, Naugler S, Blumberg E, Avery RK, et al. Solid organ transplantation from hepatitis B virus-positive donors: consensus guidelines for recipient management. Am J Transpl. 2015;15:1162–1172. Katz LH, Paul M, Guy DG, Tur-Kaspa R. Prevention of recurrent hepatitis B virus infection after liver transplantation: hepatitis B immunoglobulin, antiviral drugs, or both? Systematic review and meta-analysis. Transpl Infect Dis. 2009;12:292–308. Lenci I, Baiocchi L, Tariciotti L, Di Paolo D, Milana M, Santopaolo F, et al. Complete hepatitis B virus prophylaxis withdrawal in hepatitis B surface antigen-positive liver transplant recipients after longterm minimal immunosuppression. Liver Transpl. 2016;22:1205–1213. Lo CM, Cheung ST, Lai CL, Liu CL, Ng IO, Yuen MF, et al. Liver transplantation in Asian patients with chronic hepatitis B using lamivudine prophylaxis. Ann Surg. 2001;233:276–281. Loomba R, Rowley AK, Wesley R, Smith KG, Liang TJ, Pucino F, et al. Hepatitis B immunoglobulin and lamivudine improve hepatitis B-related outcomes after liver transplantation: meta-analysis. Clin Gastroenterol Hepatol. 2008;6:696–700. Mutimer D, Dusheiko G, Barrett C, Grellier L, Ahmed M, Anschuetz G, et al. Lamivudine without HBIg for prevention of graft reinfection by hepatitis B: long-term follow-up. Transplantation. 2000;70:809–815. Perrillo RP, Wright T, Rakela J, Levy G, Schiff E, Gish R, et al. A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology. 2001;33:424–432. Rao W, Wu X, Xiu D. Lamivudine or lamivudine combined with hepatitis B immunoglobulin in prophylaxis of hepatitis B recurrence after liver transplantation: a meta-analysis. Transpl Int. 2009;22:387–394. Roche B, Feray C, Gigou M, Roque-Afonso AM, Arulnaden JL, Delvart V, et al. HBV DNA persistence 10 years after liver transplantation despite successful anti-HBS passive immunoprophylaxis. Hepatology. 2003;38:86–95. Roche B, Roque-Afonso AM, Nevens F, Samuel D. Rational basis for optimizing short and long-term hepatitis B virus prophylaxis post liver transplantation: role of hepatitis B immune globulin. Transplantation. 2015;99:1321–1334. Saab S, Desai S, Tsaoi D, Durazo F, Han S, McClune A, et al. Posttransplantation hepatitis B prophylaxis with combination oral nucleoside and nucleotide analog therapy. Am J Transpl. 2011;11:511–517. Samuel D, Muller R, Alexander G, Fassati L, Ducot B, Benhamou JP, et al. Liver transplantation in European patients with the hepatitis B surface antigen. N Engl J Med. 1993;329:1842–1847. Schiff E, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, et al. Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results. Liver Transpl. 2007;13:349–360. Tanaka T, Renner EL, Selzner N, Therapondos G, Lilly LB. One year of hepatitis B immunoglobulin plus tenofovir therapy is safe and effective in preventing recurrent hepatitis B post-liver transplantation. Can J Gastroenterol Hepatol. 2014;28:41–44. Teperman LW, Poordad F, Bzowej N, Martin P, Pungpapong S, Schiano T, et al. Randomized trial of emtricitabine/ tenofovir disoproxil fumarate after hepatitis B immunoglobulin withdrawal after liver transplantation. Liver Transpl. 2013;19:594–601.

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Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67:1560–1599. Wong SN, Chu CJ, Wai CT, Howell T, Moore C, Fontana RJ, et al. Low risk of hepatitis B virus recurrence after withdrawal of long-term hepatitis B immunoglobulin in patients receiving maintenance nucleos(t)ide analogue therapy. Liver Transpl. 2007;13:374–381. Yi NJ, Choi JY, Suh KS, Cho JY, Baik M, Hong G, et al. Post-transplantation sequential entecavir monotherapy following 1-year combination therapy with hepatitis B immunoglobulin. J Gastroenterol. 2013;48:1401–1410.

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52 Antimicrobial Prophylaxis Following Liver Transplantation Michael J. Williams and Peter C. Hayes Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK

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Infections after liver transplantation may occur as a result of reactivation of pre-existing organisms, transmitted by the graft, or newly acquired. Bacterial infections occur most commonly in the first postoperative month and include Gram-negative bacilli such as Escherichia coli, Enterobacter, and Pseudomonas, and Gram-positive cocci such as Enterococcus, Staphylococcus aureus, and coagulase-negative Staphylococcus. Fungal infections are mainly due to Candida or Aspergillus. Prophylaxis may reduce the risk but does not affect survival; treatment should be started promptly and echinocandins are usually effective. Infections with Pneumocystis jirovecii are less commonly seen as centers use prophylaxis with co-trimoxazole, but infections may still occur, especially in those receiving high-dose immunosuppression. Tuberculosis reactivation must be considered and prophylaxis offered to those at risk.

Immunosuppression following solid organ transplantation is associated with a significant risk of bacterial, fungal, and viral infections. Infections may be the result of reactivation of pre-existing organisms in the recipient, transmitted via the graft, or newly acquired. Examples of each scenario are illustrated in Figure 52.1. The overall infection risk to the patient is determined by both the environmental exposure to specific organisms and their net degree of immunosuppression. As such, this risk is generally highest during the first few months after transplant. Patients are also predisposed to infections in the early stages after liver transplantation due to loss of the normal mucocutaneous barrier integrity as a result of the wound, drains, intravascular lines, and urinary catheter. Other common host factors that can contribute to an increased risk of early infection in patients transplanted for chronic liver disease include poor nutrition and uremia. Consequently, the use of antimicrobial prophylaxis during the early postoperative period is now routine, but there is wide variability between centers as to how this is carried out (Vandecasteele et al. 2010). There is geographic variation in the frequency of some causative organisms, and the optimal strategy for prophylaxis will depend on both the baseline incidence of infection in the population and the local antimicrobial resistance profiles. Specific antimicrobial strategies also have to be considered in terms of their efficacy, cost, toxicity (including drug–drug interactions that may affect immunosuppression), and risk of resistance selection. Prophylaxis may be universal, or tailored to specific high-risk groups, according to the incidence of particular infections. Liver Transplantation: Clinical Assessment and Management, Second Edition. Edited by James Neuberger, James Ferguson, Philip N. Newsome and Michael Ronan Lucey. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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(a)

(b)

(c)

Figure 52.1  Routes of infection. (a) Reactivation, e.g., tuberculosis, Strongyloides. (b) Transmission via graft, e.g., cytomegalovirus, hepatitis B/C. (c) De novo infection, e.g. Pneumocystis.

­Bacterial infections Bacterial infections are common in the first month, and are often related to iatrogenic loss of barrier function. Wound infections, line infections, catheter-related urinary tract infections, and nosocomial pneumonia are all relatively common in this period. Early infections may also occur as a result of postoperative complications, such as bleeding, strictures, or anastomotic leaks. Surgical site infections are not uncommon following liver transplantation, occurring in between 9 and 37% of liver transplant recipients in case series in which different antibiotic regimens were used. Such infections are associated with increased graft loss and 1-year mortality. The most common causative organisms are Gram-negative bacilli (such as Escherichia coli, Enterobacter, and Pseudomonas), although Enterococcus, Staphylococcus aureus, and coagulase-negative Staphylococcus have also been implicated (Anesi et  al. 2018). For this reason, broad-spectrum antibiotics at the time of liver transplantation are recommended. American surgical guidelines currently recommend cefotaxime plus ampicillin, or piperacillin–tazobactam alone for up to 24 hours (Bratzler et al. 2013). However, there is a lack of high-quality studies comparing different antibiotic regimens in this setting and European guidelines do not specify a regimen.

­Fungal infections Invasive fungal infections are a serious complication of immunosuppression following liver transplantation. Early case series estimated the incidence of fungal infections post liver transplant to be as high as 40%, although more recent series show an incidence of around 5%. This is likely to reflect improvements in surgical technique and reduced immunosuppression, as well as increased use of prophylaxis. Although a number of fungal pathogens have been described, the majority of infections in liver transplant recipients are due to Candida or Aspergillus.

Candida Candida accounts for more than 75% of invasive fungal infections post liver transplant, although there has been a reduction in the incidence of invasive candidiasis over time. The majority of Candida infections occur within the first 3 months, and carry a risk of mortality of up to 40%. Risk factors for invasive Candida infections include re-transplantation, ­choledochojejunostomy, high transfusion requirements or a long operation time, cytomegalovirus (CMV) viremia, and post-transplant dialysis (Eschenauer et  al. 2009). C. albicans accounts for 65% of invasive candidiasis, followed by C. glabrata in 21%. Infection with non-albicans Candida species is generally associated with a worse outcome. Azoles (such as fluconazole and ketoconazole) are available in orally administered formulations and are well tolerated. They are effective against a number of Candida species. However, they have interactions with a number of drugs, especially calcineurin inhibitors, so careful monitoring of drug levels of calcineurin inhibitors is required if these drugs are being stopped or started. A systematic review of antifungal prophylaxis in liver transplant recipients found that fluconazole was effective in reducing the incidence of invasive fungal infections, although it was not shown to have a significant impact on patient

Chapter 52  Antimicrobial Prophylaxis Following Liver Transplantation

survival (Playford et al. 2004). There was no evidence in this review of an increase in colonization with fluconazoleresistant Candida strains, although this is a concern that has been raised as a potential disadvantage to universal antifungal prophylaxis. Current European guidelines therefore recommend universal oral prophylaxis against Candida species during the first months after liver transplantation, although they do not specify either the agent or the exact duration (EASL 2016). In contrast, American guidelines favor targeted prophylaxis in high-risk individuals only.

Aspergillus Aspergillus infection is less common but is associated with a higher mortality than Candida. Mortality rates from invasive aspergillosis have fallen from around 90% in the early 1990s to around 60% in the 2000s (Barchiesi et al. 2015). The fungus usually enters via the lungs and this is the most common site of infection, although central nervous system and bone involvement are well described. The most common species in Aspergillus fumigatus. Transplantation for fulminant hepatic failure, re-transplantation, post-transplant dialysis, and CMV disease are all risk factors that are associated with an increased risk of invasive aspergillosis. There appears to have been a change in the pattern of aspergillosis in liver transplant recipients over time, perhaps related to changes in immunosuppression or surgical technique. Aspergillus infections now tend to occur later in the post-transplantation period, with most occurring more than 3 months post transplant, and are less likely to have central nervous system involvement or disseminated infection. Fluconazole lacks efficacy against Aspergillus infections. Amphotericin B has greater activity against Aspergillus, but has to be administered intravenously and has significant risk of toxicity, including febrile infusion reactions and nephrotoxicity. Small trials of post-transplant prophylaxis using low-dose intravenous amphotericin B and liposomal amphotericin have failed to demonstrate any clear benefit. Caspofungin, an echinocandin, has good activity against both non-albicans Candida and Aspergillus, with a better safety profile than amphotericin and minimal nephrotoxicity. Caspofungin prophylaxis has been shown to have a low rate of breakthrough invasive fungal infections in high-risk patients. Non-randomized comparison with a historical fluconazole-treated group suggested a lower rate of invasive aspergillosis with caspofungin, although caspofungin did produce a significant rise in bilirubin in a proportion of patients. Micafungin, another echinocandin, has also shown non-inferiority to standard care (mostly fluconazole or liposomal amphotericin) in the TENPIN study (Saliba et al. 2015). However, it failed to demonstrate any advantage in terms of overall incidence of fungal infections, or mortality. Voriconazole, a triazole antifungal, has also been shown to be safe and effective as prophylaxis against aspergillosis in high-risk liver transplant recipients, although it has not been compared with other agents.

Pneumocystis jirovecii Pneumocystis jirovecii (previously known as Pneumocystis carinii) is an opportunistic fungal infection that can cause pneumonia in immunocompromised patients. Symptoms typically develop over several days, with marked hypoxia disproportionate to the physical findings on chest examination. Diagnosis is usually based on induced sputum testing or bronchoalveolar lavage. Prior to routine prophylaxis, the incidence of infection in solid organ transplant recipients was reported to be as high as 5–15% (Martin & Fishman 2013). The risk is highest in patients receiving increased immunosuppression (such as during treatment of rejection), patients who have neutropenia, and those with CMV infection. A systematic review of prophylaxis in non-human immunodeficiency virus (HIV) patients found that cotrimoxazole was highly effective, and resulted in an 85% reduction in the occurrence of Pneumocystis pneumonia (PCP), with no rise in the rate of adverse events (Stern et al. 2014). There was no apparent difference between daily and thrice-weekly dosing. Current guidelines therefore recommend routine use of co-trimoxazole for

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6–12 months. However, this can be associated with a range of toxicities, including rash, bone marrow suppression, increased serum creatinine, and hyperkalemia. In these situations, several alternatives exist and these are outlined in Table 52.1.

­Tuberculosis Infection with Mycobacterium tuberculosis is more frequent following liver transplantation, and leads to increased morbidity and mortality. Active tuberculosis (TB) can occur as a result of reactivation of latent infection in the recipient or rarely in donor tissue. The risk of TB in transplant recipients is highly linked to the frequency of TB in the recipient and donor populations. In areas of high TB incidence, universal preventative chemotherapy may be deemed appropriate without further testing. Recipients from areas of medium TB incidence should be tested for latent TB and offered preventative chemotherapy where positive. In areas of low TB incidence, testing should be offered to individuals with an identifiable risk factor (Bumbacea et al. 2012). Unless there is universal treatment/testing as already outlined, recipients should be screened for risk factors for latent TB by full clinical history, physical examination, and a chest radiograph, as summarized in Table  52.2. Latent infection is best diagnosed by detection of a cellular immune response using an interferon-gamma-based ex vivo assay, or a tuberculin skin test. The use of anti-TB medications can be challenging in both end-stage liver disease patients and transplant recipients, due to both a high incidence of drug-related liver toxicity and significant drug–drug interactions with commonly used immunosuppressants. The risk of liver toxicity often precludes treatment pre transplant, and chemoprophylaxis is usually started as soon as the patient is stable after transplant. The most commonly used regimen is isoniazid (given along with pyridoxine) for 9 months. Alternatives include rifampicin for 4 months, or a fluoroquinolone, if toxicity or resistance occurs. Close attention should be paid to levels of immunosuppressive drugs if using rifampicin, as it is a potent liver enzyme inducer and frequently alters other drug levels. Table 52.1  Pneumocystic jirovecii prophylaxis. Drug

Dose

First-line

Trimethoprim–sulphamethoxazole

80/400 mg daily or 160/800 mg daily or 160/800 mg three times weekly

Second-line

Dapsone

50–100 mg daily

Alternatives

Atovaquone

1500 mg daily

Pentamidine (nebulized)

300 mg every 3–4 weeks

Clindamycin + pyrimethamine

300 mg + 15 mg daily

Table 52.2  Risk factors for latent tuberculosis (TB). Recent contact with a patient with TB Immigration from (or travel to) a high TB incidence country History of previous untreated or insufficiently treated TB Fibrotic/calcified lesions on chest radiograph in untreated patient

Chapter 52  Antimicrobial Prophylaxis Following Liver Transplantation

Strongyloides Strongyloides stercoralis is a parasitic roundworm that is endemic in some tropical and subtropical areas. Infection can reactivate many years or even decades after initial infection as a result of immunosuppression following solid organ transplantation. There have also been cases of donor-derived Strongyloides infection in liver transplant recipients. Strongyloides reactivation results in fever, abdominal pain, diarrhea, and sometimes a hyperinfection syndrome of enterocolitis, pulmonary hemorrhage, or shock. Patients from endemic areas should be screened with Strongyloides immunoglobulin (Ig)G serology, and treated with ivermectin prophylaxis if positive.

­Antiviral prophylaxis Prophylaxis against hepatitis B and cytomegalovirus is discussed in other chapters.

­Vaccination In addition to administration of antimicrobial drugs, vaccination has been proposed as a strategy to reduce infective complications following liver transplantation. However, it should be noted that immunosuppression may reduce the ability to mount a protective immune response to vaccination. Consequently, the effectiveness of vaccinations in a post-transplant setting should not be assumed to be the same as in the general population. Equally, the safety of vaccines may also be different in the post-transplant population. Live vaccines should generally be avoided due to safety concerns, and there is a theoretical concern that immune stimulation could trigger rejection. Influenza carries an increased risk of complications in liver transplant recipients. In practice, influenza vaccination does appear to be safe in liver transplant recipients and produces satisfactory rates of protective antibodies, with no evidence to support an increased risk of rejection. It is therefore recommended that patients should have annual influenza vaccinations following liver transplantation. Pneumococcal vaccine has been shown to produce at least some degree of protective immune response in other solid organ recipients, and is also recommended for liver transplant recipients.

­Conclusion Following liver transplantation, infective complications are common, especially in the first 3 months. Perioperative antibiotics reduce the risk of early bacterial infections, including surgical site infections. Subsequently, consideration should be given to antimicrobial prophylaxis against Candida and Pneumocystis jirovecii, and in any cases where latent TB is suspected. Specific strategies will be decided based on the local incidence of specific ­infective agents and resistance profiles.

­Further reading Anesi JA, Blumberg EA, Abbo LM. Perioperative antibiotic prophylaxis to prevent surgical site infections in solid organ transplantation. Transplantation. 2018;102(1):21–34. Barchiesi F, Mazzocato S, Mazzanti S, Gesuita R, Skrami E, Fiorentini A, et al. Invasive aspergillosis in liver transplant recipients: epidemiology, clinical characteristics, treatment, and outcomes in 116 cases. Liver Transpl. 2015;21(2):204–212.

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Bratzler DW, Dellinger PE, Olsen KM, Perl TM, Auwaerter PG, Bolon MK, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70(3):195–283. Bumbacea D, Arend SM, Eyuboglu F, Fishman JA, Goletti D, Ison MG, et al. The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement. Eur Respir J. 2012;40(4):990–1013. Eschenauer GA, Lam SW, Carver PL. Antifungal prophylaxis in liver transplant recipients. Liver Transpl. 2009;15(8):842–858. European Association for the Study of the Liver (EASL). EASL clinical practice guidelines: liver transplantation. J Hepatol. 2016;64(2):433–485. Martin SI, Fishman JA. Pneumocystis pneumonia in solid organ transplantation. Am J Transpl. 2013;13(Suppl 4):272–279. Playford EG, Webster AC, Sorell TC, Craig JC. Antifungal agents for preventing fungal infections in solid organ transplant recipients. Cochrane Database Syst Rev. 2004;(3):CD004291. doi: 10.1002/14651858.CD004291.pub2 Saliba F, Pascher A, Cointault O, Laterre P-F, Cervera, De Waele JJ, et al. Randomized trial of micafungin for the prevention of invasive fungal infection in high-risk liver transplant recipients. Clin Infect Dis. 2015;60(7):997–1006. doi:10.1093/cid/ciu1128 Stern A, Green H, Paul M, Vidal L, Leibovici L. Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients. Cochrane Database Syst Rev. 2014(10):CD005590. doi: 10.1002/14651858. CD005590.pub3 Vandecasteele E, De Waele J, Vandijck D, Blot S, Vogelaers D, Rogiers X, et al. Antimicrobial prophylaxis in liver transplant patients: a multicenter survey endorsed by the European Liver and Intestine Transplant Association. Transpl Int. 2010;23(2):182–190.

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53 Cytomegalovirus and the Liver Transplant Recipient James Ferguson Liver Unit, Queen Elizabeth Hospital, Birmingham, UK

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CMV establishes latent and persistent infections. Transplant patients have impaired cell-mediated immunity that can lead to reactivation of donor or ­recipient CMV. The presence of CMV in the blood does not necessarily indicate CMV disease. CMV can have both direct and indirect effects on the liver transplant recipient. Most centers use prophylaxis against CMV in high-risk recipients (D+/R– mismatch) to prevent the i­ ncidence of CMV disease. Treatment of CMV disease is achieved by antiviral agents and reduction in immunosuppression.

­The virus Cytomegalovirus (CMV) is a member of the human herpesvirus family. It is commonly found in humans and usually only causes a mild or asymptomatic disease in adults. However, it is a particularly important pathogen in the immunocompromised individual.

Structure and replication CMV has the largest genome of the human herpesviruses. CMV only replicates within human cells and establishes latent infection in mononuclear lymphocytes, the stromal cells of the bone marrow, and other cells.

Pathogenesis and immunity The pathogenesis of CMV is very similar to other herpesviruses, and readily establishes latent and persistent infections. CMV is spread throughout the body and is highly cell associated. Cell-mediated immunity is crucial for controlling CMV infection, which explains why it is reactivated by immunosuppression (i.e., in the context of transplantation and infection with human immunodeficiency virus, HIV). Furthermore, it has been demonstrated that allogeneically stimulated T-cells produce cytokines that can also reactivate latent CMV.

Liver Transplantation: Clinical Assessment and Management, Second Edition. Edited by James Neuberger, James Ferguson, Philip N. Newsome and Michael Ronan Lucey. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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Transmission CMV can be isolated from blood, most body secretions, and tissues obtained for transplantation.

­Cytomegalovirus and liver transplantation The leukocytic or tissue cell population from the donor can easily transmit the virus to the recipient. Transplant patients have impaired cell-mediated immunity because of their requirement for immunosuppression, which can lead to reactivation of the donor virus. This particularly occurs in recipients with no previous exposure to CMV. However, patients with prior exposure to the virus can also undergo reactivation of their own latent virus. Without prophylaxis, CMV infection occurs in the majority of CMV-naive liver transplant recipients.

­Definitions ●●

●●

CMV infection: the isolation of the CMV virus or detection of viral proteins or nucleic acid in any body fluid or tissue specimen. CMV disease: ○○

○○

fever (> 38 °C for at least 2 days within a 4-day period), neutropenia or thrombocytopenia, and the detection of CMV in blood; or CMV viremia and tissue-invasive CMV disease (symptoms or signs of organ dysfunction, evidence of localized CMV infection in a biopsy or other specimen).

­Direct effects of cytomegalovirus See Figure 53.1. ●●

●●

●●

●● ●● ●●

Liver (hepatitis): prior to prophylaxis, CMV hepatitis occurred in ~60% of high-risk recipients (seronegative recipient and seropositive donor). CMV hepatitis does not seem to have a long-term effect on the outcome of patients, but is associated with biliary complications. Gastrointestinal tract (colitis, esophagitis): patients with CMV colitis usually have diarrhea, weight loss, anorexia, and fever. Importantly, it can occur without a significant viremia. Lungs (pneumonitis, pneumonia): this can be fatal if untreated, but is less common in transplant recipients than other immunosuppressed patient groups. Eyes (chorioretinitis): uncommon but has been reported. Nervous system (polyneuritis, myelitis). Blood (leukopenia, thrombocytopenia).

­Indirect effects of cytomegalovirus ●●

Increased risk of rejection: CMV has long been recognized to be associated with rejection within the graft, but it has proven difficult to demonstrate whether CMV is the cause of rejection or occurs as a result of rejection. Nevertheless, there is a clear bidirectional interaction between CMV and rejection, illustrated by its ability to induce inflammation. In addition, CMV is also associated with chronic rejection in the allograft.

Chapter 53  Cytomegalovirus and the Liver Transplant Recipient

Direct effects Hepatitis Colitis, esophagitis Pneumonitis Chorioretinitis Polyneuritis, myelitis Leikopenia, thrombocytopenia

CMV

Indirect effects Increased risk of rejection Increased risk of bacterial and fungal infections

Figure 53.1  Direct and indirect effects of the cytomegalovirus (CMV). ●●

Increased risk of bacterial and fungal infections: CMV infection increases the risk of opportunistic infections in transplant recipients. There is good evidence to suggest that CMV infection can have an immunosuppressive effect, as the virus prevents presentation of antigens to both CD8 cytotoxic T-cells and CD4 T-cells.

­Diagnosis ●●

●●

Detection of CMV by polymerase chain reaction (PCR): PCR is rapid and sensitive, and most transplant centers now use PCR to diagnose CMV infection. As it is a quantitative test, one can use it to monitor the viral load. Tissue: the histologic hallmark of CMV is the cytomegalic cell. This is an enlarged cell containing a dense central “owl’s eye,” basophilic intranuclear inclusion body. These infected cells can be found in any tissue in the body and in urine. In the context of liver transplantation, these changes are classically seen on a liver biopsy or in rectal biopsies in patients suspected to have CMV colitis.

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Serology: CMV immunoglobulin (Ig)G is produced in primary infection and persists life-long. It is therefore a useful test to assess the immune status of the potential transplant recipient and donor. However, it is important to remember that CMV IgG-positive recipients can reactivate their latent virus.

­Preventing cytomegalovirus disease ●●

●●

●●

●●

●●

Prophylaxis: CMV prophylaxis (Levitsky et al. 2008; Asberg et al. 2007) is based on the administration of antiviral medications to patients at risk of developing CMV disease. This strategy has been shown to prevent the incidence of CMV disease. It is recommended for all CMV IgG-negative recipients of a CMV IgG-positive graft and in some units is used for other patients. Universal prophylaxis does have advantages such as ease of use, less early CMV, and in theory less indirect effects of CMV. Pre-emptive therapy: this is based on the detection of CMV reactivation prior to the development of CMV disease. This strategy is recommended for moderate-risk patients such as CMV IgG-positive recipients. Both strategies have disadvantages: ○○ Prophylaxis is associated with the development of resistance and the development of delayed-onset CMV disease. It is important to understand that prophylaxis does not prevent the development of CMV infection, but merely delays its onset. However, prophylaxis in the first 3 months after transplant does reduce the overall incidence of CMV disease in high-risk recipients. At present it is unknown whether the prolongation of prophylaxis to 6 or even 12 months will prevent late-onset CMV disease. ○○ Pre-emptive therapy can be difficult to organize due to the availability of laboratory detection of CMV and clinic appointments. This is particularly a problem in CMV-negative recipients of a CMV-positive graft that may have very rapid viral replication kinetics. At present there is no international consensus on preventing CMV disease and most centers have their own strategies. The most common strategy is prophylaxis of a high-risk patients for 3 months (CMV IgG-negative recipients of a CMV IgG-negative graft), while some centers also give prophylaxis to any recipient of a CMV IgG-positive graft, any patients grafted for acute liver failure, or those undergoing re-grafting due to their increased risk of CMV disease. The majority of centers use the medication valganciclovir for prophylaxis and pre-emptive therapy. Valganciclovir is a pro-drug of ganciclovir, a synthetic analogue of 2’-34 deoxyguanosine, which inhibits replication of CMV both in vitro and in vivo. Valganciclovir is preferred to ganciclovir due to its improved bioavailability.

­Treating cytomegalovirus disease There are two important aims in treating CMV disease (Figure 53.2; Lautenschlager 2009; British Transplantation Society 2015; Preiksaitis et al. 2005): ●● ●●

to prevent the direct and indirect effects of CMV; and to reduce the viral load and immunosuppressive load of the recipient to allow them to develop their own immunity against CMV.

A 2-week course of intravenous ganciclovir is recommended for patients with CMV disease. The oral drug valganciclovir is a more convenient alternative and is used by some centers for mild CMV disease. In addition, it is important to reduce the immunosuppressive load for the transplant recipient. This is most commonly achieved by pausing the administration of azathioprine/mycophenolate. After treatment, the risk of recurrent CMV disease is estimated at ~25%. The most important predictor of recurrence is persistent viremia at the end of antiviral therapy. Current guidelines do suggest that patients should be CMV PCR negative prior to the cessation of therapy.

Chapter 53  Cytomegalovirus and the Liver Transplant Recipient Diagnosis of CMV disease Fever (> 38 °C for at least 2 days within a 4-day period), neutropenia or thrombocytopenia, and the detecton of CMV in blood or CMV viremia and tissueinvasive CMV disease (symptoms or signs of organ dysfuntion, evidence of localized CMV infection in a biopsy or other specimen)

Treatment Intravenous ganciclovir or oral valgaciclovir (dependent on severity of disease) unitil resolution of symptoms and for a minimun of 14 days Reduce immunsuppression

Consideration should be given to an additional period of prophylaxis after the treatment period Monitor efficacy of treatment with CMV polymerase chain reation

Figure 53.2  Management of cytomegalovirus disease (CMV).

However, viral eradication is only achieved in 58% of patients after 21 days of therapy. In practice, the clinical response is used as well as viral load measurements, and at least 2 weeks’ full-dose treatment is recommended, with a longer duration of treatment if there is not a prompt fall in viral load.

­Cytomegalovirus resistance Viral resistance is uncommon, but may be under-reported in the literature. It is associated with greater immunosuppression and the duration of antiviral therapy. Clinically it manifests with progressive disease or an increasing viral load despite antiviral therapy. However, it is important to remember that during the first week of treatment an increasing viral load is not a reliable marker of resistance. Potential second-line agents include cidofovir or foscarnet. It should be noted that both have significant side effects, including nephrotoxicity.

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­Further reading Asberg A, Humar A, Rollag H, Jardine AG, Mouas H, Pescovitz MD, et al. Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. Am J Transpl. 2007;7:2106. British Transplantation Society. The Prevention and Management of CMV Disease after Solid Organ Transplantation: British Transplantation Society Guidelines, 3rd edn. Macclesfield: British Transplantation Society, 2015. Lautenschlager I. CMV infection, diagnosis and antiviral strategies after liver transplantation. Transpl Int. 2009;22(11):1031–1040. Levitsky J, Singh N, Wagener MM, Stosor V, Abecassis M, Ison MG. CMV survey of CMV prevention strategies after liver transplantation. Am J Transpl. 2008;8:158. Preiksaitis JK, Brennan DC, Fishman J, Allen U. Canadian Society of Transplantation consensus workshop on cytomegalovirus management in solid organ transplantation final report. Am J Transpl. 2005;5:218–227.

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54 Post-Liver Transplant Infections Miruna David1 and Ahmed Elsharkawy2 1

Department of Microbiology, Queen Elizabeth Hospital, Birmingham, UK Liver Unit, Queen Elizabeth Hospital, Birmingham, UK

2

Key points ●●

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Infection is a major cause of mortality and morbidity after liver transplantation, and the rates of major infective complications remain high in this population. The main determinants of infection risk include the mechanical aspects of surgery itself, host and donor factors, as well as the effects of the immunosuppression. Pre-transplant immunity and latent infections in the recipients, as well as donor-related infections, may also affect post-transplant infection. Diagnosis can be challenging; in particular, serologic diagnosis is often of limited value because of poor antibody response in the setting of immunosuppression. Successful management frequently requires contributions from a multidisciplinary team, including ­hepatologists, transplant surgeons, interventional radiologists, and clinical microbiologists or infectious disease physicians. Treatment often involves reduction of immunosuppression, with an added layer of complexity because of interactions between the immunosuppressant drugs and many of the anti-infective agents. Source control such as removal of central venous catheter or surgical drainage of abscesses is not always possible.

Infections, whether bacterial, fungal, viral, or protozoal, are common in the recipient and are often serious and may be fatal. Co-infection with two or more pathogens is more common than in the immunocompetent host, as is the risk of infection with multidrug-resistant organisms. Donor-transmitted infections, while uncommon, may present several years after transplantation. Both recipient and donor factors are involved in the risk for infection. Presentation and diagnosis of post-transplant infections are challenging, in part because of the pre-transplant health of the recipient, the complex nature of surgery, and immunosuppression. Diagnosis and management require a high degree of suspicion, deployment of a wide range of imaging and laboratory diagnostic techniques, and close collaboration between clinician and microbiologist. In this chapter, we will review the diagnosis and management of some of those challenging infections seen especially in the liver allograft recipient. Liver Transplantation: Clinical Assessment and Management, Second Edition. Edited by James Neuberger, James Ferguson, Philip N. Newsome and Michael Ronan Lucey. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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­Hepatitis E virus Epidemiology Hepatitis E occurs worldwide and every year there are an estimated 20 million hepatitis E virus (HEV) infections, with the disease most common in East and South Asia. In regions of the world with poor sanitation, the virus spreads by the consumption of sewage-contaminated food and water. The source of contamination is feces shed from other infected people (or infected animals). In the developed world, the virus may spread from animals to humans through the consumption of undercooked or raw pig and game meat, processed pork, and shellfish. There have also been reports of transfusion-transmitted HEV, which demonstrate that the virus can be also acquired parenterally. Historically, in the developed world HEV infection was considered a travel-associated infection, and the disease may have been underdiagnosed. Rates are increasing in several European countries including the UK, and in the Americas (Public Health England 2020). As one of the causes of acute infectious hepatitis, HEV infection is a notifiable disease in the UK and elsewhere (in accordance with the Health Protection (Notification) Regulations 2010 in the UK). HEV infection typically causes acute hepatitis with spontaneous recovery in almost all cases, but immunocompromised patients, including liver transplant (LT) recipients, may develop chronic HEV infections (defined as HEV RNA detectable in plasma for more than 3 months), with rapid progression of disease and cirrhosis, and may require re-transplantation (Haagsma et al. 2008). There are many HEV genotypes, of which G1–4 may infect humans; genotypes 1 and 2 have been found only in humans, whereas the zoonotic genotypes 3 and 4 are endemic worldwide. The mode of transmission correlates with the genotype: fecal–oral (G1 and G2), zoonotic (G3 and G4), and blood-borne, through the transfusion of blood/blood products (G3). In many countries (including the UK) all blood donations are screened for HEV to reduce the risk of blood-transmitted infections (Public Health England 2019a). The European Association for the Study of the Liver (EASL) also recommends that blood donations should be tested for HEV RNA by nucleic acid testing (NAT) and that the NAT method should detect all major genotypes, most importantly G3.

Presentation HEV infection in the immunosuppressed may be subclinical, presenting with abnormal liver tests, often showing just a mild acute or chronic hepatitic picture, or as established cirrhosis. It is clinically indistinguishable from other causes of viral hepatitis. Severe and fulminant hepatitis is rarely seen with G3/4 infections.

Diagnosis Serologic diagnosis of HEV infection requires testing of serum for the presence of anti-HEV immunoglobulin (Ig) M and IgG. Molecular diagnosis by polymerase chain reaction (PCR) detects viral replication and is essential for the diagnosis, as HEV antibody testing alone is not reliable in the transplant setting. HEV RNA testing can be undertaken on blood (plasma or serum) samples, as well as stool samples (see Figure 54.1).

Treatment and management In the majority of HEV cases no treatment will be required, as these infections will clear uneventfully with no long-term sequelae. Chronic HEV infection in LT recipients usually requires a reduction in the levels of immunosuppression, and this can lead to viral clearance in 30% of cases. If this reduction is not possible or not effective, antiviral treatment with ribavirin should be considered; addition of pegylated interferon may add to the efficacy, but this is not ­recommended in many solid organ transplant recipients because of concerns of acute rejection.

Chapter 54  Post-Liver Transplant Infections Anti-HEV IgM and IgG and HEV RNA

IgG Reactive IgM Reactive HEV RNA detected

IgG Negative IgM Negative HEV RNA detected

IgG Negative IgM Negative HEV RNA not detected

Report Compatibel with HEV infection. Please send follow up in 4 weeks monitor HEV RNA Monitor HEV RNA levels for up to 3 months HEV RNA becomes undetectable with detectable HEV antibody

HEV RNA remains detectable with or without detectable HEV antibody

Report: Compatible with cleared HEV infection

Report: Compatible with persistent HEV. infection. Recommend monthly HEV RNA monitoring. This patient may require antiviral therapy.

Report: No evidence of HEV infection

NB: Monthly HEV RNA testing should be undertaken in those patients undergoing treatment for persistent HEV infection. Please note that viral clearance from both stool and plasma should be confirmed prior to any cessation of anti-viral treatment.

Figure 54.1  Interpretation of testing for hepatitis E virus infection in the immunocompromised host. HEV, hepatitis E virus; Ig, immunoglobulin.

Laboratory monitoring of HEV viral load in plasma can indicate successful therapy. Therapy should be continued until there is clearance of virus from both blood and stool to ensure that relapse does not occur after stopping treatment (see Figure 54.2).

Prevention There is currently no vaccine licensed for use in the UK. A vaccine (Hecolin HEV 239) is licensed for use in adults in China. The risk of infection can be reduced by cooking meat and meat products thoroughly, avoid eating raw or undercooked meat (especially pork, deer, and wild boar) and shellfish, and washing hands thoroughly before preparing, serving, and eating food. When traveling to countries with poor sanitation, all drinking water, including water for brushing teeth, should be boiled and eating raw or undercooked meat and shellfish should be avoided.

­Epstein–Barr virus and post-transplant lymphoproliferative disorder Epidemiology Epstein–Barr virus (EBV) is a successful human pathogen, infecting virtually all the human population and persisting throughout the lifetime of its host. The transmission of EBV infection occurs primarily by the exchange of

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High-immunologic risk patients

Reduction of immunosuppression and monitoring of HEV RNA viral load for 3 months

Monitoring of HEV RNA viral load for 3 months Persistant HEV replication in the serum and/or stools at month 3 3-month course of ribavirin monotherapy HEV RNA positive in serum and/or stools

HEV RNA negative in serum and stools Relapse after ceasing ribavirin

Lengthening ribavirin for 3 other months

6-month course of Ribavirin monotherapy Persistant HEV replication In the serum and/or stools Or HEV relapse Pegylated interferon for 3 months in liver-transplant patients No alternative available therapy in other transplant patients

Figure 54.2  Proposed treatment algorithm of hepatitis E virus persistent infection in solid organ transplant patients. HEV, hepatitis E virus. Source: Reproduced with permission from Kamar et al. 2016.

saliva, most commonly in childhood or adolescence, and the primary infection with EBV manifests usually with a fever and sore throat (as infectious mononucleosis or “glandular fever”). EBV is a DNA virus and a carcinogen, associated with the development of a wide variety of neoplasms in a small subset of EBV-infected individuals, including immunosuppression-related lymphoproliferative disorders.

Diagnosis of Epstein–Barr virus infection ●●

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EBV serology (determination of IgG and IgM antibodies) is of limited value post transplantation, although pretransplant serostatus determination of the donor and recipient provides guidance on the risk assessment. There is no universal screening requirement in donor and recipients. A blood sample for EBV DNA PCR must be used to investigate primary or reactivated EBV infection in patients who are immunocompromised and at risk of severe disease, as serologic tests may be unreliable in in this setting (Public Health England 2019b). EBV viremia is common following LT, usually due to reactivation of latent infection, and is as a surrogate marker of the degree of immunosuppression (Halliday et al. 2014), as it occurs most often during the period of maximal immunosuppression. There is no evidence of adverse clinical outcomes associated with EBV reactivation. EBV-seronegative recipients are at risk of EBV-associated disease following transplantation. Primary EBV infection in LT is associated with a profound, sustained EBV viremia and subsequent EBV hepatitis.

Chapter 54  Post-Liver Transplant Infections

Diagnosis of post-transplant lymphoproliferative disorder Diagnosis and treatment of post-transplant lymphoproliferative disorder (PTLD) is covered in depth in Chapter 56. EBV viral load (VL) monitoring is an important adjunctive tool, but insufficient for the diagnosis of PTLD. Imaging with computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) can help localize and stage the disease, but is not considered diagnostic. Histopathologic diagnosis remains the gold standard for PTLD diagnosis.

Treatment of post-transplant lymphoproliferative disorder Treatment should be formulated by a multidisciplinary team familiar with PTLD treatment and usually entails: ●● ●●

●●

Reduction of immunosuppression as the most important step, if possible. Anti-B-cell monoclonal antibody therapy: rituximab is the first-line single treatment agent of choice after reduction of immunosuppression. Cytotoxic chemotherapy.

­Varicella zoster virus Clinical presentation Chickenpox (primary varicella zoster virus [VZV] infection) is a highly contagious viral illness caused by the VZV, characterized by a diffuse, generalized, and usually pruritic maculo-papulovesicular rash. Early symptoms may also include fever, fatigue, headache, and loss of appetite, which may occur 1–2 days before the appearance of the rash, especially in adults. The virus is transmitted from person to person by inhalation of or contact with respiratory secretions or lesion fluid of an infected person. The incubation period for varicella ranges between 10 and 21 days after exposure. Infected individuals are contagious approximately 2 days before the onset of the rash, until no new lesions have appeared in a 24-hour period and all the blisters have formed scabs (usually 4–7 days after rash onset). Herpes zoster (shingles) is a reactivation of VZV in a person previously infected with the virus and is characterized by vesicular lesions, usually distributed in a dermatomal pattern. In cases of localized zoster, lesions are confined to one or two adjacent dermatomes. Some patients, such as those who are immunocompromised, may develop disseminated zoster, where lesions occur in three or more dermatomes. Disseminated VZV infection can be life-threatening in an LT recipient.

Diagnosis The diagnosis is usually made clinically. Laboratory confirmation can be sought in atypical presentations, either through a positive VZV PCR assay on a vesicle swab or demonstrating the presence of VZV IgM antibodies in serum.

Treatment ●●

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Primary infection (chickenpox) or disseminated herpes zoster in an immunocompromised host requires treatment with high-dose aciclovir intravenously (IV; 10 mg/kg every 8 h if renal function normal) for at least 7 days and until there are no new vesicles for 48 hours, following which the patient can be changed to oral therapy once improved. Localized herpes zoster (shingles) can be treated with valaciclovir 1 g oral three times a day.

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Infection control in healthcare settings Hospital transmission of VZV is well recognized: ●●

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A patient with chickenpox is infectious from the incubation period until no new vesicles appear and the rash has fully dried up and crusted over. In hospital, patients with chickenpox should be isolated in a side room with airborne precautions. A patient with shingles is infectious from the appearance of the rash until all vesicles have cleared up and crusted over. In hospital, patients with shingles should be isolated in a side room with contact precautions until deemed non-infectious by the infection control team.

Post-exposure prophylaxis When assessing the risk of infection in LT recipients who have been exposed to VZV infection, the first step is to confirm their immune status. If there is a personal history of chickenpox or a documented history of two doses of vaccine, the recipient is considered immune; in this case, no specific measures are required and clinical observation suffices. If such a history is not available, a serum sample should be submitted for urgent testing for VZV IgG antibodies. In a non-immune patient, specialist virology or infectious disease advice is necessary to establish the merits of administering varicella zoster immunoglobulin (VZIG). This should occur as soon as possible after exposure. When supplies of VZIG are limited, oral aciclovir or valaciclovir from day 7 to day 14 after exposure may be recommended for susceptible immunosuppressed individuals, unless there are significant concerns of renal toxicity or malabsorption (Public Health England 2019c).

­Herpes simplex virus Epidemiology and clinical manifestations Herpes simplex viruses (HSV) 1 and 2 are DNA viruses that are transmitted through direct contact with the skin or mucosal surfaces of a person actively shedding the virus, either via oral secretions (HSV1) or sexual activity (HSV2). Acquisition through transplantation from the donor is also possible but rare (Campsen et  al. 2006; Macesic et al. 2017). Primary HSV1 infection is usually acquired during childhood and can cause gingivostomatitis, although most of the time it is asymptomatic. Seroprevalence of HSV2 remains low until puberty and onset of sexual activity. Primary and recurrent HSV2 infections are characterized by clusters of painful vesicles and ulcers in the genital and perianal area. After primary infection, both HSV1 and HSV2 viruses establish latency and remain dormant in the nerve root ganglia, and thus can cause reactivation. The majority of transplant recipients are seropositive for HSV1 or 2. Compared with immunocompetent persons, LT recipients shed HSV more frequently, have more severe clinical manifestations, and are slower to respond to therapy. Primary HSV1 infection in an LT recipient can manifest as a severe disseminated infection associated with acute hepatitis, which represents an infectious disease emergency.

Diagnosis Most HSV infections are diagnosed on clinical grounds, but patients may present with atypical skin or mucosal lesions and/or other clinical manifestations (such as hepatitis, esophagitis, or pneumonitis), in which case PCR on a vesicle sample, tissue biopsy, or blood is the preferred diagnostic test. Serology (detection of HSV IgG antibodies in the blood) may be used during the pre-transplantation period to determine whether a patient has latent HSV infection, but usually has little value in the acute infection setting. A

Chapter 54  Post-Liver Transplant Infections

possible exception is the confirmation of seroconversion during primary infection by evaluating and comparing a historical sample and current/convalescent serum antibody titers.

Treatment Oral therapy with aciclovir or valaciclovir usually suffices for limited mucocutaneous lesions; however, severe, disseminated, or central nervous system involvement requires treatment with IV aciclovir of 5–10 mg/kg every 8 hours intravenously (dosing adjusted in the presence of renal impairment). Aciclovir-resistant HSV is less common in solid organ transplant recipients than in stem cell transplant patients; in these cases, the recommended second-line treatment is with IV foscarnet.

Prophylaxis Recent guidance from the Infectious Diseases Community of Practice of the American Society of Transplantation recommend that HSV-specific prophylaxis should be considered for all HSV1 and HSV2-seropositive organ recipients who are not receiving antiviral medication for cytomegalovirus (CMV) prevention that has activity against HSV (Lee et al. 2019).

­Human adenovirus infection Epidemiology and clinical manifestations Adenoviruses are DNA viruses typically associated with self-limited disease during childhood, which can establish latency in the lymphoid tissue. In most patients, infections are minimally symptomatic and involve the respiratory tract, gastrointestinal tract, urinary bladder, and eyes. In contrast, infections in immunocompromised patients can cause significant adverse events, including disseminated life-threatening infections. Specifically, in LT patients, human adenovirus (HAdV) infection can be associated with graft infections such as hepatitis, resulting in graft failure. Additionally, the presentation can vary, as both the severity of disease and organ/tissue predilection can vary by HAdV type (for example, serotypes 40 and 41 are associated with gastroenteritis and disseminated disease). Prospective studies have shown that viremia is relatively common in adult solid organ transplant recipients; Humar et al. (2005) detected viremia in 7.2% of patients at various time points throughout the first year posttransplant. Viremia was associated with self-limited respiratory or gastrointestinal symptoms or was asymptomatic. No association with acute cellular rejection was found.

Diagnosis The diagnosis in solid organ transplant recipients is often challenging; the cornerstone of laboratory diagnosis revolves around demonstrating significant levels of HAdV viremia. HAdV infection can involve the graft only and is not always easily detected in blood by PCR, so a liver biopsy with specific immunohistochemical stains may be the only way of diagnosing this infection.

Treatment There are no generally accepted treatment guidelines for HAdV. In immunocompetent patients, the infection is usually self-limiting. In immunocompromised patients, reduction in immunosuppression is generally the first step in treatment. Cidofovir is active against HAdV, but its low oral bioavailability and potential for

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nephrotoxicity are major dose-limiting factors. Consultation with an infectious diseases expert is advisable to decide if antiviral treatment should be considered.

­Human immunodeficiency virus With the advent of highly active antiretroviral therapy (HAART), orthoptic LT is possible in some patients with end-stage liver disease and human immunodeficiency virus (HIV). The assessment of LT candidates should be made by an HIV specialist and include a detailed history of HIV RNA levels, CD4 cell counts, previous antiretroviral therapy, and resistance testing. A comprehensive post-transplant plan should be implemented to minimize HIV-related complications (Kumar & Humar 2011). The major challenge in the treatment with HAART is management of immunosuppression, since many of the antiviral agents interact with immunosuppressive agents, especially the calcineurin inhibitors (CNIs; see Chapter 59). There is also increasing levels of interest in utilising organs from HIV positive donors in HIV positive recipients.

­Tuberculosis Epidemiology Tuberculosis (TB) in LT recipients is a rare but clinically significant complication in the solid organ transplant population, who are overall at a higher risk of infection compared to the general population (Bumbacea et al. 2012). The rates of TB in transplant recipients are correlated to the prevalence of Mycobacterium tuberculosis infection in the general population. Active TB in transplant recipients can result from one of the following routes of acquisition: ●● ●● ●●

latent infection with M. tuberculosis (LTBI) in the transplant candidate (endogenous reactivation); LTBI in the donor tissue (donor-derived reactivation); or de novo post-transplant infection. The risk of TB is highest in the first year post transplant, during the time of maximal immunosuppression.

Diagnosis The clinical diagnosis of active TB in transplant recipients is challenging because of the higher proportion of extrapulmonary cases and the broad differential diagnosis with infective and non-infective conditions. If in doubt, always consider TB as part of an undiagnosed illness, and especially in a pyrexia of unknown origin syndrome. The laboratory diagnosis is usually made after the isolation of M. tuberculosis from cultures of relevant samples (sputum, bronchoalveolar lavage, tissue biopsy), or after a positive molecular test such as PCR, or through demonstrating typical granulomas on histology examination.

Treatment Treatment of latent Mycobacterium tuberculosis infection

Given the risk of reactivation of infection in patients with evidence of previous infection, transplant candidates with evidence of LTBI should be offered treatment according to national guidelines, as these generally reflect regional drug availability and resistance patterns. The treatment should be discussed with a respiratory or infectious disease physician and usually involves isoniazid (INH) given along with pyridoxine. INH poses low risk of hepatotoxicity in persons with compensated liver disease awaiting LT, although usually the treatment is delayed until after LT. Patients should be evaluated carefully to exclude active TB before initiating single-drug therapy for LTBI.

Chapter 54  Post-Liver Transplant Infections

Treatment of active Mycobacterium tuberculosis infection

This is often challenging, because of more frequent adverse events from first-line anti-TB drugs and significant interactions with immunosuppressive drugs (Bumbacea et al. 2012). TB treatment decisions should be individualized with the assistance of transplant infectious disease expertise. Treatment is usually commenced with quadruple therapy (isoniazid, rifampicin, pyrazinamide, ethambutol) pending culture results and sensitivities, followed by dual therapy with isoniazid and rifampicin, assuming the isolate is sensitive to both these agents. Great care needs to be employed when using rifampicin, due to the drug’s interactions with immunosuppressants such as tacrolimus (see Chapter 59), both when starting therapy as well as after the end of therapy.

­Selected fungal infections Candidiasis Sites of infection

Candida infections may take the form of: ●● ●● ●●

mucocutaneous candidiasis (including oral thrush); esophageal candidiasis; invasive infections (bloodstream infections, peritonitis, or intra-abdominal abscess).

Candida albicans is the commonest species, but there are many other pathogenic species such as C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei; correct identification is important in predicting susceptibility to antifungal agents. Nevertheless, susceptibility testing is indicated for all isolates from sterile sites such as blood, ascitic fluid, or cerebrospinal fluid. Risk factors

Risk factors for invasive infections in LT recipients include: ●● ●● ●● ●● ●● ●●

CMV disease; re-transplantation; prolonged operation time; hemodialysis; fulminant hepatic failure; and fungal colonization.

Diagnosis

The diagnosis is often challenging and usually is made directly through the isolation of the fungus from microbiologic samples, or indirectly through the employment of fungal markers assays such as serum β-D-glucan. Isolation of Candida sp. from normally sterile samples such as blood (i.e., presence of candidemia) usually represents genuine, potentially disseminated infection and requires aggressive treatment, whereas isolation from superficial samples such as wound swabs or sputum samples may often just represent colonization, which does not require specific treatment. Treatment

Treatment of invasive Candida infections is often empirical, based on clinical suspicion. Several agents are available, belonging mainly to three classes of antifungals: azoles (such as fluconazole), echinocandins (caspofungin, anidulafungin, or micafungin), or amphotericin-based preparations (see Table 54.1).

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Table 54.1  Choice of antifungals for treatment of invasive Candida infections.

Empirical

Cultureproven Candida infection

First choice

Alternative therapy

Comments

Fluconazole

An echinocandin if the patient has already received azoles in the recent past

Known significant increase in cyclosporine and tacrolimus levels Suggested pre-emptive dose reduction 40–50% Close tacrolimus therapeutic drug monitoring recommended

Candida albicans

Fluconazole

An echinocandin

Candida glabrata

An echinocandin

Lipid formulation of amphotericin B

Candida krusei

An echinocandin

Lipid formulation of amphotericin B

C. krusei is always resistant to fluconazole Risk of nephrotoxicity with lipid formulation of amphotericin B, although less marked than with conventional amphotericin B deoxycholate

Source: Reproduced with permission from Pappas et al. 2016.

Invasive Aspergillus infections Invasive aspergillosis (IA) is the most common invasive mold infection in LT recipients, with its frequency reported at 1–9.2% (Patterson et al. 2016). Aspergillus sp. can often be isolated from superficial samples such as sputum samples, where it may just represent contamination or colonization. Genuine IA (such as invasive pulmonary aspergillosis, cerebral or intra-abdominal invasive aspergillosis) carries high mortality (65–90%; Neofytos et al. 2018), but early diagnosis and treatment can lead to a better prognosis. The commonest pathogenic species is A. fumigatus; others include A. flavus and A. terreus. Identification to species level is important in predicting pathogenicity (A. niger, for example, is rarely a cause of IA) as well as response to treatment (e.g., A. terreus can have reduced susceptibility to amphotericin-based preparations). Risk factors

Risk factors include: ●● ●● ●● ●●

fulminant hepatic failure; reoperation; re-transplantation; renal failure (Patterson et al. 2016).

Diagnosis

The diagnosis of IA is challenging because of atypical radiographic presentations and suboptimal sensitivity and specificity of fungal biomarker assays. Several diagnostic tools should be combined and a close liaison with the laboratory is crucial to appropriately diagnose IA (Danion et al. 2019): ●●

●●

Imaging: a chest CT scan should be performed whenever there is a clinical suspicion for invasive pulmonary aspergillosis, irrespective of the chest X-ray findings. Cultures of samples such as sputum, bronchial alveolar lavage, or tissue biopsy samples. Culturing of tissue sampling should be accompanied by histopathologic diagnosis, where special fungal stains can complement the culture-based diagnosis.

Chapter 54  Post-Liver Transplant Infections ●●

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The usefulness of fungal markers such as serum β-D-glucan or galactomannan detection in serum or bronchoalveolar lavage is controversial, with less evidence base of applicability than in hemato-oncology and stem cell transplant recipients. Molecular testing such as panfungal PCR or Aspergillus PCR assays.

Treatment

Treatment should be discussed with a clinical microbiologist or infectious disease physician and should include reduction of immunosuppression where possible. Voriconazole is the first-line agent of choice for the treatment of invasive pulmonary or cerebral aspergillosis. There are significant drug interactions between voriconazole and CNIs; CNI dose reduction and close therapeutic drug monitoring (TDM) for both CNIs and voriconazole is indicated (Patterson et al. 2016). Alternative agents include lipid formulation of amphotericin B and isavuconazole. Prophylaxis

In high-risk LT recipients, prophylaxis with either liposomal amphotericin B or an echinocandin should be considered, according to local policies. Azole prophylaxis is complicated by drug interactions with the CNIs, as well as liver toxicity Each transplant center should develop an antifungal prophylactic strategy based on the local institutional epidemiologic data and assessment of individual risk factors (Patterson et al. 2016).

­Further reading Bumbacea D, Arend SM, Eyuboglu F, Fishman JA, Goletti D, G Ison MG, et al. The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement. Eur Respir J. 2012;40:990–1013. Campsen J, Hendrickson R, Bak T, Wachs M, Kam I, Nash R, et al. Herpes simplex in a liver transplant recipient. Liver Transpl. 2006;12:1171–1173. Danion F, Rouzaud C, Duréault A, Poirée S, Bougnoux M-E, Alanio A, et. al. Why are so many cases of invasive aspergillosis missed? Med Mycol. 2019;57(Suppl 2):S94–S103. Haagsma EB, van den Berg AP, Porte RJ, Benne CA, Vennema H, Reimerink JHJ, et al. Chronic hepatitis E virus infection in liver transplant recipients. Liver Transpl. 2008;14(4):547–553. Halliday N, Smith S, Atkinson C, O’Beirne J, Patch D, Burroughs AK, et al. Characteristics of Epstein–Barr viraemia in adult liver transplant patients: a retrospective cohort study. Transpl Int. 2014;27(8):838–846. Humar A, Kumar D, Mazzulli T, Razonable RR, Moussa G, Paya CV, et al. A surveillance study of adenovirus infection in adult solid organ transplant recipients. Am J Transpl. 2005;5(10):2555–2559. Kamar N, Lhomme S, Abravanel F, Marion O, Peron J-M, L, et al. Treatment of HEV infection in patients with a solid-organ transplant and chronic hepatitis. Viruses. 2016;8(8):222. doi:10.3390/v8080222 Kumar D, Humar A. The AST handbook of transplant infections. Chichester: Wiley-Blackwell, 2011. Lee DH, Zuckerman RA; on behalf of the AST Infectious Diseases Community of Practice. Herpes simplex virus infections in solid organ transplantation: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transpl. 2019;33(9):e13526. Macesic N, Abbott IJ, Kaye M, Druce J, Glanville AR, Gow PJ, et al. Herpes simplex virus-2 transmission following solid organ transplantation: Donor-derived infection and transplantation from prior organ recipients. Transpl Infect Dis. 2017;19(5). doi: 10.1111/tid.12739 Neofytos D, Chatzis O, Nasioudis D, Boely Janke E, Doco Lecompte T, Garzoni C, et al. Epidemiology, risk factors and outcomes of invasive aspergillosis in solid organ transplant recipients in the Swiss Transplant Cohort Study. Transpl Infect Dis. 2018;20(4):e12898.

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Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1–50. Patterson TF, Thompson G, Denning D, Fishman J, Hadley S, Herbrecht R, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63(4):e1–60. Public Health England. Public health operational guidelines for hepatitis E: health protection response to reports of hepatitis E infection. London: Public Health England, 2019a. https://assets.publishing.service.gov.uk/ government/uploads/system/uploads/attachment_data/file/845090/Public_Health_Operational_Guidelines_ for_Hepatitis_E-protection_response.pdf (accessed August 6, 2020). Public Health England. UK standards for microbiology investigations: Epstein–Barr virus serology. London: Public Health England, 2019b. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_ data/file/773292/V_26i6.pdf (accessed August 6, 2020). Public Health England. Updated guidelines on post exposure prophylaxis (PEP) for varicella/shingles. London: Public Health England, 2019c. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_ data/file/812526/PHE_PEP_VZIG_guidance_for_health_professionals.pdf (accessed August 6, 2020). Public Health England. Guidance: hepatitis E: symptoms, transmission, treatment and prevention. London: Public Health England, 2020. https://www.gov.uk/government/publications/hepatitis-e-symptoms-transmissionprevention-treatment/hepatitis-e-symptoms-transmission-treatment-and-prevention (accessed 5 February 2020).

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55 De Novo Malignancies after Liver Transplantation Simone I. Strasser1, Ken Liu1,2, Avik Majumdar1, and Geoffrey W. McCaughan1,2 1

AW Morrow Gastroenterology and Liver Centre; Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, University of Sydney, Sydney, Camperdown, Australia Centenary Institute of Cancer Medicine and Cell Biology, Camperdown, Australia

2

Key points ●●

●●

●●

●●

●●

Liver transplant recipients have increased risk of developing de novo malignancies compared with the ageand sex-matched population. The major risk factors for cancer include older age, male sex, white race, smoking, multiorgan transplant, previous malignancy, and initial diagnosis of primary sclerosing cholangitis or alcohol-related liver disease. Malignancy risk increases with the number and cumulative dose of immunosuppression agents used and over-immunosuppression should be avoided. Sirolimus and everolimus have anti-cancer effects that may reduce the impact and severity of some de novo cancers. Increased screening (in addition to general population screening for malignancy) in select high-risk groups may reduce the impact of de novo cancer. Efforts should be made to prevent or reduce exposure to carcinogens, including sun exposure, smoking, and human papilloma virus.

It is clear that the immune system plays an important physiologic role in the surveillance and control of carcinogenesis. It contributes to the elimination of pathogens that are associated with malignancy, as well as direct immune surveillance of cancer cells via the recognition of tumor-specific antigens. Furthermore, the role of immune control of established cancers has been recently highlighted by the success of immune-based therapies such as immune checkpoint blockade. It is well recognized that immunosuppressed transplant recipients are at particular risk of malignancy. Pre-transplant malignancies may recur in the post-transplant setting and, rarely, malignancy may be transmitted from a donor. This chapter will focus on the development of new cancers following liver transplantation. Post-transplant lymphoproliferative disorders (PTLDs) are discussed in detail in Chapter 56. Along with cardiovascular disease, malignancy is an important cause of mortality in patients surviving liver transplantation without allograft or surgical complications. Cancers arising in transplant recipients are commonly more aggressive and associated with higher mortality than in non-transplant patients. Many questions arise when considering the development of de novo cancer in transplant recipients, including whether the incidence of all cancers is increased after transplant, what factors predispose to cancer development, which patients Liver Transplantation: Clinical Assessment and Management, Second Edition. Edited by James Neuberger, James Ferguson, Philip N. Newsome and Michael Ronan Lucey. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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should be screened for cancer and how, and whether the choice of immunosuppression impacts the risk and outcome of cancer.

­De novo malignancy is increased in liver transplant recipients While malignancy is common in the general population, liver transplant recipients have been reported to have a two- to threefold increase in solid organ malignancy and at least a 30-fold increase in lymphoproliferative malignancy and non-melanoma skin cancer, particularly squamous cell cancers (Table 55.1). Kaposi’s sarcoma is also increased in liver transplant recipients compared with the age- and sex-matched general population. Although the risk of cancers is greater in the older recipient, the standardized incidence ratio (SIR) is greater in younger recipients, as most cancers are less common in these younger people. In a recent analysis of over 100,000 individuals in the US Scientific Registry for Transplant Recipients (SRTR) database, the 10-year probability of de novo malignancy was 11.5%. A recent single-center report from Germany similarly reported a 10-year probability of developing malignancy of 12.9%. These reported rates are significantly lower than in previous studies, which may be influenced by reporting bias. With broadening indications for liver transplantation, and increasing age and comorbidities, there is concern that the rates of malignancy after transplant are increasing. Risk factors for de novo malignancy are shown in Box 55.1. Patients transplanted for alcohol-related liver disease and primary sclerosing cholangitis (PSC) appear to be at particularly increased risk and are recommended for enhanced cancer surveillance (discussed below). Furthermore, patients with a history of immunosuppression prior to transplantation, particularly those on longterm azathioprine, a recognized photosensitizing agent, and those with prior skin cancer related to cumulative sun exposure are at increased risk. Table 55.1  Rates, risk factors, and recommendations for malignancy after liver transplantation.

Malignancy

Non-melanoma skin cancer (SCC > BCC)

Standardized incidence rate (SIR)* Risk factor

> 30

Kaposi’s sarcoma > 100

Screening

Prevention

Intervention

Enhanced screening Immuno suppression, prior skin with annual skin cancer or precancerous checks lesions, age, race, cumulative ultraviolet light exposure

High-potency sunscreen, minimize sun exposure

Enhanced screening, education, chemoprevention, conversion to mTOR inhibitor

HHV-8 infection

Minimize immuno suppression

Chemotherapy; conversion to mTOR inhibitor

Colorectal cancer No increase except PSC–IBD PSC–IBD

Annual high-definition colonoscopy with chromoendoscopy in PSC–IBD

PTLD

Monitor EBV DNA levels in children

8

EBV infection HCV infection

Colectomy if high-grade dysplasia or neoplasia Minimize immuno suppression Treat HCV

Treat according to lymphoma management guidelines Reduce immuno suppression (Continued)

Chapter 55  De Novo Malignancies after Liver Transplantation

Table 55.1  (Continued)

Malignancy

Standardized incidence rate (SIR)* Risk factor

Screening

Prevention

Smoking cessation

Esophageal cancer

2–18

Obesity, smoking, alcohol-related liver disease

Lung cancer

2

Smoking, alcoholrelated liver disease

Annual chest X-ray or chest CT scans in active smokers

Smoking cessation

HPV infection, smoking, age, immuno suppression (high-dose azathioprine), alcohol-related liver disease

Annual ENT review and low-radiation CT scan in smokers or ceased  90% positive

Polymorphic PTLD

Monoclonal

> 90% positive

Monomorphic PTLD ●● B-cell neoplasms Diffuse large B-cell lymphoma Burkitt lymphoma Plasma cell myeloma Plasmocytoma Others ●● T-cell neoplasms Peripheral T-cell neoplasm Hepatosplenic T-cell lymphoma Other

Monoclonal

Positive and negative

Classic Hodgkin lymphoma-like PTLD

Monoclonal

> 90% positive

●●

EBV, Epstein–Barr virus; PTLD, post-transplant lymphoproliferative disorder.

Chapter 56  Post-Transplant Lymphoproliferative Disorders

Radiologic staging Radiologic staging of PTLD is usually based on computed tomography (CT) scans of the chest, abdomen, and pelvis. Many experts usually recommend scanning of the neck and brain, even in the absence of neurologic symptoms. Magnetic resonance imaging may also be an adequate alternative to CT for the study of non-pulmonary sites, in order to reduce exposition to ionizing radiation. Positron-emission tomography/computed tomography (PET-CT) has become increasingly used as a tool for staging and assessing treatment response, but its role has not been clearly defined.

Prevention EBV serostatus should be determined for all transplant recipients and donors. EBV-seronegative recipients of grafts from EBV-positive donors are the patients with the highest risk of PTLD. In these patients, it is recommended that T-cell–depleting agents are avoided. Universal antiviral prophylaxis does not seem to reduce the incidence of PTLD in these patients. The results with immune prophylaxis with intravenous immunoglobulin or with EBV vaccine are controversial. The most recommended approach for those high-risk patients is pre-emptive management, but the way of doing it is not clearly defined. Recent guidelines recommend monitoring EBV viral load every 1–2 weeks in the first post-transplant year, but other consensus documents recommend less frequent monitoring. In general, patients with PTLD have higher EBV viral loads than non-PTLD patients, but there is an important overlap between these groups of patients. Thus, there is no clear-cut level of viral load that could be recommended for starting intervention. A rapid increase of EBV viral load is more important as a potential risk of PTLD. The preferred pre-emptive intervention is reduction of immunosuppression. The risk of early PTLD has significantly reduced in recent years, but it does not seem to be a consequence of monitoring EBV viral load and pre-emptive reduction of immunosuppression. Conversion to mTOR inhibitors has been proposed due to their antiviral and antiproliferative effects, but there is not sufficient evidence to recommend this change. Other potential pre-emptive interventions are antiviral therapy with ganciclovir or valganciclovir, rituximab administration, or adoptive immunotherapy, but there is not enough evidence to recommend any of them.

Treatment Treatment of PTLD is not based on randomized control studies comparing different treatment strategies, but there is wide consensus about it (see Figure 56.1). Treatment should always be undertaken in consultation with the appropriate specialists.

Reduction of immunosuppression The first step in the management of PTLD is to reduce immunosuppression with the aim of allowing EBV-specific cellular immunity. Response rates to this approach are highly variable (ranging between less than 20% to 80%). Assessment of response should be based on imaging studies. Monitoring of EBV viral load is not recommended to assess the efficacy of PTLD treatment. Patients with a lower rate of response to immunosuppression reduction include those: ●● ●● ●● ●●

with EBV-negative disease; with bulky disease (neoplastic nodule > 7 cm); at an advanced stage; aged > 50 years.

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PTLD Consider surgery/radiotherapy if localized disease or local complications

Reduction of immunosuppression Assess response after 2–6 weeks If no response, rituximab (induction + consolidation)

If no response or if recurrence, citotoxic chemotherapy Figure 56.1  Steps in the treatment of post-transplant lymphoproliferative disorder (PTLD).

In patients with clinically aggressive PTLD or with critical organ compromise, the next steps of therapy (rituximab and/or cytotoxic chemotherapy) should be considered at any time following PTLD diagnosis. Usually, antimetabolic agents (azathioprine or mycophenolate) are discontinued and calcineurin inhibitors are reduced by 30–50%. In critically ill patients with advanced disease, discontinuing all non-glucocorticoid immunosuppressive agents is often recommended. There is no evidence to recommend switching from calcineurin inhibitors to mTOR inhibitors. Graft function should be frequently monitored to allow early detection of graft rejection. Responses to this approach are usually evident in 2–6 weeks.

Rituximab Rituximab is an anti-CD20 monoclonal antibody. It is recommended as the second step in the treatment of CD20+ B-cell PTLD. The overall response rate to this drug is 50%, but relapse after four weekly doses of rituximab is frequent. Thus, it should be followed by a consolidation regimen.

Cytotoxic chemotherapy Patients with CD20-negative PTLD or those who did not respond to reduction of immunosuppression and rituximab should receive cytotoxic chemotherapy (in combination with rituximab in CD20-positive PTLD). The most frequently used regimen is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). This combination regimen obtains a higher rate of response than rituximab monotherapy, but mortality is high (13–50%), mostly because of infectious complications. Pneumocystis jirovecii prophylaxis is recommended during this treatment.

Other potential treatments Surgical resection or irradiation has been used for localized disease or for the management of local complications. There is not enough evidence to support antiviral therapy against EBV, adoptive immunotherapy, anti-cytokine therapy or immunomodulatory agents in the treatment of patients with PTLD.

Chapter 56  Post-Transplant Lymphoproliferative Disorders

­Prognosis Survival after a diagnosis of PTLD in solid organ transplant recipients ranges between 30 and 70%. These results have improved since the use of rituximab. Median survival of patients with PTLD in a recent clinical trial was 6.6 years. Several factors have been related to a worse prognosis: ●● ●● ●●

central nervous system involvement; late onset; and T-cell origin of the PTLD.

A response to rituximab confers a better prognosis. EBV status is not prognostic or predictive of treatment response. Most indices used to assess prognosis in PTLD are general indices used for non-transplanted patients with lymphoma. Three of them are the most frequently used (Table 56.2). The Mayo Clinic identified three factors related to prognosis in a cohort of 107 patients with PTLD: poor performance status, monomorphic pathology, and involvement of the graft (Ghobrial et al. 2005). Patients with two or three of these risk factors had a fivefold mortality, compared with patients with one or none of these risk factors. Another prognostic score was proposed on the basis of a French registry of PTLD in the rituximab era (Choquet et al. 2007). This score includes five variables: age, serum creatinine, lactate dehydrogenase level, localization, and histologic features. This score was not superior to the International Prognostic Index (IPI), which is widely used by hematologists and oncologists to assess the prognosis of aggressive lymphomas. IPI consists of five variables: age, performance status, stage, lactate dehydrogenase level, and number of extranodular sites. In recent studies, IPI score and response to rituximab were found to be the only two factors predictive of survival in PTLD patients.

­Re-transplantation Patients who develop advanced graft damage after PTLD could undergo repeat transplantation. Series published to date show a low risk of recurrent PTLD after transplantation. The optimal time from PTLD remission to retransplantation is unknown, but it is advisable to wait for a significant disease-free interval before re-transplantation, and to avoid induction immunosuppression with anti-thymocyte preparations, if possible. A period of at least 1 year from control of PTLD to re-transplantation is recommended by the British Committee for Standards in Haematology and the British Transplantation Society. Table 56.2  Prognostic indices most frequently used in patients with post-transplant lymphoproliferative disorders. Mayo score

French score

International Prognostic Index (IPI)

Age > 55 years

Age > 60 years

Performance status 3–4

Performance status 2–4 Creatinine > 1.5 mg/dL High lactate dehydrogenase

Monomorphic histology

Monomorphic histology Disseminated disease

Graft involvement

High lactate dehydrogenase Stage III–IV > 1 extranodal site

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­Further reading Allen UD, Preiksaitis JK; on behalf of the AST Infectious Disease Community of Practice. Post-transplant lymphoproliferative disorders, Epstein–Barr virus infection and disease in solid organ transplantation: guidelines from the American Society of Transplantation Infectious Diseases community of practice. Clin Transpl. 2019;33 (9):e13652. doi: 10.1111/ctr.13652 Choquet S, Oertel S, LeBlond V, Riess H, Varoqueaux N, Dörken B, et al. Rituximab in the management of posttransplantation lymphoproliferative disorder after solid organ transplantation: proceed with caution. Ann Hematol. 2007;86(8):599–607. doi:10.1007/s00277-007-0298-2 Dharnidharka VR. Comprehensive review of post-transplant hematologic cancers. Am J Transpl. 2018;18:537–549. Dierickx D, Habermann TM. Post-transplantation lymphoproliferative disorders in adults. N Engl J Med. 2018;378:549–563. Ghobrial IM, Habermann TM, Maurer MJ, Geyer SM, Ristow KM, Larson TS, et al. Prognostic analysis for survival in adult solid organ transplant recipients with post-transplantation lymphoproliferative disorders. J Clin Oncol. 2005;23(30):7574–7582. doi:10.1200/JCO.2005.01.0934 Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, et al. Diagnosis of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients – BCSH and BTS guidelines. Br J Haematol. 2010;149:675–692. Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, et al. Management of post-transplant lymphoproliferative disorder in adult solid organ transplant recipients – BCSH and BTS guidelines. Br J Haematol. 2010;149:693–705. San-Juan R, Comoli P, Caillard S, Moulin B, Hirsch HH, Meylan P, et al. Epstein–Barr virus-related post-transplant lymphoproliferative disorder in solid organ transplant recipients. Clin Microbiol Infect. 2014;20(Suppl 7):109–118.

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57 Quality of Life and Employment after Liver Transplantation Santiago Tome1, Esteban Otero1, and Michael Ronan Lucey2 1

Liver Transplantation Unit, University Hospital, Santiago de Compostela, Spain Section of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

2

Key points ●●

●● ●●

●●

●● ●●

Orthotopic liver transplantation (OLT) significantly improves quality of life (QOL). Physical domains are the most improved domains and psycho-social domains show the smallest gains. Liver transplantation patients show relevant deficiencies in terms of QOL compared to general population. Etiology of liver disease, indefinite immunosuppression, sex, and mental illness are the most determining factors of QOL impairment. Pediatric patients show lower scores than general population: school functioning and health general ­perception are the most affected domains. Employment decreases after OLT: the rate of return to work does not run in parallel to QOL improvement. Liver disease etiology, age, mental illness, sex, unskilled work, and low income are the most important ­factors for a low rate of employment.

Liver transplantation (LT) has become a successful life-saving intervention for many patients with end-stage liver disease. According to the European Liver Transplant Registry and data on LTs performed in adults in the US (Scientific Registry for Transplant Recipients, SRTR), survival rates at 1 and 5 years are 90% and 70%, respectively and more than 50% are still alive after 20 years. The observed rate of patient survival varies depending on etiology, with cholestatic liver diseases showing the best survival characteristics. Due to the excellent extended survival, more attention has been focused among survivors on issues related to both longterm graft and patient survival and quality of life (QOL). What are some of the important reasons for paying attention to QOL in LT recipients? ●●

●●

Many patients are more concerned about QOL than longevity. Therefore, assessing interventions in terms of length of life do not reflect patients’ concerns. Most patient complaints have physical findings, but others have no bodily manifestations and are poorly evaluated by conventional clinical testing.

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●●

Assessment of QOL may assist healthcare professionals in understanding the demands of LT on recipients and their families, and thereby better inform prospective patients as they make the decision whether or not to have an LT. For a full account of the effect of an intervention on QOL, it is key to assess both effectiveness (the patient experience) and cost-effectiveness (resource expenditure). Quality-adjusted life-year (QALY) is a surrogate marker looking at both economic assessment and QOL as they occur throughout a full year of health.

Current interest in QOL studies, particularly in chronic diseases, has been justified by a number of different factors. Among the research questions of particular interest are: ●● ●● ●● ●●

Consideration of the impact of the disease (or disease and transplantation) on daily activities. Identification of specific problems linked to each disease complex. Assessment of treatments and their determining factors, as well as adherence by patients to these treatments. Acquisition of data to allow comparison of different treatments and interventions to improve patient well-being.

­What is quality of life? The World Health Organization (WHO) defines QOL as “an individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns. It is a broad ranging concept affected in a complex way by the person’s physical health, psychological state, personal beliefs, social relationships and their relationship to salient features of their environment.” In the context of a specific disease, the assessment of health-related QOL (HRQOL) has to be measured with regard to the impact that disease and treatment have on patient function and well-being. There are many studies published dealing with QOL before and after LT, and over the last 20 years several meta-analyses and systematic reviews have been published (Bravata et al. 1999; Tome et al. 2008; Yang et al. 2014). QOL studies after LT have been constrained by several limitations. Some were performed too soon after transplantation; most of them use heterogeneous instruments to perform the assessment; and they tend to exclude sick patients, even those with fulminant liver disease, patients transplanted with more than one organ, or those with psychiatric conditions. In addition, most of the instruments to measure QOL are self-administered questionnaires; the return rate tends to be low and consequentially bias is assured. Furthermore, in many instances the instruments have not been well validated in LT. Indeed, the lack of a uniform tool for assessment of QOL has made it difficult to compare studies. For example, a meta-analysis published in 1999 included 49 studies (Bravata et al. 1999). The tools ranged from Karfnosky Performance Status, used in 11 studies, to self-designed, unvalidated questionnaires in 16 studies. SF-36, a generic 36-item questionnaire developed to measure eight of the most relevant areas of health (physical functioning, physical role, emotional role, social function, pain, energy, general health, and mental health) that recently has become a more frequently used tool, was used only in 6 of these studies. In order to gain uniformity, one systematic review (Tome et  al. 2008) focused on studies utilizing SF-36. The lack of an overall score, the absence of an assessment of cognitive function, as well as the inability to take into account changes in patient responses over time have been highlighted as the main weaknesses of SF-36. Even so, it has become is the most utilized tool to measure QOL after LT, and consequently permits comparisons across studies. In the first meta-analysis, Bravata et al. (1999) found that LT improves all domains of QOL, with the greatest increase in those domains related to physical function and the least gains in the psychosocial areas. The authors speculated that the main impediments to improved QOL were related to “immunosuppression, dependence on the health system, potential discrimination at the work place,” as well as “incomplete recovery from preceding liver disease.” These findings were confirmed by Tome et al. (2008) and more recently by Yang et al. (2014). Despite this dramatic improvement, when we compared a LT cohort with the general population of transplant patients, we found relevant deficiencies in most of the domains of QOL, particularly in those related to physical function.

Chapter 57  Quality of Life and Employment after Liver Transplantation Deterioration

Improvement

P values: the Sign Test Psychological health p = 0.014 Physical functioning p < 0.0001 Sexual funtioning p = 0.58 Psychosocial adaptation p = 0.0001 General QOL

–10

0

10

20

30

40 p < 0.0001

Figure 57.1  Longitudinal studies comparing pre- and post-transplant quality of life domains (using different tools). n = 44. Source: Reproduced with permission from Tome et al. 2008.

When we focus on the longitudinal studies (Tome et al. 2008) exploring QOL before and after orthotopic liver transplant (OLT) with a follow-up of 25 months using different instruments, the sign test performed showed that the higher increases were in general QOL, social functioning, physical health, and psychological health, but not sexual dysfunction (Figure 57.1). Nevertheless, the perception of improvement is not immediate after LT. Recently, several studies have focused on mid- to long-term follow-up (Yang et al. 2014; Sullivan et al. 2014). The overall scores and the perception of general health remain high in the mid to long term; nevertheless, physical functioning continues to score lower than the general population. The perception for transplants other than liver is the same, although LTs score better when compared with kidney transplants (Yang et al. 2014). Again, for all transplanted patients, the scores are lower than the general population and several factors have been identified as contributors.

­Variables that influence quality of life One of the most relevant factors is indefinite immunosuppression. The number and frequency of side effects are quite high and include gastrointestinal symptoms, kidney injury, diabetes mellitus and all its cardiovascular complications, hypertension, gout, osteoporosis, increased risk of infection, and the requirement for attendance at or admission to hospital. There might be psychologic and neurologic side effects in as many as 30% of patients. Whether the type of immunosuppression (calcineurin inhibitor [CNI] versus mammalian target of rapamycin [mTOR]) has a differential influence on QOL needs to be confirmed. In countries without universal medical access, the long-term survivor of LT may face the personal financial strain of paying for medicines and tests. In an economic assessment for three different group of transplanted diseases, using QUALYs, cholestatic liver disease revealed the best cost-effectiveness ratio. Recurrence of hepatitis C virus (HCV) after LT impairs QOL (Feurer et al. 2002). The eradication of HCV by oral direct-acting antiviral agents (DAA) significantly improves QOL after transplant. A similar feature has been found in patients who start drinking heavily after LT. While alcohol use disorder LT recipients appear to return to society to lead active and productive lives, they tend to be less involved in structured social activities than patients transplanted for non-alcoholic causes (Tome et al. 2008). Assessments of QOL in patients transplanted for acute liver failure (ALF) are similar to other LT patients with chronic liver disease. In addition, no differences were found between those with acetaminophen overdose and other ALF etiologies (Longworth et al. 2003). Initial findings demonstrated no impact of sex differences in terms of QOL after OLT. However, recent studies have found lower scores in women than in men. One of them, performed in Spain and using the Psychosocial

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Adjustment to Illness Scale (PAIS) as a tool (Blanch et al. 2004), found that women presented a higher rate of poor adjustment and a lower rate of good adjustment. It is not easy to explain sex differences, but most studies have pointed to social and psychologic factors. More studies concentrating on the impact of sex, and gender roles in society, on the QOL outcome of LT are needed. Mental health has been excluded in most studies of QOL, resulting in a lack of uniformity in study populations. As expected, mental health is a predictor for QOL impairment after transplantation. Of the common problems before transplant, like anxiety and depression, the latter has a greater impact on several domains of QOL, preventing patients from achieving full recovery. Anxiety appears to have a minor influence (Miller et al. 2013). Finally, donation after circulatory determination of death (DCDD) is related to increased rate of graft failure and ischemic cholangiopathy. Nevertheless, no influence on QOL has been detected in different studies between DCD donors and deceased from brain death (DBD) donors (Croome et al. 2017).

­Pediatric patients A total of 25 studies were collected in a recent meta-analysis dealing with QOL in pediatric transplanted patients (Parmar et al. 2017). The two most common generic tools were the Pediatric Quality of Life Inventory (PedsQL™) and the Child Health Questionnaire™ (CHQ). The former assesses the school functioning domain, which is considered the most important outcome for pediatric patients. QOL is impaired in pediatric patients compared to healthy controls. Besides school functioning, general health perception is the domain most affected. The scores are comparable to other pediatric patients with chronic diseases and other solid organ transplant patients. School functioning has to do with absence related to medical attendance. Interestingly, low scores were not seen in pre-school patients. The main contributors to this impairment are sleep disturbances, medication adherence, and age at transplantation. The impairment of HRQOL and cognitive functioning has been evaluated in a prospective evaluation recently published, confirming that these findings persist into adolescence (Ohnemus et al. 2020).

­Employment after liver transplantation Employment is a useful surrogate for social functioning. However, good data are still lacking because of the heterogeneity of studies and number of candidate variables that have been omitted. For example, the rates of employed people after LT show striking variation across different countries (Table 57.1). We do not know how these environments vary in regard to opportunity to return to work. In addition, very little information has been collected related to the type of work: full-time remunerated work, household work, unremunerated (school, university), and part-time work. Paradoxically, anecdotal studies have shown that unemployed LT recipients display better QOL scores (Tome et al. 2008). Waclawski and Noone (2018) analyzed 35 studies dealing with employment and LT. The main conclusion is that employment decreases after the procedure and does not run in parallel to the improvement of QOL. The average percentage of patients returning to work is 37%, a figure lower than in kidney transplant patients and higher than in lung transplant patients. The majority of LT recipients return to work after 6 months to 2 years. The rate of employment declines after 8 years (Yang et al. 2014). Several variables determine return to work after a transplant: ●●

●●

Indication: etiology of the disease. Cholestatic liver disease correlates with a higher rate of employment after transplant than alcohol-related liver disease and ALF. Mental health co-morbidities – mainly depression – have been implicated as co-factors as well.

Chapter 57  Quality of Life and Employment after Liver Transplantation

Table 57.1  Employment rate after liver transplant across different countries.

Authors

Country

Number

 Follow-up (months)

 Mean age

Return to work

 % Working full time

Knechtle et al. 1993

USA

60

N/A

49

56%

40%

Adams et al. 1995

Canada

203

9

46

57%

40%

Loinaz et al. 1999

Spain

137

3

49

41%

38%

Newton 1999

USA

122

60

47

55%

47%

Paterson et al. 2000

USA

87

48

48

45%

N/A

Moyzes et al. 2001

Germany

103

60

47

22%

22%

Karam et al. 2003

France

125

120

51

53%

39%

Cowling et al. 2004

USA

152

53

53

36%

24%

Blanch et al. 2004

Spain

126

12

56

33.1

N/A

Björnsson et al. 2005

Sweden

103

31

53

18% ALD 52% NALD

N/A

Kirchner et al. 2006

Germany

23

62

48

26%

17%

Sahota et al. 2006

USA

105

34

54

49%

N/A

Sargent & Wainwright 2006

UK

60

36

35

37%

N/A

Saab et al. 2007

USA

308

48

51

27%

22%

Gorevski et al. 2011

USA

91

N/A

56

38.5%

N/A

Huda et al. 2012

USA (SRTR)

21,942

24

41–55

26%

N/A

Weng et al. 2012

Taiwan

111

44

54

44%

N/A

Zahn et al. 2013

Germany

281

42

50

28%

N/A

Kelly et al. 2016

Canada

110

104

57

30%

15%

Rudler et al. 2016

France

314

73

49

43%

N/A

ALD, alcohol-related liver disease; N/A, not available; NALD, non=non alcohol-related liver disease; SRTR, Scientific Registry for Transplant Recipients. Source: Data from Tome et al. 2008.

●● ●● ●● ●●

Age at transplant procedure. Length of disability prior to transplant, including interval without paid employment. Female sex. Being an unskilled worker.

The latter have been identified as predictors of unemployment. More difficult to explain is the relationship between unemployment and the concurrent benefits that the patient has, like health insurance and state coverage. While some patients try to work to pay health insurance, others are unemployed because of their health coverage. In the US, the employer-paid requirement for health insurance is a negative incentive to hiring a patient after LT. While the different rates of the employment after transplant may vary across different countries due to country-specific influences, the simple rule holds true: the better coverage, the lower the unemployment rate. Working with LT patient associations along with institutions seems crucial to improve the low rates of unemployment after LT. Well-designed studies are needed to clarify this topic.

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­Conclusion In conclusion, QOL improves dramatically after LT. The most improved domains are physical, with modest improvements in psychosocial domains, although QOL scores remain less than those seen in the general population. Identifying contributing factors that mitigate QOL is a crucial step on the path to designing treatment strategies to enhance QOL after LT and avoid deterioration. Employment, a relevant domain of social functioning, is the area that improves least after transplant. Determining the factors that contribute, such as physical disabilities, mental illness, and social impediments, including the impact on employers’ insurance in the US, will be necessary before we can increase employment and activities, especially in the long-term survivor.

­Further reading Adams PC, Kertesz A, Valberg LS. Screening for hemochromatosis in children of homozygotes: prevalence and cost-effectiveness. Hepatology. 1995;22:1720–1727. Björnsson E, Olsson J, Rydell A, Fredriksson K, Eriksson C, Sjöberg C, et al. Long-term follow-up of patients with alcoholic liver disease after liver transplantation in Sweden: impact of structured management on recidivism. Scand J Gastroenterol. 2005;40(2):206–216. doi:10.1080/00365520410009591 Blanch J, Sureda B, Flavia M, Marcos V, de Pablo J, De Lazzari E, et al. Psychosocial adjustment to orthotopic liver transplantation in 266 recipients. Liver Transpl. 2004;10(2):228–234. Bravata DM, Olkin I, Barnato AE, Keefe EB, Owens DK. Health-related quality of life after liver transplantation: a meta-analysis. Liver Transpl Surg. 1999;5:318–331. Croome KP, Lee DD, Perry DK, Burns JM, Nguyen JH, Keaveny AP, et al. Comparison of longterm outcomes and quality of life in recipients of donation after cardiac death liver grafts with a propensity-matched cohort. Liver Transpl. 2017;23(3):342–335. Cowling T, Jennings LW, Goldstein RM, Sanchez EQ, Chinnakotla S, Klintmalm GB, et al. Societal reintegration after liver transplantation: findings in alcohol-related and non-alcohol-related transplant recipients. Ann Surg. 2004;239(1):93–98. doi:10.1097/01.sla.0000103064.34233.94 Feurer ID, Wright JK, Payne JL, Kain AC, Wise PE, Hale P, et al. Effects of hepatitis C virus infection and its recurrence after liver transplantation on functional performance and health-related quality of life. J Gastrointest Surg. 2002;6(1):108–115. Gorevski E, Succop P, Sachdeva J, Scotte R, Benjeye J, Varughese G, et al. Factors influencing posttransplantation employment: does depression have an impact. Transplant Proc. 2011;43:3835–3839. Huda A, Newcomer R, Harrington C, Blegen MG, Keeffe EB. High rate of unemployment after liver transplantation: analysis of the United Network for Organ Sharing database. Liver Transpl. 2012;18(1):89–99. Karam V, Castaing D, Danet C, Delvart V, Gasquet I, Adam R, et al. Longitudinal prospective evaluation of quality of life in adult patients before and one year after liver transplantation. Liver Transpl. 2003;9:703–711. Kelly R, Hurton S, Ayloo S, Cwinn M, De Coutere-Bosse S, Molinari M. Societal reintegration following cadaveric orthotopic liver transplantation. Hepatobil Surg Nutr. 2016;5(3):234–244. Kirchner GI, Rifai K, Cantz T, Nashan B, Terkamp C, Becker T, et al. Outcome and quality of life in patients with polycystic liver disease after liver or combined liver-kidney transplantation. Liver Transpl. 2006;12(8):1268–1277. doi:10.1002/lt.20780 Knechtle SJ, Fleming MF, Barry KL, Steen D, Pirsch JD, D’Alessandro AM, et al. Liver transplantation in alcoholics: assessment of psychological health and work activity. Transplant Proc. 1993;25:1916–1918. Loinaz C, Clemares M, Marqués E, Pasiero G, Gomez R, Gonzales-Pinto I, et al. Labor status of 137 patients with liver transplantation. Transplant Proc. 1999;31;2470–2471.

Chapter 57  Quality of Life and Employment after Liver Transplantation

Longworth L, Young T, Buxton MJ, Ratcliffe J, Neuberger J, Burroughs A, et al. Midterm cost-effectiveness of the liver transplantation program of England and Wales for three disease groups. Liver Transpl. 2003;9(12):1295–1307. Miller LR, Paulson D, Eshelman A, Bugenski M, Brown KA, Moonka D, et al. Mental health affects the quality of life and recovery after liver transplantation. Liver Transpl. 2013;19(11):1272–1278. Moyzes D, Walter M, Rose M, Neuhaus P, Klapp BF. Return to work 5 years after liver transplantation. Transplant Proc. 2001;33:2878–2880. Newton SE. Recidivism and return to work posttransplant: recipients with substance abuse histories. J Subst Abuse Treat. 1999;17(1–2):103–108. doi:10.1016/s0740-5472(98)00059-2 Ohnemus D, Neighbors K, Rychlik K, Venick RS, Bucuvalas JC, Sundaram SS, et al. Health-related quality of life and cognitive functioning in pediatric liver transplant recipients. Liver Transpl. 2020;26(1):45–56. Parmar A, Vandriel SM, Ng VL. Health related quality of life after pediatric liver transplantation: a systematic review. Liver Transpl. 2017;23(3):361–374. Paterson DL, Godowsky T, Waggener MM, Wagener MW, Marino IR, Vargas H, et al. Quality of life in long-term survivors after liver transplantation: impact of recurrent viral hepatitis C virus hepatitis. Clin Transplant 2000;14(1):48–54. Rudler M, Rousseau G, Lebray P, Méténier O, Vaillant J-C, Savier E, et al. Rate of employment after liver transplantation in France. Eur J Gastroenterol Hepatol. 2016;28(2):159–163. 10.1097/MEG.0000000000000522 Saab S, Wiese C, Ibrahim AB, Peralta L, Durazo F, Han S, et al. Employment and quality of life in liver transplant recipients. Liver Transpl, 2007;13:1330–1338. doi:10.1002/lt.21247 Sahota A, Zaghla H, Adkins R, Ramji A, Lewis S, Moser J, et al. Predictors of employment after liver transplantation. Clin Transpl. 2006;20:490–495. doi:10.1111/j.1399-0012.2006.00511.x Sargent S, Wainwright SP. Quality of life following emergency liver transplantation for acute liver failure. Nurs Crit Care. 2006;11:168–176. Sullivan KM, Radosevich DM, Lake JR. Health-related quality of life: two decades after liver transplantation. Liver Transpl. 2014;20(6):649–654. Tome S, Wells JT, Said A, Lucey MR. Quality of life after liver transplantation: a systematic review. J Hepatol. 2008;48(4):567–577. Waclawski ER, Noone P. Systematic review: impact of liver transplantation on employment. Occup Med. 2018;68(2):88–95. Weng LC, Chen HC, Huang HL, Wang YW, Lee WC. Change in the type of work of post-operative liver transplant patients. Transplant Proc. 2012;44:544–547. Yang LS, Shan LL, Saxena A, Morris DL. Liver transplantation: a systematic review of long-term quality of life. Liver Int. 2014;34(9):1298–1313. Zahn A, Seubert L, Jünger J, Schellberg D, Weiss KH, Schemmer P. Factors influencing long-term quality of life and depression in German liver transplant recipients: a single-centre cross-sectional study. Ann Transpl. 2013;18:327–335.

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58 Sexual Function, Fertility, and Pregnancy in Liver Disease and after Liver Transplantation Patrizia Burra1, Salvatore Stefano Sciarrone1, and Patrizio Bo2 1

Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy Obstetrics and Gynecology Unit, Cittadella Hospital, Cittadella, Padua, Italy

2

Key points ●●

●●

●●

●●

After liver transplantation, normal hormone homeostasis is restored in male recipients. Their sexual ­dysfunction may persist, however, due to their medication (immunosuppressants) and/or psychologic issues. Female recipients also return to normal hormone homeostasis after liver transplantation, and to a resumption of their menstrual cycle. Contraception is essential, however, as pregnancies in such patients must be properly planned. Pregnancy after liver transplantation is possible, but must be carefully planned. It is advisable only for women with an optimal graft function and stable levels of immunosuppressants. Breastfeeding is also feasible, at no risk to the newborn, but it is fundamentally important to prescribe appropriate, adequate immunosuppressant therapy in this setting.

­Overview Sexual dysfunction is characterized by disturbances in sexual desire and in the psychophysiologic changes associated with the sexual response cycle in men and women. It is a common problem in both sexes, reportedly affecting between 10% and 50% of men, and between 25% and 60% of women. Despite the potential impact of these disorders on quality of life, epidemiologic data are relatively scant, and even less information is available for liver transplant recipients.

­Sexual function after liver transplantation Successful liver transplantation (LT) leads to improvements in sex hormone disturbances in both men and women, but post-LT medication (including immunosuppressants) can interfere with hormone metabolism.

Liver Transplantation: Clinical Assessment and Management, Second Edition. Edited by James Neuberger, James Ferguson, Philip N. Newsome and Michael Ronan Lucey. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

Chapter 58  Sexual Function, Fertility, and Pregnancy

­Male recipients Medication Among the types of medication that may be involved in the pathogenesis of erectile dysfunction in male patients, antihypertensives and corticosteroids should also be borne in mind. The role of immunosuppressants is still not clear. In the early post-transplant period (up to a month after surgery), plasma levels of total and free testosterone may be significantly reduced with respect to a patient’s levels before the procedure. The same situation has also been seen after kidney transplantation, which coincides with a drop in sex hormone-binding protein (SHBG) levels. This has been attributed to the high doses of immunosuppressants administered during this phase, including both corticosteroids and calcineurin inhibitors. The pathogenesis of erectile dysfunction is multifactorial and causes include hypogonadism as well as treatment with calcineurin inhibitors. Calcineurin is strongly expressed in the testes and involved in the cell mechanisms fundamental to a normal sperm function. An altered spermatogenesis might also explain the increased follicle-stimulating hormone (FSH) levels encountered, especially in the first 12 months after LT. A recent review (Jesus et al. 2017) of published studies on transplant patients who received mammalian target of rapamycin (mTOR) inhibitors found consistent evidence of sirolimus-related suppression of gonadal function and increased concentrations of FSH and luteinizing hormone (LH). In a recent cross-sectional study (Lee et al. 2005), on the other hand, despite lower total testosterone levels and higher FSH and LH levels, there was no significant difference in sexual function scores between patients treated with sirolimus and a control group. In short, it seems that immunosuppression is one of the aspects of transplantation that needs to be considered with care to strike the right balance between the benefits for the graft and the patient’s quality of life.

Hormone homeostasis A study found that the proportion of sexually inactive men decreased from 29% before LT to 15% afterward, while the proportion of men with erectile dysfunction remained unchanged. The absence of sexual activity after LT was associated with pre-transplant sexual inactivity, age, cardiovascular disease, and use of diuretics, anticoagulants, statins, and treatment for diabetes. Cardiovascular disease, post-transplantation diabetes, alcohol abuse, and the use of antidepressants and angiotensin II receptor blockers were all associated with erectile dysfunction after LT. A study by Burra (2009) on patients before and after transplantation at the Multivisceral Transplant Unit at Padua University Hospital showed that patients with liver cirrhosis awaiting LT had significantly higher levels of prolactin and SHBG than patients with an LT. Sexual dysfunction also correlated with old age, but after LT it was more strongly associated with depression. So sexual dysfunction was confirmed for both men and women with liver cirrhosis, and it was surprisingly persistent after LT, with depression being the main risk factor. Other studies have since shown that even patients with marked hypogonadism before LT frequently achieve functional recovery of their hypothalamic–pituitary–testicular axis in terms of testosterone and prolactin secretion, and regained fertility. Some authors have found, however, that – despite a marked reduction in SHBG – normalized free testosterone levels derive from a greater output of gonadotropins (especially LH) already in the first 12 months after LT. The rise in free testosterone levels after LT still fails to reach normal levels in more than one in three patients, however, and there is a concomitant increase in LH.

­Female recipients Fertility Women achieve normal menstrual function and fertility a few months after LT, and the recommendation for women of reproductive age who undergo LT is to monitor their menstrual function and use of contraception. In the year before LT, 42% of women reported regular menstrual cycles, 28% reported irregular and unpredictable

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bleeding, and 30% reported amenorrhea. After transplantation, 48% experienced regular menses, 26% irregular bleeding, and 26% amenorrhea. Women currently account for one in three LT recipients, and approximately a third of them are of reproductive age (18–49 years old). The first successful pregnancy following LT occurred in 1978, with excellent maternal and fetal outcomes. Numerous studies have since been published, and there are registries for pregnancies after LT, but no randomized control trials have been conducted to date, and much of the evidence regarding drug safety during pregnancy comes from animal studies. In one study by Burra (2009) on women who underwent LT at the Multivisceral Transplant Unit in Padua, psychologic status seemed to play a key part in sexual dysfunction after LT. In fact, depression has emerged as the main risk factor for sexual dysfunction persisting after LT in both sexes. As for the role of patients’ previous liver disease in determining any sexual dysfunction after LT, female patients who underwent the procedure for virusrelated liver disease had more severe sexual dysfunction than those transplanted for other causes of liver disease. Previous studies also found hepatitis C virus (HCV) to be a major determinant of both clinical and psychologic outcomes after LT, and it has been associated with a poor subsequent quality of life.

Contraception Contraception is needed for women who undergo LT, especially in the first year after the procedure. Ineffective and unsafe methods such as coitus interruptus or abstinence cannot be recommended. Because of the possible drug interactions and the risk of infection due to the use of immunosuppressants, the safest contraceptive method remains the barrier method. Intrauterine devices are not safe, partly because of the risk of infection and also because there is evidence of them being less effective in immunosuppressed patients. Concerning oral or transdermal contraceptives, the same contraindications apply as in the general population (they are not recommended for women with a history of myocardial infarction, stroke, deep vein thrombosis, or migraine with focal aura). Since these contraceptives are metabolized by the hepatic cytochrome P4503A4 system, drug–drug interactions may also be a concern – especially with cyclosporine and tacrolimus, which are both metabolized by this same enzyme. Oral contraceptives should therefore be used with caution after LT, frequently monitoring liver function. They should only be recommended in recipients whose graft function has remained stable for at least 6–8 months, and who have no other contraindications.

Pregnancy Maternal complications after liver transplantation

Women return to a normal reproductive function one month after LT. The most important factors for the good outcome of a subsequent pregnancy are stable graft function, stable immunosuppression, and no hypertension prior to conception. The pregnancy must be planned, and the physician should optimize the woman’s immunosuppression and check for good graft function. On this premise, the American Society of Transplantation recommends that pregnancy be considered for women who undergo LT providing: ●● ●● ●● ●●

there is no sign of rejection for a year prior to the intended conception; graft function is stable; health status is good, with no infections in particular; and immunosuppressant dosage is stable.

In short, although there is no specific mention of the recommended timing of a conception after LT, waiting a year or two is generally considered a good idea. An important issue concerning pregnancy in women who have undergone LT concerns their immunosuppression and the risk of rejection. The question is how to strike the right balance between the teratogenic risk of the drugs and the risk of graft rejection. The reported incidence of rejection during pregnancy varies considerably (from 0% to 20%), as opposed to an incidence of about 2–3% for women who do not become pregnant after LT.

Chapter 58  Sexual Function, Fertility, and Pregnancy

Fetal complications

Most fetal complications – including spontaneous abortion, pre-term birth, intrauterine growth restriction, and fetal distress – are statistically more common in recipients of an LT than in the general population (although this is not true of all such complications). Some authors have suggested that the higher risk of pre-term birth might be partly due to episodes of graft rejection and early-onset pre-eclampsia, but this has yet to be confirmed. Immunosuppressants and pregnancy Calcineurin inhibitors

These drugs (cyclosporine and tacrolimus) have not been definitively associated with teratogenesis. Fetal malformation rates are much the same for pregnancies in women who were or were not taking this type of medication. Several studies on the consequences of high doses of this medication found a higher risk of intrauterine growth restriction, spontaneous abortion, and premature birth, but these results were not confirmed in all studies on the issue. In patients with an LT, it is important to monitor renal function and blood concentrations of these drugs frequently, especially since cytochrome 450 is inhibited during pregnancy (and this can lead to an increase in tacrolimus levels). Steroids  Steroids are often used as immunosuppressants after LT, but also to treat liver disease during pregnancy

(autoimmune disorders) or rejection after LT, and to induce fetal lung maturation when there is a risk of pre-term delivery. Whatever the reason for taking them, steroids can complicate pregnancy, with the side effects observable in any patient (high risk of infection, osteopenia, hypertension, hyperglycemia, cataracts). Steroids can also exacerbate gestational diabetes.

Azathioprine  Azathioprine (AZA) apparently has no teratogenic effects. It crosses the placenta, but the fetus does

not have the enzyme needed to convert it into its active form. The issue with this drug mainly concerns the associated oncogenic risk. During pregnancy and breastfeeding, AZA also seems to be associated with a higher risk of growth retardation. Infants exposed to AZA in early pregnancy (including pregnancies in organ transplant recipients) may be at a moderately increased risk of congenital malformations, and ventricular/atrial septal defects in particular. There is also a greater risk of growth restriction and pre-term delivery, but it is not clear whether or not these complications depend partly on the severity of the mother’s illness. Because of the potential for carcinogenesis and the unknown long-term effects of fetal immunosuppression, AZA should be withheld if possible; if not, the AZA dose should be reduced at 32 weeks of gestation

Breastfeeding Breastfeeding is strongly recommended by pediatric associations as the sole diet for the newborn until they are 6 months old at least. Then it should gradually be reduced over a further 6 months as the infant’s diet becomes more varied. This approach reduces the incidence of allergies, celiac disease, infectious diseases, diarrhea, and colitis in children. The doses of immunosuppressants taken during breastfeeding are lower than during gestation, so it is important to adjust a new mother’s immunosuppressant therapy after delivery to allow for breastfeeding, if possible.

Conclusion The liver has a fundamental role in sex hormone homeostasis in both males and females, and cirrhosis causes dysfunction in this mechanism. Like all chronic diseases, cirrhosis also causes psychologic discomfort, and sexual dysfunction stems from a combination of these two elements. Sexual dysfunction in cirrhosis can have various

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etiologies (depending on the primary liver disease) and different outcomes after LT. Despite their return to a normal hormone balance, men’s and women’s sexual function may not always improve after LT due to psychologic and pharmacologic factors. Pregnancy after LT is possible, but the guidelines recommend waiting at least 1–2 years before conceiving, and ensuring good graft function and optimal, stable levels of immunosuppression. Breastfeeding is also possible at no risk to the newborn if an appropriate dosage of immunosuppressants is adopted. The outcome of a transplant should be assessed by a multidisciplinary team, considering not only graft function, but also the patient’s quality of life and psychological well-being.

­Further reading Burra P. Sexual dysfunction after liver transplantation, Liver Transpl. 2009;15(Suppl 2):S50–S56. Coffin CS, Shaheen AAM, Burak KW, Myers RP. Pregnancy outcomes among liver transplant recipients in the United States: a nationwide case-control analysis. Liver Transpl. 2010;16(1):56–63. Constantinescu S, Pai A, Coscia LA, Davison JM, Moritz MJ, Armenti VT. Breast-feeding after transplantation. Best Pract Res Clin Obstet Gynaecol. 2014;28(8):1163–1173. De Bona M, Ponton P, Ermani M, Iemmolo RM, Feltrin A, Boccagni P, et al. The impact of liver disease and medical complications on quality of life and psychological distress before and after liver transplantation. J Hepatol. 2000;33(4):609–615. Deshpande NA, Coscia LA, Gomez-Lobo V, Moritz MJ, Armenti VT. Pregnancy after solid organ transplantation: a guide for obstetric management. Rev Obstet Gynecol. 2013;6(3–4):116–125. Foresta C, Schipilliti M, Ciarleglio FA, Lenzi A, D’Amico D. Male hypogonadism in cirrhosis and after liver transplantation. J Endocrinol Invest. 2008;31(5):470–478. Italian Association for the Study of the Liver. AISF position paper on liver disease and pregnancy. Dig Liver Dis. 2016;48(2):120–137. Jankowska I, Oldakowska-Jedynak U, Jabiry-Zieniewicz Z, Cyganek A, Pawlowska J, Teisseyre M, et al. Absence of teratogenicity of sirolimus used during early pregnancy in a liver transplant recipient. Transpl. Proc. 2004;36(10):3232–3233. Jesus TT, Oliveira PF, Sousa M, Cheng CY, Alves MG. Mammalian target of rapamycin (mTOR): a central regulator of male fertility? Crit Rev Biochem Mol Biol. 2017;52(3):235–253. doi:10.1080/10409238.2017.1279120 Lee S, Coco M, Greenstein SM, Schechner RS, Tellis VA, Glicklich DG. The effect of sirolimus on sex hormone levels of male renal transplant recipients. Clin Transpl. 2005;19(2):162–167. doi:10.1111/j.1399-0012.2005.00257.x Rodríguez-Castro KI, De Martin E, Gambato M, Lazzaro S, Villa E, Burra P. Female gender in the setting of liver transplantation. World J Transpl. 2014;4(4):229–242. doi:10.5500/wjt.v4.i4.229 Sifontis NM, Coscia LA, Constantinescu S, Lavelanet AF, Moritz MJ, Armenti VT. Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus. Transplantation. 2006;82(12):1698–1702. Veroux M, Corona D, Veroux P. Pregnancy under everolimus-based immunosuppression. Transpl. Int. 2011;24(12):e115–e117. Women in Hepatology Group, Italian Association for the Study of the Liver (AISF). AISF position paper on liver transplantation and pregnancy. Dig Liver Dis. 2016;48(8):860–868.

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59 Common Drug Interactions Amanda Smith Queen Elizabeth Hospital, Birmingham, UK

Key points ●● ●● ●●

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Potential drug interactions are common with immunosuppressants. Interactions may cause serious toxicity or graft loss. Monitoring of immunosuppressant concentrations is crucial when an interacting drug is concomitantly prescribed. Plasma immunosuppressant concentrations should also be monitored when stopping an interacting drug. Immunosuppressants may affect the plasma concentration of other drugs and potentially increase their toxicity.

Potential drug interactions with immunosuppressants following transplantation are ­common. Calcineurin inhibitors (CNIs) in particular are prone to interactions, the consequences of which may be clinically serious, such as severe toxicity or graft loss. It is crucial to consider the implications of concomitant prescribing in transplant recipients and to ­tailor prescribing accordingly. It is important to remember also to monitor immunosuppression plasma concentrations carefully when stopping an interacting drug, as corresponding adjustments to the immunosuppressant dose may be needed. Some examples of commonly prescribed drugs that may interact with immunosuppressants are included in this chapter; it is not exhaustive. The main focus is on interactions that affect the plasma concentration or toxicity of immunosuppression, but it should be remembered that immunosuppressants may also affect the plasma concentration or toxicities of other drugs. It should be borne in mind too that, while some drug interactions are almost universal, others may only be observed in some cases. For further information or advice, a transplant pharmacist should be consulted. Other drugs, such as immunomodulators and checkpoint inhibitors, may also affect immunosuppression, and so lead to graft rejection.

Liver Transplantation: Clinical Assessment and Management, Second Edition. Edited by James Neuberger, James Ferguson, Philip N. Newsome and Michael Ronan Lucey. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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­Tacrolimus, ciclosporin, and sirolimus Sirolimus and the CNIs tacrolimus and ciclosporin are all metabolized by cytochrome P450 3A4 (CYP3A4), and as such are subject to interactions with drugs that induce or inhibit the enzyme (see Table 59.1). The interaction may be profound in some cases, requiring substantial changes in immunosuppression dose. All patients prescribed a CYP3A4 inducer or inhibitor should have their immunosuppression carefully monitored. Tacrolimus, ciclosporin, and sirolimus are all also substrates for P-glycoprotein, which may be a contributing factor in their drug interactions. Some enzyme induction interactions can be slow in onset and in reaching the maximum effect. CNI levels need to be carefully monitored and adjusted as appropriate until it is certain that the interaction is stabilized. On Table 59.1  Common inhibitors and inducers of cytochrome P450 3A4. Common CYP3A4 inhibitors that may increase immunosuppression plasma concentrations

Common CYP3A4 inducers that may reduce immunosuppression plasma concentrations

fluconazole

carbamazepine

itraconazole

primidone

ketoconazole

phenobarbital

miconazole

phenytoin

posaconazole voriconazole

bosentan

ciclosporin

efavirenz

tacrolimus

nevirapine

diltiazem

rifabutin

nicardipine

rifampicin

verapamil

rifapentine

cimetidine

St John’s wort

grapefruit juice clarithromycin erythromycin telithromycin delavirdine protease inhibitors dasatinib imatinib nilotinib fluoxetine fluvoxamine amiodarone

Chapter 59  Common Drug Interactions

stopping the enzyme inducer, it may take a similar time for the effects on the enzymes to reverse, again necessitating close monitoring of CNI levels and dose adjustment until stable. Enzyme inhibition interactions often have a more rapid effect. Commonly seen interactions include the use of macrolides such as erythromycin, which can increase CNI plasma concentrations markedly by inhibition of CYP3A4, leading to toxicity, for example acute renal failure. Many transplant units advocate the avoidance of macrolides due to the potentially serious nature of the interaction. Azithromycin has been suggested as a safer option than the other drugs in this class as it does not inhibit CYP3A4, but there have been cases of increased CNI plasma concentrations with azithromycin, so it should still be used with caution. Azole antifungals are also commonly prescribed drugs that can have the same effect of significantly increasing plasma CNI concentrations. Fluconazole in particular is often used for antifungal prophylaxis following liver transplantation. The interaction is more marked with higher doses of fluconazole, but even the lower doses used for prophylaxis may necessitate changes in CNI dose. There have been published cases of oromucosal clotrimazole and miconazole causing increased tacrolimus plasma concentrations, possibly due to some ingestion. Alternatives that do not interact, such as nystatin, should be considered; if these are not appropriate, careful monitoring of CNI levels should always be undertaken. Patients on a protease inhibitor for human immunodeficiency virus (HIV) or hepatitis C need particularly careful monitoring, as the interaction with CNIs can be profound, and the CNI dose may need to be substantially reduced. Wherever possible, potential interactions should be considered prior to transplantation, and a plan to manage the interactions formulated in advance. Figure 59.1 shows the effect on the plasma tacrolimus concentration of a new liver transplant recipient whose regular regimen of lopinavir/ritonavir was restarted post transplantation, and the corresponding effect on renal function. Some herbal remedies, such as St John’s wort, have been shown to affect blood CNI concentrations. There is in vitro evidence that other herbal remedies may induce or inhibit CYP3A4, and thus possibly affect CNI blood concentrations. Until more is known regarding the in vivo effects in transplant recipients, it would be prudent to

lopinavir/ritonavir

250

tacro dose tacro level

30

creatinine

200

25 150

20 15

100

10

Serum creatinine μmol/L

tacrolimus level (ng/mL) and total daily dose (mg)

35

50 5 0

0

2

4

6

8 10 12 14 Day post transplantation

16

18

20

0

Figure 59.1  Effects of lopinavir/ritonavir on tacrolimus trough plasma concentration. Source: Data reproduced with kind permission of Professor David Mutimer, Queen Elizabeth Hospital, Birmingham, UK.

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avoid those specific remedies. It is recommended that these cases should be discussed with a transplant pharmacist for advice. There is some evidence in transplant recipients that cannabidiol may cause a clinically significant interaction with tacrolimus, probably due to enzyme inhibition.

­Tacrolimus See above for interactions with CYP3A4 inducers and inhibitors. ●●

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CYP3A4 inducers can decrease the plasma concentration of tacrolimus. Decreased plasma concentrations of tacrolimus can lead to graft loss. CYP3A4 inhibitors can increase the plasma concentration of tacrolimus. Increased plasma concentrations of tacrolimus can lead to toxicity, for instance nephrotoxicity.

Other drugs reported to increase plasma tacrolimus concentrations include nifedipine, felodipine, basiliximab, and chloramphenicol. Monitoring of tacrolimus plasma concentrations is recommended when commencing, stopping, or switching proton pump inhibitors, as some have been reported to increase plasma tacrolimus concentrations in some patients. Caspofungin may reduce plasma tacrolimus concentrations. The toxicity of tacrolimus may be increased by the concomitant administration of other nephrotoxic or neurotoxic drugs. Drugs that increase the plasma tacrolimus concentration may also cause a corresponding increased risk of toxicity. There is an increased risk of hyperkalemia with potassium, or other drugs that may increase serum potassium. Tacrolimus is itself a CYP3A4 inhibitor, so may increase plasma concentrations of other CYP3A4 substrates. As tacrolimus may prolong the QT interval, caution is advised with other medications that can also have this effect.

­Ciclosporin See above for interactions with CYP3A4 inducers and inhibitors. ●●

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CYP3A4 inducers can decrease the plasma concentration of ciclosporin. Decreased plasma concentrations of ciclosporin can lead to graft loss. CYP3A4 inhibitors can increase the plasma concentration of ciclosporin. Increased plasma concentrations of ciclosporin can lead to toxicity, for instance nephrotoxicity.

Other commonly prescribed drugs that have been reported to increase ciclosporin plasma concentrations include acetazolamide, allopurinol, azithromycin, carvedilol, chloramphenicol, chloroquine, colchicine, danazol, ezetimibe (also leading to an increase in ezetimibe plasma concentration), lercanidipine (concomitant administration may also lead to a threefold increase in AUC of lercanidipine), high-dose methylprednisolone (possibly leading to a risk of convulsions), and metoclopramide. Both increases and decreases in plasma ciclosporin concentrations have been reported with ursodeoxycholic acid. Drugs that may decrease plasma ciclosporin concentrations include octreotide, orlistat, sulfadiazine, and sulfinpyrazone. The risk of nephrotoxicity is increased with the concomitant use of other nephrotoxic drugs, and interactions with drugs that increase plasma ciclosporin concentrations may also cause a corresponding increased risk of renal impairment. There is an increased risk of hyperkalemia with the concomitant administration of other drugs that can increase serum potassium. The risk of other adverse events may also be increased by the concomitant administration of drugs that may cause similar effects, for example an increased risk of gingival overgrowth has been reported when

Chapter 59  Common Drug Interactions

nifedipine is used with ciclosporin. Raised liver enzymes have been observed with caspofungin. Close monitoring of liver enzymes is advised when caspofungin is used with ciclosporin. Ciclosporin is an inhibitor of CYP3A4, and a highly potent inhibitor of P-glycoprotein, so may increase the plasma concentrations of their substrates. Some important examples where there is an increased risk of toxicity by these or other mechanisms are statins, digoxin, colchicine, aliskiren, bosentan, and dronedarone.

­Azathioprine ●●

Allopurinol increases the plasma concentration of azathioprine, leading to a risk of serious toxicity, which may be life-threatening.

Xanthine oxidase inhibitors such as allopurinol inhibit the conversion of an active metabolite of azathioprine to an inactive compound, leading to accumulation and an increased risk of toxicity, which may be life-threatening. Many transplant units advise avoiding the combination completely. If azathioprine and allopurinol are used concomitantly, the UK manufacturer of Imuran® (azathioprine) recommends that the dose of azathioprine should be reduced to one-quarter of the original dose. Patients should also be closely monitored, with frequent measurement of blood count. As expected, the newer xanthine oxidase inhibitor febuxostat has also been reported to probably interact with azathioprine, and their concomitant use is not recommended. The hematological toxicity of azathioprine may be increased by the addition of other drugs that may also cause myelosuppression. The anticoagulant effect of warfarin may be decreased by azathioprine.

­Mycophenolate Mycophenolate mofetil is metabolized to the active mycophenolic acid (MPA). A reduction of the plasma concentration of MPA has been reported with various drugs, including rifampicin, ciclosporin, sodium valproate, antacids with magnesium and aluminum hydroxides, sevelamer, and the combination of norfloxacin plus metronidazole. As MPA is subject to enterohepatic circulation, colestyramine may decrease plasma MPA concentrations. Pantoprazole and lansoprazole have been reported to decrease MPA plasma concentrations in patients receiving mycophenolate mofetil. There is possibly an increased risk of myelotoxicity when mycophenolate is prescribed concomitantly with other drugs that can cause similar toxicities, such as ganciclovir and valganciclovir, although this is not always observed. Mycophenolate may increase the plasma concentration of ganciclovir, so patients receiving both drugs should be monitored carefully.

­Corticosteroids Corticosteroids are substrates of CYP3A4, and as such their plasma levels may be affected by inducers and inhibitors of the enzyme. In addition, high doses of antacids may decrease the absorption of corticosteroids. Carbimazole has been reported to increase the clearance of prednisolone; estrogens may decrease the clearance of prednisolone and methylprednisolone. Corticosteroids can affect anticoagulant therapy, and the international normalized ratio (INR) should be closely monitored. Corticosteroids may antagonize the therapeutic effects of antihypertensives, diuretics, and hypoglycemics, and the concomitant use of corticosteroids with non-steroidal anti-inflammatory drugs may increase the risk of gastrointestinal ulceration.

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There may be an increased risk of hypokalemia with the concomitant use of loop and thiazide diuretics, acetazolamide, digoxin, theophylline, beta-2 agonists, and amphotericin, which may be potentially serious. If concomitant administration is deemed necessary, plasma potassium should be closely monitored. Dexamethasone is a moderate inducer of CYP3A4, and also an inducer of P-glycoprotein. The possibility of interactions should be considered when prescribing CYP3A4 or P-glycoprotein substrates. Other corticosteroids may also affect CYP3A4.

­Further reading Boogaerts MA, Zachee P, Verwilghen RL. Cyclosporin, methylprednisolone, and convulsions. Lancet. 1982;2:1216–1217. Doligalski CT, Tong Logan A, Silverman A. Drug interactions: a primer for the gastroenterologist. Gastroenterol Hepatol. 2012;8(6):376–383. Garg V, van Heeswijk R, Lee JE, Alves K, Nadkarni P, Luo X. Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus. Hepatology. 2011;54(1):20–27. Kaczmorski S, Doares W, Winfrey S, Al-Geizawa S, Farney A, Rogers J, et al. Gout and transplantation: new treatment option – same old drug interaction. Transplantation. 2011;92(3):e13–e14. Leino AD, Emoto C, Fukuda T, Privitera M, Vinks AA, Alloway RR. Evidence of a clinically significant drug–drug interaction between cannabidiol and tacrolimus. Am J Transpl. 2019; 19(10):2944–2948. Mañez R, Martin M, Raman D, Silverman D, Jain A, Warty V, et al. Fluconazole therapy in transplant recipients receiving FK506. Transplantation. 1994;57(10):1521–1523. Marr KA, Hachem R, Papanicolaou G, Somani J, Arduino JM, Lipka CJ, et al. Retrospective study of the hepatic safety profile of patients concomitantly treated with caspofungin and cyclosporin A. Transpl Infec Dis. 2004;6(3):110–116. Molina Perez E, Fernández Castroagudín J, Seijo Ríos S, Mera Calviño J, Tomé Martínez de Rituerto S, Otero Antón E, et al. Valganciclovir-induced leukopenia in liver transplant recipients: influence of concomitant use of mycophenolate mofetil. Transplant Proc. 2009;41(3):1047–1049. Nowack R. Review article: cytochrome P450 enzyme, and transport protein mediated herb–drug interactions in renal transplant patients: grapefruit juice, St John’s wort – and beyond! Nephrology. 2008;13(4):337–347. Stamp L, Searle M, O’Donnell J, Chapman P. Gout in solid organ transplantation: a challenging clinical problem. Drugs. 2005;65(18):2593–2611.

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60 Immunization and Liver Transplantation Jessica Hause and Erin Spengler Gastroenterology & Hepatology Faculty, University of Wisconsin, Madison, WI, USA

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Immunization, while very safe, is not free of risk. Risks and benefits of each vaccination should be discussed in detail with patients prior to administration. Transplant candidates should be checked for immunity to hepatitis A and B viruses and immunization should be offered to those who are not immune. All recommended vaccines should be administered prior to liver transplantation, if possible, with live virus vaccinations particularly prioritized pre transplantation in those who are not receiving immunosuppression. Live and attenuated vaccines should not be given to liver transplant recipients; these include some polio and typhoid vaccines, Bacille Calmette–Guerin (BCG), measles, mumps, and rubella (MMR), rotavirus, and live varicella zoster virus. All liver transplant candidates and recipients should be offered annual influenza vaccination. Monitoring of immune status is available and may be considered for hepatitis A virus, hepatitis B virus, pneumococcus, Haemophilus influenzae type B (HiB), measles, mumps, and rubella. Other vaccines may be given as clinically indicated. Healthcare workers and close contacts should remain up to date with standard immunizations and should receive a yearly influenza vaccination.

­General principles Vaccine-preventable illnesses are a source of considerable morbidity and mortality in liver transplant recipients. Nearly all liver transplant recipients require life-long immunosuppression, significantly increasing their risk of infections. Immunization provides a safe and effective means to reduce the risk of such infections. The primary strategy for immunizing liver transplant recipients is to deliver all vaccines prior to liver transplantation. However, this is not always possible, and live virus vaccination should be prioritized pre transplantation for those who are not receiving immunosuppression. Evidence suggests that inactivated vaccines are both safe and effective following

Liver Transplantation: Clinical Assessment and Management, Second Edition. Edited by James Neuberger, James Ferguson, Philip N. Newsome and Michael Ronan Lucey. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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Table 60.1  Lists of more commonly offered vaccines. Live or attenuated vaccines

Inactivated vaccines

Measles

Influenza

Mumps

Pneumococcus

Rubella

Hepatitis A

Varicella zoster (live)

Hepatitis B

Bacille Calmette–Guerin (BCG)

Human papillomavirus

Polio (oral)

Haemophilus influenzae type B (HiB)

Rotavirus

Meningococcal

Typhoid (oral)

Tetanus

Yellow fever

Varicella zoster (recombinant) Anthrax Botulism Cholera Diphtheria Polio (not oral) Rabies Tick-borne encephalitis Typhoid (not oral)

liver transplantation, but live vaccines should be avoided (see Table  60.1). The level of protection achieved by immunizations post liver transplant may not be optimal, but partial protection has proven superior to none.

­Liver transplant candidates Liver transplant candidates are more likely to develop vaccine-induced immunity compared to transplant recipients receiving immunosuppression. Physicians should vaccinate liver transplant candidates as early as possible in the course of their end-stage liver disease and prioritize live vaccinations to the pre-transplant period, if possible. It is recommended to check liver transplant candidates for immunity against hepatitis A, hepatitis B, varicella, measles, mumps, and rubella, and offer pre-transplant vaccination if non-immune. The attenuated live vaccines most commonly recommended for liver transplant candidates, if non-immune, have typically included measles, mumps, and rubella (MMR) and varicella zoster virus (VZV). Liver transplant candidates who are receiving immunosuppressive therapy should not be offered live or attenuated vaccines. MMR vaccination is usually given in childhood, and together, although some individual vaccines are available. MMR vaccine should not be given within 1 month of liver transplantation, and should therefore be avoided in the setting of urgent transplant listing. Since 2017, a recombinant, rather than attenuated live, VZV vaccine is the preferred VZV vaccination. Recently, the recombinant VZV vaccine (Shingrex) has been recommended for liver transplant recipients more than 50 years of age. The vaccine is administered in 2 doses 2–6 months apart. Note that VZ immunoglobulin is available for patients who are non-immune and in close contact with individuals infected with VZV.

Chapter 60  Immunization and Liver Transplantation

­Liver transplant recipients Induction immunosuppression in liver transplant recipients could result in ineffective vaccine response in the early post-transplant period. Waiting 6 months after liver transplantation, or until baseline immunosuppression is achieved, is generally recommended to improve immunogenicity. Several large studies have demonstrated no increased risk of allograft rejection in liver transplant recipients receiving vaccinations. Yearly influenza vaccination is recommended both in liver transplant candidates and recipients. Influenza can be clinically severe and predispose patients to bacterial infections, multiorgan failure, and allograft dysfunction. Guidelines recommend injected influenza vaccine with a preparation that is likely to be relevant to current epidemiologic data. Some studies suggest improved immunogenicity in solid organ recipients if high-dose influenza vaccines are administered. If a patient is exposed to influenza, post-exposure chemoprophylaxis should be initiated within 48 hours and administered for up to 10 days. The influenza vaccine should also be administered to all family members and close contacts of liver transplant recipients. Invasive pneumococcal disease is 13 times more common in liver transplant recipients compared with the general population. All liver transplant recipients should receive a single dose of the 13-valent pneumococcal conjugate vaccine (PCV-13) in addition to the 23-valent pneumococcal polysaccharide vaccine (PPSV-23). PCV-13 may elicit a more robust response in immunocompromised patients, while PPSV-23 contains a larger number of serotypes. Patients who are pneumococcal vaccine naive should receive a dose of PCV-13 first, followed by a dose of PPSV-23 8 weeks later. In patients who have previously received PPSV-23, PCV-13 should be administered at least 1 year after the last dose of PPSV-23. Subsequent doses of PPSV-23 should be given at least 5 years after the most recent dose of PPSV-23, and no sooner than 8 weeks after PCV-13. Hepatitis A vaccination should be offered to all patients with chronic liver disease. Unfortunately, some patients are not vaccinated prior to liver transplant and may require vaccination post transplant. The vaccine is administered in 2 doses at 0 and 6 months. A recent study has demonstrated dramatically lower seroconversion rates in liver transplant recipients compared to those with chronic liver disease and healthy controls at 6 months. Antibody titers should be considered in liver transplant recipients following vaccination. Hepatitis B virus (HBV) vaccination is recommended for all patients whose anti-hepatitis B surface antibody (HBsAb) is