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Evidence-Based Gastroenterology and Hepatology [4 ed.]
 2018046910, 2018047954, 9781119211396, 9781119211402, 9781119211389

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Evidence-Based Gastroenterology and Hepatology Fourth Edition


John W. D. McDonald Professor, Department of Medicine, Schulich School of Medicine, Western University Honorary Consultant, Department of Medicine, London Health Sciences Centre Editor, Cochrane Inflammatory Bowel Diseases and Functional Bowel Disorders Review Group Lead Central Reader, Central Image Management Systems, Robarts Clinical Trials London, Ontario, Canada

Brian G. Feagan Professor of Medicine and Epidemiology and Biostatistics Division of Gastroenterology, Department of Medicine; Robarts Clinical Trials, Robarts Research Unit; Department of Biostatistics and Epidemiology University of Western Ontario London, Ontario, Canada

Rajiv Jalan Professor of Hepatology Head, Liver Failure Group Institute for Liver and Digestive Health, Division of Medicine UCL Medical School Royal Free Campus London, UK

Peter J. Kahrilas Professor of Gastroenterology and Hepatology Department of Medicine Feinberg School of Medicine, Northwestern University Chicago, Illinois, USA

This edition first published 2019 © 2019 John Wiley & Sons Ltd Edition History 1e, 2010; 2e, 2004; 3e, 1999 by Blackwell Publishing Ltd 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 John W. D. McDonald, Brian G. Feagan, Rajiv Jalan, and Peter J. Kahrilas 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: McDonald, John W. D., editor. | Feagan, Brian G., editor. | Jalan, Rajiv, 1962– editor. | Kahrilas, Peter, editor. Title: Evidence-based gastroenterology and hepatology [electronic resource] / edited by John W. D. McDonald, Brian G. Feagan, Rajiv Jalan, Peter Kahrilas. Description: Fourth edition. | Hoboken, NJ : Wiley-Blackwell, 2019. | Includes bibliographical references and index. | Identifiers: LCCN 2018046910 (print) | LCCN 2018047954 (ebook) | ISBN 9781119211396 (Adobe PDF) | ISBN 9781119211402 (ePub) | ISBN 9781119211389 (hardcover) Subjects: | MESH: Gastrointestinal Diseases–diagnosis | Gastrointestinal Diseases–therapy | Liver Diseases–diagnosis | Liver Diseases–therapy | Evidence-Based Medicine–methods Classification: LCC RC816 (ebook) | LCC RC816 (print) | NLM WI 195 | DDC 616.3/3–dc23 LC record available at https://lccn.loc.gov/2018046910 Cover Design: Wiley Cover Image: © David Litman/Shutterstock; © magicmine/iStock.com Set in 9/12pt MeridienLTStd by Aptara Inc., New Delhi, India

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We dedicate this edition to the authors Dr. David Sackett and Professor Andrew Burroughs.

David Sackett

Dr. David Sackett, in his final year as a medical student, David “Dave” Sackett was involved in the care of a young patient with acute viral hepatitis, who was being managed with the conventional treatment of enforced bedrest. Dave read a small, simple randomized trial of bedrest for this disease and realized that there was no evidence for this approach. He was always brave and sometimes unconventional, and he released the young man from bedrest, defying convention in favor of evidence. This started his 60-year career in promoting the approach for which he initially coined the term “critical appraisal” and which one of his students, Dr. G. Guyatt, eventually named “evidence-based medicine.” He promoted this approach very strongly from his primary academic base at McMaster University, but also from his career from 1994 to 1996 at the University of Oxford, where he established the International Centre for EvidenceBased Medicine and served as the first Chair of the Cochrane Collaboration. It was during his time at Oxford, and in collaboration with BMJ Books, that he strongly promoted the creation of several evidence-based medical textbooks, including this one, of which the first edition was published in 1997. Born in Chicago, Dr. Sackett became a Canadian citizen after his move to McMaster University in 1974. In his long and distinguished career, Dr. Sackett accepted many prestigious awards, but was most proud of being named an officer of the Order of Canada, an award that in his view recognized his contribution to the larger community, not just to medicine. He was a direct participant and leader in the

design and execution of many important randomized trials; however, one of his greatest legacies is the work of the 300 young students and clinical scientists whom he mentored in their learning of evidence-based approaches to care. Many of these students, including such leaders as Dr. Brian Haynes and Dr. Gordon Guyatt, learned from Dave when he served at his academic base at McMaster University and its hospitals. A great many young people benefited from his approach when with his wife Barbara and he hosted them at his rural and rustic “retirement” site, which he named the Trout Research & Education Centre. “Dave” died of metastatic cholangiocarcinoma in 2015.

Andrew Burroughs

Andrew Burroughs was instrumental in bringing and implementing the practice of modern hepatology to the great Royal Free Hospital that was started by late Dame Sheila Sherlock, who was Andy’s proud mentor, and afterwards by Prof Neil McIntyre. His contributions to hepatology are innumerable but his research made a real difference to the understanding and clinical management of portal hypertension, primary biliary cirrhosis, hepatocellular carcinoma, and liver transplantation. His H-index is well over a 100 and he has over 600 peer-reviewed publications. He mentored over 100 fellows from around the world, most of whom are now leaders in the field. He provided leadership to British and European hepatology by getting involved in policy and advocacy at every level. Andy was an excellent example of a true blue clinicalacademic; a great physician, a dedicated and inspiring teacher, a questioning researcher, and a true leader in the field of hepatology.


Contributors, xi Preface, xix

Part I Gastrointestinal disorders 1

Gastroesophageal reflux disease, 3 Sabine Roman and Peter J. Kahrilas


Barrett’s esophagus, 21 Anh D. Nguyen, Stuart J. Spechler, and Kerry B. Dunbar


Esophageal motility disorders, 35 Gabriel Lang, C. Prakash Gyawali, and Peter J. Kahrilas


Eosinophilic esophagitis, 50 Craig C. Reed and Evan S. Dellon


Ulcer disease and Helicobacter pylori infection: current treatment, 68 Naoki Chiba


Nonsteroidal anti-inflammatory drug-gastropathy and enteropathy, 86 Moe H. Kyaw, Alaa Rostom, Katherine Muir, Catherine Dub´e, Emilie Jolicoeur, Michel Boucher, Peter Tugwell, George Wells, and Francis K.L. Chan


Acute non-variceal gastrointestinal hemorrhage: treatment, 110 Kathryn Oakland and Vipul Jairath


Functional dyspepsia, 127 Sander Veldhuyzen van Zanten


Celiac disease: diagnosis, screening, and prognosis, 139 Adam S. Faye and Benjamin Lebwohl


Therapy for Crohn’s disease, 150 Reena Khanna, Barrett G. Levesque, John W.D. McDonald, and Brian G. Feagan


Ulcerative colitis, 173 Vipul Jairath, John W.D. McDonald, and Brian G. Feagan


Pouchitis after restorative proctocolectomy, 187 Mathurin Fumery, Siddharth Singh, Darrell S. Pardi, and William J. Sandborn


Microscopic colitis: collagenous and lymphocytic colitis, 196 ´ ˜ Johan Bohr, Fernando Fernandez-Ba nares, and Ole K. Bonderup





Drug-induced diarrhea, 208 Bincy P. Abraham, and Joseph H. Sellin


Prevention and treatment of travelers’ diarrhea, 225 David R. Tribble


Metabolic bone disease in gastrointestinal disorders, 240 Herman Bami, Arthur N. Lau, and Jonathan D. Adachi


Colorectal cancer in ulcerative colitis: surveillance, 258 Paul Collins, Bret A. Lashner, and Alastair J.M. Watson


Colorectal cancer: population screening and surveillance, 271 Catherine Dub´e and Linda Rabeneck


Clostridium difficile infections: epidemiology, diagnosis, and treatment, 284 Lynne V. McFarland, Christina M. Surawicz, and Stephen M. Vindigni


Irritable bowel syndrome, 306 Alexander C. Ford


Intestinal pseudo-obstruction (Ogilvie’s syndrome), 332 Meihuan Chang and Alexander G. Heriot


Gallstone disease, 342 Kurinchi S. Gurusamy and Brian R. Davidson


Acute pancreatitis, 353 Kurinchi S. Gurusamy and Brian R. Davidson

Part II Liver disease 24

Acute-on-chronic liver failure: diagnosis, prognosis, and treatment, 363 Jane Macnaughtan


Acute liver failure: prognosis and management, 374 Jennifer Price, Brian J. Hogan, and Banwari Agarwal


Infection in cirrhosis, 384 Elisa Brauns and Thierry Gustot


Liver biopsy, 395 Benjamin H. Mullish, Naveenta Kumar, Robert D. Goldin, and Pinelopi Manousou


Pregnancy and liver disease, 408 J.J. King and R.H. Westbrook


Cholangiocarcinoma, 425 Peter L. Labib, Giuseppe K. Fusai, and Stephen P. Pereira


Noninvasive tests of liver fibrosis, 445 Laurent Castera


Hepatitis C: treatment, 454 Mary D. Cannon, Kosh Agarwal, and Geoffrey Dusheiko


Hepatitis C virus (HCV) infection: in special situations, 470 Eleni Koukoulioti and Thomas Berg


Hepatitis B: prognosis and treatment, 490 Apostolos Koffas, Upkar Gill, and Patrick Kennedy



Alcoholic liver disease, 503 Meritxell Ventura-Cots, Nambi Ndugga, and Ramon Bataller


Nonalcoholic fatty liver disease, 523 Marie Boyle and Quentin M. Anstee


Hemochromatosis, 547 Gary P. Jeffrey and Paul C. Adams


Wilson’s disease, 554 Claire Kelly, Aftab Ala, and Michael L. Schilsky


Primary biliary cholangitis (formerly primary biliary cirrhosis), 574 Palak J. Trivedi and Gideon M. Hirschfield


Autoimmune hepatitis, 592 Martha M. Kirstein, Arndt Vogel, and Michael P. Manns


Primary sclerosing cholangitis, 602 Mette Vesterhus and Tom H. Karlsen


Variceal bleeding, 619 Damien Leith and Rajeshwar P. Mookerjee


Hepatic venous outflow syndromes and splanchnic venous thrombosis, 645 Laure Elkrief and Dominique Valla


Ascites, hyponatremia, spontaneous bacterial peritonitis, and hepatorenal syndrome, 662 Salvatore Piano, Marta Tonon, and Paolo Angeli


Hepatic encephalopathy: classification, diagnosis, and treatment, 676 Radha K. Dhiman and Sahaj Rathi


Hepatocellular carcinoma: diagnosis and prognosis, 693 Massimo Colombo and Massimo Iavarone


Hepatocellular carcinoma: treatment, 703 Alexa Childs and Tim Meyer


Drug-induced liver disease: mechanism and diagnosis, 715 ´ J. Andrade Camilla Stephens, M. Isabel Lucena, and Raul


Liver transplantation: prevention and treatment of rejection, 729 Franc¸ois Durand and Claire Francoz


Liver transplantation: prevention and treatment of infection, 744 ´ Marta Bodro, Javier Fernandez, and Asunci´on Moreno


Management of HCV infection after liver transplantation, 753 Audrey Coilly, Bruno Roche, and Didier Samuel

Index, 765



Bincy P. Abraham

Paolo Angeli

Division of Gastroenterology and Hepatology Houston Methodist Hospital Houston, TX, USA

Unit of Internal Medicine and Hepatology, Department of Medicine University of Padova Padova, Italy

Jonathan D. Adachi

Quentin M. Anstee

Department of Medicine McMaster University, Alliance for Better Bone Health Chair in Rheumatology Hamilton, ON, Canada

Institute of Cellular Medicine, Newcastle University & Freeman Hospital Liver Unit Newcastle upon Tyne, UK

Herman Bami Paul C. Adams Department of Medicine London Health Sciences Centre Western University University Hospital London, ON, Canada

Banwari Agarwal Intensive Care Unit Royal Free Hospital UCL Institute for Liver and Digestive Health London, UK

Kosh Agarwal Institute of Liver Studies King’s College Hospital London, UK

Aftab Ala Departments of Medicine and Surgery Division of Digestive Diseases and Transplant and Immunology Yale University New Haven, CT, USA

Raul ´ J. Andrade ´ Cl´ınica de Aparato Digestivo, Servicio de Unidad de Gestion Farmacolog´ıa Cl´ınica ´ Biomedica ´ ´ Instituto de Investigacion de Malaga-IBIMA, Hospital ´ Universitario Virgen de la Victoria, Universidad de Malaga, CIBERehd ´ Malaga, Spain

Schulich School of Medicine and Dentistry, Western University Medical Sciences Building London, ON, Canada

Ramon Bataller Division of Gastroenterology and Hepatology, Department of Medicine and Nutrition University of North Carolina at Chapel Hill Chapel Hill, NC, USA

Thomas Berg Section of Hepatology, Clinic for Gastroenterology and Rheumatology Department of Internal Medicine, Neurology, and Dermatology, University Hospital Leipzig Leipzig, Germany

Marta Bodro Infectious Disease Department, Hospital Clinic Barcelona Barcelona, Spain

Johan Bohr Department of Medicine School of Medical Sciences, Faculty of Medicine and Health ¨ Orebro University Hospital ¨ Orebro, Sweden

Ole K. Bonderup Section of Gastroenterology, Diagnostic Centre University Research Clinic for Innovative Patient Pathways Silkeborg Regional Hospital Silkeborg, Denmark




Michel Boucher

Massimo Colombo

HTA Development, Canadian Agency for Drugs and Technologies in Health (CADTH) Ottawa, ON, Canada

Center for Translational Research in Hepatology Humanitas Clinical and Research Center Rozzano, Italy

Marie Boyle

Brian R. Davidson

Institute of Cellular Medicine, Newcastle University & Freeman Hospital Liver Unit Newcastle upon Tyne, UK

Royal Free Campus, University College London Royal Free Hospital London, UK

Elisa Brauns Department of Gastroenterology and Hepato-Pancreatology, C.U.B. Erasme Universite´ Libre de Bruxelles Brussels, Belgium

Mary D. Cannon Institute of Liver Studies King’s College Hospital London, UK

Laurent Castera ´ ˆ ˆ Service d’Hepatologie, Hopital Beaujon, Assistance Publique-Hopitaux de Paris Clichy, France

Francis K.L. Chan Department of Medicine & Therapeutics, Prince of Wales Hospital The Chinese University of Hong Kong Hong Kong

Meihuan Chang Division of Cancer Surgery Peter MacCallum Cancer Centre Melbourne, VIC, Australia

Evan S. Dellon Center for Esophageal Diseases and Swallowing, and Center for Gastrointestinal Biology and Disease Division of Gastroenterology and Hepatology; Department of Medicine University of North Carolina School of Medicine Chapel Hill, NC, USA

Radha K. Dhiman Department of Hepatology Postgraduate Institute of Medical Education and Research Chandigarh, India

Catherine Dube´ Department of Medicine Division of Gastroenterology University of Ottawa Ottawa, ON, Canada

Kerry B. Dunbar Esophageal Diseases Center Division of Gastroenterology and Hepatology Department of Medicine Dallas VA Medical Center and University of Texas Southwestern Medical Center Dallas, TX, USA

Naoki Chiba Division of Gastroenterology McMaster University Hamilton, ON, Canada

Alexa Childs Department of Oncology, UCL Medical School Royal Free Campus UCL Cancer Institute London, UK

Audrey Coilly ´ ˆ Centre Hepato-Biliaire, AP-HP Hopital Paul Brousse Inserm, Unite´ 1193 Univ Paris-Sud, UMR-S 1193 Universite´ Paris-Saclay Hepatinov Villejuif, France

Franc¸ois Durand Hepatology & Liver Intensive Care University Paris Diderot, Hospital Beaujon Clichy, France

Geoffrey Dusheiko University College London Medical School Institute of Liver Studies King’s College Hospital London, UK

Laure Elkrief Transplantation and Hepatogastroenterology Units Geneva University Hospitals Geneva, Switzerland

Adam S. Faye Paul Collins Royal Liverpool University Hospital Prescot Street Liverpool, UK

Department of Medicine Columbia University Medical Center New York City, NY, USA


Brian G. Feagan

Kurinchi S. Gurusamy

Division of Gastroenterology, Department of Medicine Robarts Clinical Trials Department of Biostatistics and Epidemiology University of Western Ontario London, ON, Canada

Royal Free Campus, University College London Royal Free Hospital London, UK

´ Javier Fernandez Liver Unit, Hospital Clinic Barcelona IDIBAPS University of Barcelona CIBEREHED EASL-CLIF Consortium-Efclif Barcelona, Spain


Thierry Gustot Department of Gastroenterology and Hepato-Pancreatology, C.U.B. Erasme Laboratory of Experimental Gastroenterology Universite´ Libre de Bruxelles Brussels, Belgium; Inserm Unite´ 1149, Centre de Recherche sur l’inflammation (CRI) Paris, France

C. Prakash Gyawali ´ Fernando Fernandez-Ba˜ nares Department of Gastroenterology ´ Centro de Investigaciones Biomedicas en Red de Enfermedades ´ Hepaticas y Digestivas Hospital Universitari Mutua Terrassa Barcelona, Spain

Alexander C. Ford Leeds Institute of Medical Research at St. James’s University of Leeds Leeds Gastroenterology Institute St. James’s University Hospital Leeds, UK

Claire Francoz Hepatology & Liver Intensive Care University Paris Diderot, Hospital Beaujon Clichy, France

Mathurin Fumery Amiens-Picardie University Hospital Amiens, France

Division of Gastroenterology Washington University School of Medicine St. Louis, MO, USA

Alexander G. Heriot Division of Cancer Surgery Peter MacCallum Cancer Centre Melbourne, VIC, Australia

Gideon M. Hirschfield National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Centre (BRC), Institute of Immunology and Immunotherapy University of Birmingham Birmingham, UK Toronto Centre for Liver Disease University Health Network and Department of Medicine University of Toronto Toronto, ON, Canada

Brian J. Hogan Critical Care and Hepatology King’s College Hospital NHS Foundation Trust London, UK

Giuseppe K. Fusai UCL Institute for Liver and Digestive Health Royal Free Hospital Campus London, UK

Upkar Gill Barts Liver Centre Blizard Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London London, UK

Massimo Iavarone C.R.C. “A.M. & A. Migliavacca Center for Liver Disease” Division of Gastroenterology and Hepatology, University of Milan Fondazione IRCCS Ca’ Granda Maggiore Hospital Milan, Italy

Vipul Jairath Department of Medicine; Division of Epidemiology and Biostatistics Western University London, ON, Canada

Robert D. Goldin

Gary P. Jeffrey

Division of Integrative Systems Medicine and Digestive Disease Department of Surgery and Cancer Faculty of Medicine Imperial College London Department of Histopathology St. Mary’s Hospital Imperial College Healthcare NHS Trust London, UK

Western Australia Liver Transplantation Service, Sir Charles Gairdner Hospital Nedlands, Australia



Emilie Jolicoeur

Naveenta Kumar

Department of Gastroenterology, Montfort Hospital Ottawa, ON, Canada

Department of Medicine, Feinberg School of Medicine Northwestern University Chicago, IL, USA

Department of Hepatology St Mary’s Hospital Imperial College Healthcare NHS Trust Division of Integrative Systems Medicine and Digestive Disease Department of Surgery and Cancer Faculty of Medicine Imperial College London London, UK

Tom H. Karlsen

Moe H. Kyaw

Norwegian PSC Research Center Division of Cancer Medicine, Surgery and Transplantation Department of Transplantation Medicine Oslo University Hospital Rikshospitalet, Oslo, Norway

Department of Medicine & Therapeutics, Prince of Wales Hospital The Chinese University of Hong Kong Hong Kong

Peter J. Kahrilas

Claire Kelly Departments of Medicine and Surgery Division of Digestive Diseases and Transplant and Immunology Yale University New Haven, CT, USA

Patrick Kennedy Barts Liver Centre Blizard Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London London, UK

Peter L. Labib UCL Institute for Liver and Digestive Health Royal Free Hospital Campus London, UK

Gabriel Lang Division of Gastroenterology Washington University School of Medicine St. Louis, MO, USA

Bret A. Lashner Cleveland Clinic Cleveland, OH, USA

Arthur N. Lau Reena Khanna Division of Gastroenterology, Department of Medicine Robarts Clinical Trials University of Western Ontario London, ON, Canada

J.J. King Sheila Sherlock Liver Centre The Royal Free Hospital London, UK

Apostolos Koffas Gastroenterology Unit University Hospital of Larisa Larisa, Greece

Martha M. Kirstein Department of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Hannover, Germany

Eleni Koukoulioti Section of Hepatology, Clinic for Gastroenterology and Rheumatology Department of Internal Medicine, Neurology, and Dermatology University Hospital Leipzig Leipzig, Germany

Department of Medicine McMaster University Hamilton, ON, Canada

Benjamin Lebwohl Department of Medicine Columbia University Medical Center New York City, NY, USA

Damien Leith Royal Free Hospital London, UK

Barrett G. Levesque Department of Veterans Affairs San Diego Healthcare System Division of Gastroenterology San Diego, CA, USA

M. Isabel Lucena ´ Cl´ınica de Aparato Digestivo, Servicio de Unidad de Gestion Farmacolog´ıa Cl´ınica ´ Biomedica ´ ´ Instituto de Investigacion de Malaga-IBIMA, Hospital ´ Universitario Virgen de la Victoria, Universidad de Malaga, CIBERehd ´ Malaga, Spain



Jane Macnaughtan

Nambi Ndugga

Institute for Liver and Digestive Health University College London London, UK

Division of Gastroenterology and Hepatology, Department of Medicine and Nutrition University of North Carolina at Chapel Hill Chapel Hill, NC, USA

Pinelopi Manousou Department of Hepatology St Mary’s Hospital Imperial College Healthcare NHS Trust Division of Integrative Systems Medicine and Digestive Disease Department of Surgery and Cancer Faculty of Medicine Imperial College London London, UK

Anh D. Nguyen

Michael P. Manns

Kathryn Oakland

Department of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Hannover, Germany

NHS Blood and Transplant Oxford, UK

John W.D. McDonald

Esophageal Diseases Center Division of Gastroenterology and Hepatology Department of Medicine Dallas VA Medical Center and University of Texas Southwestern Medical Center Dallas, TX, USA

Darrell S. Pardi

Robarts Clinical Trials, Robarts Research Unit University of Western Ontario London, ON, Canada

Inflammatory Bowel Disease Clinic Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester, MN, USA

Lynne V. McFarland

Stephen P. Pereira

Department of Medicinal Chemistry, School of Pharmacy University of Washington Seattle, WA, USA

UCL Institute for Liver and Digestive Health Royal Free Hospital Campus London, UK

Tim Meyer Department of Oncology, UCL Medical School Royal Free Campus UCL Cancer Institute London, UK

Rajeshwar P. Mookerjee Institute for Liver and Digestive Disease Health University College London Royal Free Hospital London, UK

´ Moreno Asuncion Infectious Disease Department Hospital Clinic Barcelona IDIBAPS University of Barcelona Barcelona, Spain

Katherine Muir University of Toronto Toronto, ON, Canada

Benjamin H. Mullish Department of Hepatology St Mary’s Hospital Imperial College Healthcare NHS Trust Division of Integrative Systems Medicine and Digestive Disease Department of Surgery and Cancer Faculty of Medicine Imperial College London London, UK

Salvatore Piano Unit of Internal Medicine and Hepatology, Department of Medicine University of Padova Padova, Italy

Jennifer Price Intensive Care Unit Royal Free Hospital London, UK

Linda Rabeneck University of Toronto Cancer Care Ontario Toronto, ON, Canada

Sahaj Rathi Department of Hepatology Postgraduate Institute of Medical Education and Research Chandigarh, India

Craig C. Reed Center for Esophageal Diseases and Swallowing, and Center for Gastrointestinal Biology and Disease Division of Gastroenterology and Hepatology; Department of Medicine University of North Carolina School of Medicine Chapel Hill, NC, USA



Bruno Roche

Camilla Stephens

´ ˆ Centre Hepato-Biliaire, AP-HP Hopital Paul Brousse Inserm, Unite´ 1193 Univ Paris-Sud, UMR-S 1193 Universite´ Paris-Saclay Hepatinov Villejuif, France

´ Cl´ınica de Aparato Digestivo, Servicio de Unidad de Gestion Farmacolog´ıa Cl´ınica ´ Biomedica ´ ´ Instituto de Investigacion de Malaga-IBIMA, ´ Hospital Universitario Virgen de la Victoria, Universidad de Malaga, CIBERehd ´ Malaga, Spain

Sabine Roman

Christina M. Surawicz

Digestive Physiology Hospices Civils de Lyon and Lyon I University Lyon, France

Division of Gastroenterology, Department of Medicine University of Washington School of Medicine Seattle, WA, USA

Alaa Rostom

Marta Tonon

Forzani & MacPhail Colon Cancer Screening Centre University of Calgary Calgary, AB, Canada

Unit of Internal Medicine and Hepatology, Department of Medicine University of Padova Padova, Italy

Didier Samuel

David R. Tribble

´ ˆ Centre Hepato-Biliaire, AP-HP Hopital Paul Brousse Inserm, Unite´ 1193 Univ Paris-Sud, UMR-S 1193 Universite´ Paris-Saclay Hepatinov Villejuif, France

Infectious Disease Clinical Research Program, Department of Preventive Medicine and Biostatistics Uniformed Services University of the Health Sciences Bethesda, MD, USA

Palak J. Trivedi

Division of Gastroenterology, Inflammatory Bowel Disease Center University of California San Diego and UC San Diego Health System La Jolla, CA, USA

National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Centre (BRC), Institute of Immunology and Immunotherapy University of Birmingham Birmingham, UK

Michael L. Schilsky

Peter Tugwell

Departments of Medicine and Surgery Division of Digestive Diseases and Transplant and Immunology Yale University New Haven, CT, USA

Department of Epidemiology and Community Medicine University of Ottawa and Ottawa Hospital Research Institute Ottawa, ON, Canada

William J. Sandborn

Dominique Valla Joseph H. Sellin Section of Gastroenterology and Hepatology, Baylor College of Medicine Houston, TX, USA

´ ˆ DHU UNITY, Service d’Hepatologie, Hopital Beaujon, APHP, Clichy CRI-UMR1149 Inserm and Universite´ Paris Diderot Paris, France

Sander Veldhuyzen van Zanten Siddharth Singh Division of Gastroenterology, Inflammatory Bowel Disease Center University of California San Diego and UC San Diego Health System La Jolla, CA, USA

Division of Gastroenterology, Department of Medicine University of Alberta Edmonton, AB, Canada

Meritxell Ventura-Cots Stuart J. Spechler Center for Esophageal Diseases Research Baylor Scott and White Research Institute Baylor University Medical Center Dallas, TX, USA

Division of Gastroenterology and Hepatology, Department of Medicine and Nutrition University of North Carolina at Chapel Hill Chapel Hill, NC, USA


Mette Vesterhus

Alastair J.M. Watson

Department of Medicine Haraldsplass Deaconess Hospital, Bergen, Norway Norwegian PSC Research Center Division of Cancer Medicine, Surgery and Transplantation Department of Transplantation Medicine Oslo University Hospital Rikshospitalet, Oslo, Norway

Norwich Medical School University of East Anglia Bob Champion Building Norwich, Norfolk, UK

Stephen M. Vindigni Division of Gastroenterology, Department of Medicine University of Washington School of Medicine Seattle, WA, USA

Arndt Vogel Department of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Hannover, Germany

George Wells Department of Epidemiology and Community Medicine and Cardiovascular Research Methods Centre University of Ottawa Ottawa, ON, Canada

R.H. Westbrook Sheila Sherlock Liver Centre The Royal Free Hospital London, UK



Over the past four decades the emergence of evidence-based medicine (EBM) has had a substantial impact on clinical practice. In the first half of the twentieth century, diagnostic tests or treatments, usually based on a strong scientific rationale and experimental work in animals, were routinely introduced into clinical care without good scientific proof of efficacy in people. Some of these interventions, such as gastric freezing for the treatment of ulcers and penicillamine therapy for primary biliary cirrhosis, were ultimately shown to be ineffective and harmful [1, 2]. Fortunately, the need for a more critical approach to medical practice was recognized. In 1948, the first randomized controlled trial (RCT) in humans was carried out under the direction of the British Medical Research Council [3]. Epidemiologists and statisticians, notably Sir Richard Doll and Sir Bradford Hill, provided scientific leadership to the medical community, which responded with improvements in the quality of clinical research. The use of randomized allocation to control for confounding variables and to minimize bias was recognized as invaluable for conducting valid studies of treatments. The RCT soon became the benchmark for the evaluation of medical and surgical interventions. In 1955, Professor Sidney Truelove conducted the first randomized trial in the discipline of gastroenterology [4], proving that cortisone was more effective than a placebo for the treatment of ulcerative colitis. Gastroenterologists, hepatologists, and general surgeons are fortunate to have many excellent textbooks that provide a wealth of information regarding digestive diseases. Many traditional textbooks concentrate on the pathophysiology of

disease and are comprehensive in their scope. Evidence-Based Gastroenterology and Hepatology is not intended to replace these texts, since its focus is on clinical evidence. Excellent electronic databases are available, and many traditional publications contain relevant research evidence and important summaries and reviews to support evidence-based practice. However, physicians in clinical practice find that locating relevant articles and analyzing relevant data from these sources is very time consuming. This book has been written for the purpose of saving valuable time for busy practitioners of gastroenterology and hepatology, and for general internists and general surgeons who deal with substantial numbers of patients with disorders ranging from gastroesophageal reflux disease to liver transplantation. Authors have endeavored to provide the most recent evidence as the basis for recommendations. The introduction to the third edition of this book presented detailed examples of the analysis of evidence for decision-making regarding causation, diagnosis, prognosis, and therapy. This chapter has been made available online at https://media.wiley.com/product_data/excerpt/31/ 14051819/1405181931.pdf and can be accessed by students and practitioners who would like to review this detailed and comprehensive discussion. However, the principles of EBM are now widely taught and accepted, reducing the need for this kind of detail in the introductory chapter. Instead, we wish to use this space to recognize the extremely important contributions made by two physicians to the development of this book, both of whom have died since the last edition was published, Dr. David Sackett and Professor Andrew Burroughs.



Gastrointestinal disorders



Gastroesophageal reflux disease Sabine Roman1 and Peter J. Kahrilas2 1 Digestive

Physiology, Hospices Civils de Lyon and Lyon I University, Lyon, France of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

2 Department

Introduction Gastroesophageal reflux disease (GERD) is a “condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications” [1]. It is frequently encountered in clinical practice; in 2004, GERD accounted for about 18 million ambulatory care visits or 17% of all digestive disease encounters in the United States of America [2]. Although a variety of symptoms might be associated with GERD, none are pathognomonic. However, in cases presenting with the typical GERD symptoms of heartburn and regurgitation and without “alarm symptoms” of bleeding, dysphagia, or weight loss, it is common practice to treat GERD without investigation.

Definition of GERD Gastroesophageal reflux (GER) is a physiological event that commonly occurs during and after meals. Such physiological reflux episodes are rapidly cleared by esophageal peristalsis and the residual acidity neutralized by the bicarbonate in swallowed saliva. Physiologic GER is generally asymptomatic [3]. GER becomes pathological when reflux episodes are frequent, occur outside of the postprandial period, and induce typical (heartburn, regurgitation) or atypical symptoms (dysphagia, chest pain, cough, etc.) of sufficient magnitude that they become “troublesome” to the individual. It is difficult to precisely demarcate the transition between physiological GER and GERD based on symptom frequency or intensity, but the “troublesome” threshold was adopted to imply a decrement in quality of life [1]. Having some degree of heartburn is considered normal. Moreover, only a small proportion of patients with GERD seek medical care for the condition [4]. According to the Montreal definition, GERD can also be defined by syndromes characterized by esophageal injury, including reflux esophagitis, Barrett’s esophagus, peptic stricture, or adenocarcinoma [1]. This umbrella definition was

devised to encompass the broad spectrum of GERD inclusive of both erosive reflux disease (endoscopically defined esophagitis and complications thereof), nonerosive reflux disease (NERD) (patients with troublesome esophageal GERD symptoms, but without esophagitis on endoscopy), and patients with extra-esophageal manifestations of GERD such as laryngitis or cough.

Clinical presentation The typical symptoms of GERD are heartburn (a burning sensation arising behind the breastbone toward the neck) and regurgitation (experienced as refluxed fluid moving in the chest or a bitter taste in the mouth). However, even these typical symptoms are not specific for GERD as demonstrated by the Diamond study, which evaluated the accuracy of the reflux disease questionnaire (RDQ) for the diagnosis of GERD. The RDQ utilizes six items to score the occurrence and frequency of heartburn, regurgitation, and dyspepsia. In a cohort of 308 patients with troublesome upper gastrointestinal symptoms, the sensitivity and specificity of the RDQ to diagnose GERD were 62% and 67%, respectively, when using the findings from endoscopy and wireless pH-metry as the reference standard [5]. Atypical GERD symptoms can be esophageal or extraesophageal. Dysphagia is experienced by one-third of GERD patients [6]. This “warning sign” should lead to upper GI endoscopy with esophageal biopsies to evaluate for esophagitis, tumor, stricture, and eosinophilic esophagitis. Chest pain may also be attributed to GERD in up to 50% of patients [7]. However, due to the potential life-threatening nature of cardiac disease, a cardiac evaluation should be prioritized in such patients before accepting an esophageal etiology. GERD is an etiology of chronic cough and estimates of the prevalence of GERD-associated cough range from 0% to 41% of chronic cough cases [8]. Half of asthma patients have evidence of GERD [9]. A variety of ear nose and throat (ENT) symptoms have been attributed to reflux: dysphonia, globus

Evidence-Based Gastroenterology and Hepatology, Fourth Edition. Edited by John W. D. McDonald, Brian G. Feagan, Rajiv Jalan, and Peter J. Kahrilas. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd.



Part I: Gastrointestinal disorders

sensation (perception of a lump or fullness in the throat, irrespective of swallowing), throat clearing, sore throat, chronic laryngitis, and laryngospasm. However, controversy persists regarding diagnostic criteria for these “laryngopharyngeal reflux” syndromes, especially between gastroenterologists and ENT physicians [10]. Gastrointestinal symptom scales were recently developed using the National Institutes of Health (NIH) PatientReported Outcomes Measurement Information System (PROMIS® ) [11]. These scales are intended for use in clinical care and research. Items were determined based on literature searches and administered to patients with gastrointestinal conditions and to the general population. The GER domain items assess: (i) sensations associated with food intake (reflux, regurgitation) or not associated with food intake (lump in the throat); (ii) painful sensations (heartburn, chest pain, throat burn); and (iii) belching, gas (burping), and hiccups. Symptoms occurring during the past seven days are scored.

Epidemiology Since the criteria used to define GERD in epidemiological studies differ from the Montreal definition, it is difficult to know the actual prevalence of GERD in the general population. However, based on self-reporting of at least weekly heartburn and/or regurgitation estimates of the prevalence of GERD range from 9% to 33% (Table 1.1) [12]. The pitfalls of GERD prevalence estimates were well elucidated by the Diamond study, conducted in primary care practices in Europe and Canada [5]. Three hundred and eight patients with upper GI symptoms underwent a systematic evaluation with endoscopy, esophageal pH monitoring, structured interviews, questionnaires, and a trial of proton pump inhibitor (PPI) medication. Among these patients, 38% were found to have esophagitis, 28% had abnormal esophageal pH-metry, and 49% identified heartburn or regurgitation as their most bothersome symptom. Response to two-week PPI treatment did not clarify these discrepancies. Even though a beneficial PPI response was more Table 1.1 GERD prevalence worldwide Geographic location

Estimates of GERD prevalence based on self-reporting heartburn and/or regurgitation

USA Europe South America Middle East East Asia Australia Source: Adapted from El-Serag et al. 2014 [12].

18–28% 9–26% 23% 9–33% 3–8% 12%

frequent in patients with esophagitis (69%) and in patients with normal endoscopy and abnormal esophageal pH-metry (49%), 35% of patients with normal examinations also had symptom improvement [13]. Major risk factors associated with GERD are age, pregnancy, and obesity. The incidence of GERD increases with age [14]. Half to two-thirds of pregnant women report GERD symptoms [15]. In Western countries, the increased prevalence of GERD has occurred in parallel with increased obesity, evident by an increased prevalence in both obese (body-mass index (BMI) > 30 kg/m2 ) and overweight (BMI 25–30 kg/m2 ) patients [16]. GERD is also associated with other disease entities including diabetes mellitus [17] and pulmonary disease. Chronic pulmonary diseases and asthma were associated with new GERD diagnoses in a study utilizing the UK General Practice Research Database [14]. Impaired esophageal function is encountered in 80% of scleroderma patients and this frequently leads to GERD symptoms [18]. Esophagitis was observed in 42% of patients with Zollinger–Ellison syndrome, which promotes GERD by increasing the acidity and quantity of gastric acid in the refluxate [19].

Pathophysiology During physiological reflux, gastric content enters the distal esophagus and is then rapidly cleared by peristalsis. Physiological reflux occurs almost entirely by transient lower esophageal sphincter relaxation (TLESR), which is a complex vago-vagal reflex involving non-deglutitive lower esophageal sphincter (LES) relaxation [20], crural diaphragm inhibition, and distal esophageal shortening. TLESRs are triggered by gastric distension with food, liquid or gas and are the physiological mechanism of belching. Only a fraction of TLESRs are associated with acid reflux and that fraction is greater in GERD patients than in controls [21]. Another differentiating feature of GERD patients is that reflux can occur by mechanisms other than TLESR. This is especially true in patients with hiatus hernia, a situation in which the LES and the crural diaphragm (CD) are spatially separated. Normally, these elements act in concert as the antireflux barrier at the esophagogastric junction (EGJ), but their spatial separation, be that intermittent or constant, facilitates the occurrence of reflux [22]. Hiatus hernia also predisposes to swallow-induced reflux and straininduced reflux, especially when associated with a hypotensive LES [23]. Yet another impairment associated with hiatus hernia is of prolonged acid clearance as gastric juice within the hernia refluxes back and forth across the LES with swallows while subjects are in a recumbent posture [23]. Not surprising, hiatus hernia is observed in up to 70% of patients with esophagitis, more so with increasing severity of the esophagitis [24]. Finally, hiatus hernia interacts with the acid pocket, the newly secreted acid that layers on the top of

Chapter 1: Gastroesophageal reflux disease

gastric content in the postprandial period, serving as the reservoir for postprandial acid reflux. With hiatus hernia, the acid pocket is displaced proximally into the hernia compartment, greatly facilitating its access to the distal esophageal mucosa [25]. Although the dominant mechanism of prolonged acid clearance, and consequently prolonged esophageal acid exposure time, in GERD patients is hiatus hernia, clearance is also compromised by weak, or even absent, peristalsis [26]. Peristalsis, primary or secondary, clears the refluxed fluid back to the stomach and ineffective esophageal motility is associated with impaired esophageal clearance [27]. The final step in acid clearance after a reflux event is neutralization of residual acid by swallowed saliva [28]. Hence, hyposalivation, as occurs with many medications, certain collagen vascular diseases, and during sleep can prolong the process of acid clearance and thereby exacerbate the severity of GERD [29, 30]. There is also interplay between the efficacy of gastric emptying and GERD, which is a frequent accompaniment of gastroparesis. However, the relationship is less clear with marginal abnormalities of gastric emptying. In a series of 30 patients referred for both a gastric emptying study and esophageal pH-impedance monitoring, delayed gastric emptying was associated with an increased number of postprandial reflux episodes, but no significant difference in acid esophageal exposure [31]. On the other hand, accelerating gastric emptying with the 5-HT4 receptor agonist prucalopride reportedly decreased esophageal exposure time, but had no effect on the number of reflux episodes in 21 healthy controls [32]. Although the severity of esophagitis correlates with the extent of esophageal acid exposure as determined by pH monitoring studies, the same relationship does not hold for reflux symptom severity. Only 20–40% of patients with GERD symptoms have erosive reflux disease defined by esophageal mucosal breaks [33, 34] and pathological reflux on esophageal pH-metry is reportedly found in only 21–61% of NERD patients [35, 36]. Hence, the determinants of symptom severity are somewhat distinct from those of mucosal erosion. Mucosal injury is facilitated by prolonged exposure to refluxed acid, pepsin, and bile acids. Symptoms, on the other hand, are strongly modulated by sensitivity. Only about 10% of reflux episodes are symptomatic [37], and patients with pathological GERD are more sensitive to acid and esophageal distension than are control subjects [38]. Reflux episodes during which the refluxate reaches the proximal esophagus, which are more common among GERD patients, are also more likely to be symptomatic, and recent physiological data suggest that the proximal esophagus is more sensitive to reflux than is the distal esophagus [39]. Finally, the phenomena of hypersensitivity and hypervigilance are increasingly recognized as major determinants of symptom severity among subsets of NERD patients [40].


Natural history and complications GERD can present as erosive reflux disease with esophageal mucosal breaks on endoscopy or as NERD, in which case there are symptoms attributable to GERD without endoscopically evident disease. NERD is the dominant form, encountered in about 70% overall [41]. Potential complications of GERD include bleeding, esophageal stricture, Barrett’s esophagus, and esophageal adenocarcinoma. Barrett’s esophagus is defined as the replacement of normal squamous esophageal mucosa with columnar epithelium found to contain intestinal metaplasia on histopathology. Barrett’s esophagus is the major risk factor for the development of esophageal adenocarcinoma (see Chapter 2). Only a few studies have examined the natural history of GERD. Both progression from NERD and regression from erosive disease have been observed. Illustrative of this are data from a large multicenter study of 6215 patients conducted in Germany, Austria, and Switzerland reporting progression, regression and stability of GERD within that population [42]. Among 2721 patients who completed the five-year follow up, most remained stable or improved with routine clinical care. Among patients with severe esophagitis at baseline, 61% had NERD at five years. On the other hand, disease progression was observed in 6% of NERD patients, 12% of patients with grade A/B esophagitis, and 19% of patients with grade C/D. In a recent comprehensive review, Savarino reported progression from NERD to erosive disease in 0–30% of patients, progression from mild to severe esophagitis in 10–22%, and progression from erosive disease to Barrett’s esophagus in 1–13% [41]. While GERD does not decrease life expectancy [14], it does impair quality of life. In the Kalixanda study, daily symptoms were associated with a greater decrement in quality of life than were less frequent symptoms [43]. Interestingly, esophagitis did not significantly alter quality of life in that study. GERD is also responsible for absenteeism and up to 30% of patients with heartburn reported reduced productivity at work, especially those with nocturnal symptoms [44].

Diagnostic tests GERD is usually a clinical diagnosis based on a symptom assessment. Testing is reserved for cases in which there are warning signs of complication, atypical symptoms such that the diagnosis is in doubt, an inadequate response to medical treatment, or as a preoperative evaluation to confirm the diagnosis prior to surgical treatment. Hence, the diagnostic approach utilized varies greatly depending on a symptom assessment, an assessment of the risk that complications exist, the history and success of treatment trials, whether or not a potentially morbid therapy is under consideration, and the history of prior testing. As a general rule, the extent of diagnostic testing pursued should be limited to that which


Part I: Gastrointestinal disorders

guides management decisions and/or protects the patient from risk.

Symptom assessment and questionnaires The occurrence of typical heartburn and/or acid regurgitation in a patient without signs of potential complications (dysphagia, odynophagia, weight loss, bleeding, or anemia) is sufficient to diagnose GERD and initiate therapy. Standardized questionnaires have been developed to aid in the clinical diagnosis of GERD. These were devised to facilitate screening patients for GERD in primary care settings and to provide a standardized evaluation. In a recent review, Bolier et al. identified 39 questionnaires to assess GERD symptoms, 14 to assess response to treatment, and 18 to assess GERDrelated quality of life [45]. The RDQ is the most widely used, consisting of six items that assess the frequency and severity of heartburn, regurgitation, and dyspepsia. Alternatively, the GerdQ questionnaire includes six items (heartburn and regurgitation frequencies, stomach pain, nausea, nocturnal symptoms, and requirement of additional medication) and was also translated in multiple languages. The accuracy of these questionnaires in diagnosing GERD varies with what is being used as the reference standard. If the comparison is with the diagnoses rendered by an experienced clinician [5], the correspondence is very good; if the comparison is to physiological testing and endoscopy, the sensitivity and specificity are only about 65% [46]. PPI trial The high prevalence of GERD and the impressive therapeutic efficacy of PPIs led some authors to propose using a PPI trial to diagnose GERD. However, as evident from the findings of the Diamond study, responsiveness to PPI therapy, abnormal pH-metry, and symptom-based assessments each detect unique patient populations, which only partially overlap. Illustrative of this, a positive PPI trial was observed in 69% of patients meeting pH-metry and/or endoscopic criteria of GERD in the Diamond study and in 51% of patients not meeting these criteria [13]. Similar findings were reported in a meta-analysis of 15 studies using many variations of the “PPI test.” With 24-hour pH-metry as the reference standard, the positive likelihood ratio of the PPI trial for predicting GERD ranged from only 1.63 to 1.87 [47]. The imperfect overlap between patient populations defined by physiologic testing and response to a PPI trial does not negate the practicality and cost-effectiveness of empiric therapy. Fass et al. reported that, although a protocol of omeprazole 60 mg daily had relatively poor test characteristics for detecting physiologically defined GERD (sensitivity 80%, specificity of 57%), this protocol saved an average of US $348 per patient with a 64% reduction in the number of upper GI endoscopies and 53% reduction in the use of pH-monitoring [48]. However, empiric PPI therapy also has its limitations.

A positive response may be attributable to a placebo effect or the presence of an alternative acid-peptic disorder, while a negative response may occur in truly PPI-refractory GERD. Other considerations are the potential to mask malignancies and to foster inappropriate long-term PPI use, which has clinical and economic implications. In summary, empiric PPI therapy is a simple and cost-effective way to manage typical reflux symptoms in patients without warning signs, but the effectiveness of the therapy does not equate to a diagnosis of GERD.

Upper GI endoscopy Upper GI endoscopy is the best test for detecting GERD complications and for excluding alternative diagnoses such as malignancy, eosinophilic esophagitis, or peptic ulcer. With respect to establishing a GERD diagnosis, the minimal endoscopic lesion with acceptable inter-observer agreement (kappa 0.4) is a mucosal break, the basis for the Los Angeles classification. Grades A–D of the LA classification are illustrated in Figure 1.1 [49]. The severity of esophageal acid exposure is significantly related to the LA grade of esophagitis, but it is important to note that mild esophagitis (grade A) was found in 5% of asymptomatic controls [34] leading some to question the significance of this finding. Among 280 075 upper GI endoscopies performed between 2000 and 2005 in the Clinical Outcomes Research Initiative (CORI) database, esophagitis was found in 17.3%, esophageal stricture in 9.5%, and Barrett’s esophagus in 4.5% [50]. Esophagitis was graded according to the LA classification in fewer than 50% of endoscopies; when documented, esophagitis was grade A or B in 79% of patients. Upper GI endoscopy might also be useful to detect hiatus hernia. However, estimates of the prevalence of hiatus hernia in the adult population vary enormously from 10% to 80% [51] likely due to subjectivity of diagnostic criteria. In the CORI database, hiatal hernia was observed in 33% of upper GI endoscopies and in 40–45% of patients undergoing endoscopy for reflux symptoms [50]. Thus, even though relevant to a GERD diagnosis, the presence of hiatal hernia is not sufficient to establish that diagnosis. Histologic examination of distal esophageal mucosal biopsies might increase the diagnostic yield of endoscopy for GERD. Microscopic esophagitis was observed in 65% of NERD patients, but also 15% of controls [52]. Kandulski et al. proposed a histological score combining degree of basal cell hyperplasia, presence of papillary elongation, dilated intercellular spaces and inflammation. A score ≥5 had a sensitivity of 85% and a specificity of 64% to differentiate NERD from functional heartburn [53]. In summary, endoscopy is an important test to detect complications of GERD and for excluding alternative diagnoses that might explain a patient’s symptoms. However, its sensitivity for diagnosing GERD is poor.

Chapter 1: Gastroesophageal reflux disease


Figure 1.1 Los Angeles Classification. Grade A is defined as one (or more) mucosal break no longer than 5 mm that does not extend between the tops of two mucosal folds. Grade B is defined as one (or more) mucosal break longer than 5 mm that does not extend between the tops of two mucosal folds. Grade C is defined as one (or more) mucosal break that is continuous between the tops of two or more mucosal folds but which involves less than 75% of the circumference. Grade D is defined as one (or more) mucosal break which involves at least 75% of the esophageal circumference.

Ambulatory GERD testing: pH and pH-impedance monitoring Ambulatory reflux monitoring can detect pathological reflux in patients without endoscopic esophagitis. Conventional (or wireless) pH-metry detects reflux events on the basis of their acidity, while pH-metry combined with impedance detects all

liquid and/or gas reflux. Both methods can be used to correlate reflux events with patient-reported symptoms, albeit in the case of pH-metry this analysis is restricted to acid reflux events. Ambulatory pH-metry studies are done positioning the pH electrode 5 cm above the proximal margin of the LES or, in


Part I: Gastrointestinal disorders

the case of wireless monitoring, 6 cm above the squamocolumnar junction. Esophageal acid exposure is defined as the percentage of the recording time with esophageal pH < 4; the threshold that is most discriminative in differentiating physiological and pathological reflux [54]. Reported upper limits of normal for esophageal acid exposure with catheterbased systems range from 3.9% to 7.2% and for the wireless system from 4.4% to 5.3% [55–57]. The sensitivity and specificity of pH-metry for differentiating control subjects from esophagitis patients are 77–100% and 85–100%, respectively [58–61]. Advantages of wireless pH-metry over catheterbased studies are of improved tolerability and studies that can be prolonged for up to 96 hours, thereby improving the yield for detecting abnormal reflux. Illustrative of this, among 38 patients with normal acid exposure on catheter pH-metry, pathological acid exposure was detected in up to 47% of patients using the wireless technology [62]. Compared to pH-metry, pH-impedance monitoring characterizes reflux not only by its acidity, but also by its gas/liquid content, its direction of flow, and the proximal extent to which it flows into the esophagus. These are all factors potentially relevant to symptom perception, especially in patients taking acid suppressive medication [63]. As with catheter-based pH-metry, the pH-impedance probe is passed transnasally into the esophagus and connected to an external receiver. Combined pH-impedance studies are analyzed both for esophageal acid exposure time and for the number of reflux events, acid or otherwise, with the upper limit of normal reported as ranging from 54 to 75 per 24 hours [64, 65]. When the study is performed withholding PPI therapy there is a nominal increased yield relative to pHmetry alone reported to range from 6% to 11%, attributable to weakly acidic reflux events that correlate with reported symptoms [64]. However, the significance of that increased yield is unclear, given that abnormal acid exposure, but not an abnormal number of reflux episodes, correlates with medical or surgical treatment outcome [66]. Both pH-metry and pH-impedance monitoring are also used to test the relationship between reflux events and patient-reported symptoms. The two most popular indices are the symptom index (SI) and the symptom association probability (SAP). The SI is defined as the percentage of symptom events that occur within two minutes of reflux episodes, irrespective of the number of reflux episodes recorded, with a value of >50% considered positive [67]. A high SI can occur by chance, especially in a patient with numerous reflux episodes. To improve upon this, the SAP is a statistical calculation assessing the probability that the reflux and symptoms co-occur by chance; an SAP >95% is considered significant [68]. However, according to the Rome IV criteria for functional esophageal disorders, the finding of a normal esophageal acid exposure and a positive SI or SAP is now considered reflux hypersensitivity rather than GERD [69]. Consequently, although the SI and SAP may

be useful to establish a relationship between reflux events and symptoms, the most relevant outcome of reflux monitoring studies is esophageal acid exposure and the role of symptom indices in patient management is unclear. Similarly, except in unusual circumstances where the pharmacological effectiveness of PPIs is in question, reflux monitoring studies should be done withholding PPI therapy for a week prior to (and during) the study to best address the question “does my patient have pathological GERD?” [54].

Esophageal high-resolution manometry Esophageal high-resolution manometry (HRM) has no direct role in diagnosing GERD. However HRM can be useful to identify conditions that can facilitate or exacerbate reflux (hiatal hernia, hypotensive EGJ, ineffective esophageal contractions), to identify GERD mechanisms (TLESR, strain), or to diagnose conditions that can mimic GERD (rumination syndrome). Esophageal manometry is also usually performed before pH-metry or pH-impedance monitoring to localize the LES for probe positioning. Finally, manometry is required prior to antireflux surgery to verify the adequacy of peristaltic function and to rule out major motility disorders (achalasia) masquerading as GERD [70]. Barium swallow Similar to manometry, barium radiography has minimal role in the diagnosis of GERD, but can be useful to identify conditions associated with GERD (hiatal hernia) or anatomical complications that may have bearing on treatment (e.g. short esophagus, stricture, paraesophageal hernia). A recent study reported that barium swallow alone had a sensitivity of 73% to detect hiatal hernia, the same as endoscopy, while HRM had a sensitivity of 92% and a specificity of 93% [71]. Mucosal impedance Reflux injury to the esophageal mucosa makes it more permeable to ions and small molecules, which in turn alters its resting electrical impedance as can be measured during reflux monitoring studies or with a probe passed through the instrument channel of an endoscope. Recent reports suggest that measurement of esophageal mucosal impedance might be useful to diagnose GERD [72]. An Italian study proposed measuring baseline impedance during the overnight period of 24-hour pH-impedance monitoring studies reporting that a mean nocturnal baseline impedance 6 mo

Surgical intervention Mechanical ventilation Use of catheters Immunosuppression Wound infection Cholangitis, abdominal abscess Pneumonia Catheter-related infections

Immunosuppressive therapy Acute rejection Altered cellular immunity

Immunosuppressive therapy Chronic rejection Altered of cellular immunity

Pneumonia Disseminated viral infection Colitis Meningitis

Common community infections Pneumonia Skin infections

Escherichia coli Klebsiella pneumoniae Pseudomonas aeruginosa Staphylococcus aureus Coagulase negative Staphylococcus

Nocardia asteroides Listeria monocytogenes Legionella pneumophilla Mycobacterial infections


Candida spp. Aspergillus spp.


Herpes simplex virus Human herpesvirus 6

Aspergillus spp. Cryptococcus neoformans Pneumocystis jirovecii Cytomegalovirus Human herpesvirus 6 Varicella zoster virus

Streptococcus pneumoniae Haemophilus influenza Nocardia asteroides Listeria monocytogenes Legionella pneumophilla Mycobacterial infections Aspergillus spp. Pneumocystis jirovecii


Risk factors

Type of infection

Microorganisms Bacteria

abdominal abscesses due to leaks at the anastomosis site. The postoperative care may involve periods of intubation and the insertion of central venous lines or indwelling urinary catheters. These breaks in the mucocutaneous barrier place patients at increased risk for nosocomial infections including ventilator-associated pneumonia, bloodstream and urinary tract infections. Patients often receive broad-spectrum antibiotics that may contribute to the development of antimicrobial-resistant pathogens (MDR), an emergent problem worldwide associated with worse outcomes. Although the vast majority of infections are nosocomial, donor- and recipient-derived infections may also occur in this period. The intermediate posttransplantation period occurs one to six months following transplantation. During this period, most transplant recipients are at their highest net state of immunosuppression as immunosuppressive drugs exert their full effect at this time. Apart from nosocomial infections, patients can develop opportunistic infections, specially CMV infections, invasive fungal infections (IFIs), listeriosis, nocardiosis, and other viral, fungal, or parasitic infections. P. jirovecii pneumonia may present if prophylaxis is discontinued. By six months after transplantation most transplant recipients are doing well with good allograft function and low levels of immunosuppression. Infection risk at this time is similar to that observed in the general population. Nonetheless, some recipients may present late opportunistic infections.

Toxoplasma gondii

Cytomegalovirus Epstein–Barr virus Poliomavirus Varicella zoster virus Toxoplasma gondii

Epidemiology and prevention Bacterial infections Bacterial infections represent up to 70% of all posttransplant infections. The majority of them occur within the first month after transplantation. Nowadays, opportunistic infections such as nocardiosis or listeriosis are very uncommon, since all recipients receive trimethoprim-sulfamethoxazole prophylaxis for the first 6–12 months after transplantation. In contrast, especially in last years, infections caused by MDR bacteria have become a major public health problem in many countries [22]. Management of infections caused by MDR organisms is a major therapeutic challenge [7]. In transplant recipients, the incidence of infections caused by these organisms is high. In addition, MDR bacterial infection jeopardizes patient and graft survival. Infections caused by MDR gram-negative bacteria such as Pseudomonas aeruginosa and Acinetobacter spp. are relevant in intensive care-hospitalized patients. Extended-spectrum beta-lactamase- producing (ESBL) Enterobacteriae or carbapenemase-producing Enterobacteriae are increasing in the transplant population, and in some cases are responsible for up to 30% of bloodstream infections occurring in transplant recipients [23]. Staphylococcus aureus is also a relatively frequent cause of bacteremia (the sixth one) in solid organ transplant recipients [24]. The occurrence of invasive S. aureus infection after transplantation is associated with very high mortality.

Chapter 49: Liver transplantation: prevention and treatment of infection

Although the rate of methicillin resistance among S. aureus isolates has decreased in recent years in Europe and in the United States, the spectrum of methicillin-resistant S. aureus (MRSA) infection in solid organ transplant patients mainly includes bacteremia (catheter-related or primary), surgical-site infection, and pneumonia. Preventive measures should therefore be implemented to combat MDR bacteria, including infection control practices (aimed at preventing colonization) and recommendations on antibiotic prescription. European guidelines recommend hand hygiene, educational programs, contact precautions to avoid horizontal transmission of MDR organisms during hospital stay, environmental cleaning, and antimicrobial stewardship programs (i.e. short duration of antibiotic regimens to decrease antibiotic selective pressure) to reduce the spread of MDR infections in the health-care environment [25]. Tuberculosis (TB) in transplant recipients is often due to reactivation of a previous infection. It usually occurs after six months posttransplantation and classic symptoms may not be present, making its diagnosis frequently problematic. Moreover, extrapulmonary and disseminated TB occurs more frequently in transplant recipients than in normal hosts and is associated with worse prognosis [26]. All transplant candidates should undergo evaluation for latent TB infection. This includes a chest radiograph looking for old healed lesions suggestive of TB and a tuberculin skin test (TST) or interferon (IFN)-γ release assays (IGRA). Daily isoniazid for six to nine months is the standard therapy to prevent TB reactivation after liver transplantation [27]. All preventive strategies are described in Table 49.3.

Fungal infections Incidence of fungal infection in solid organ transplant recipients ranges from 2% to 40% and mortality is very high, especially in IFI [28]. Although most IFIs are due to Candida spp., the risk and severity of invasive aspergillosis

(IA) in liver transplant recipients is well-known. Risk factors of IA in liver recipients are retransplantation, need for renal replacement therapy, fulminant hepatitis, intraoperative or perioperative transfusion of 20 or more units of blood products, choledochojejunostomy, reintervention within seven days of LT, Aspergillus spp. colonization prior to transplantation, high doses of steroids, and CMV disease [29]. In high-risk patients, antifungal prophylaxis with liposomal amphotericin B, echinocandins, itraconazole, or voriconazole should be considered. However, the benefit of voriconazole or itraconazole IA prophylaxis is limited by their potential liver toxicity.

Viral infections Cytomegalovirus CMV is the most common viral infection in transplant recipients and a major source of morbidity and mortality in liver transplant recipients [30]. Infection occurs either through the reactivation of the latent virus in response to immunosuppression or through the “de novo” transmission of CMV from a seropositive donor to a seronegative recipient [31]. Without any therapy, CMV infection develops in 36–100% of solid organ transplant recipients, and symptomatic disease occurs in 11–72%, most often during the first 100 days after transplantation. Clinical sequelae of CMV infection have been divided into direct effects of viral replication (including fever, leukopenia, and thrombocytopenia with or without specific organ dysfunction) and indirect effects resulting from the influence of the virus on the host’s immune response [32]. Indirect effects include acute allograft rejection, reduced long-term graft function, and an increased risk of other opportunistic infections. Along with the common presentations of symptomatic CMV disease (viral syndrome, colitis, gastroduodenitis, and pneumonitis), CMV can also present as hepatitis after liver transplantation, an entity that is rarely observed in other solid organ recipients.

Table 49.3 Preventive strategies recommended in liver transplant recipients Microorganisms

Recommended prophylaxis


In high-risk patients (CMV-seronegative recipients/CMV-seropositive donors). Oral valganciclovir or IV ganciclovir for 3 mo Reduce immunosuppression In seronegative recipients, pretransplant vaccination is recommended Trimethoprim/sulfamethoxazole HBIG, lamivudine, or other HB antiviral therapy Daily isoniazid for 6–9 mo in latent infections Only in patients coming from endemic areas. Treatment only when positive cultures. Ivermectin Perioperative prophylaxis with IV antibiotics for 24–48 h Only in high-risk patients. Liposomal amphotericin B, echinocandins, azoles Trimethoprim/sulfamethoxazole for 6–12 mo and when increase in immunosuppression is needed Trimethoprim/sulfamethoxazole Pneumococcal vaccine pretransplantation and additional revaccination after 5 yr Yearly influenza vaccination

Epstein–Barr virus Varicella zoster virus Toxoplasma gondii Hepatitis B virus Tuberculosis Strongyloides spp. Bacterial infections Aspergillus spp. Pneumocystis jirovecii Listeria monocytogenes Streptococcus pneumoniae Influenza virus



Part II: Liver disease

Risk factors associated with CMV infection apart of mismatched donor and recipient serostatus, are the use of OKT3 anti-CD3 monoclonal antibodies, polyclonal antithymocyte antibodies, and acute fulminant hepatitis [9]. Moreover, CMV infection is a risk factor for bacterial and invasive fungal infections and accelerates hepatitis C recurrence after liver transplantation [33]. There are two strategies to prevent CMV disease after liver transplantation: antiviral prophylaxis and preemptive therapy [30]. CMV-seronegative recipients of liver allografts from CMV-seropositive donors are at the highest risk for CMV disease because of the lack of a preexisting CMV-specific immunity. In these patients, international guidelines recommend the use of prophylaxis with ganciclovir IV or oral valganciclovir for at least three months after transplantation. An alternative option is a preemptive strategy, which consists of periodical CMV surveillance by performing CMV polymerase chain reaction (PCR).

Epstein–Barr virus EBV reactivates in case of major immunosuppression. The disease commonly manifests as a mononucleosis syndrome, although in up to 1% of liver transplant recipients it causes a posttransplant lymphoproliferative disease (PTLD) [34]. This lymphoproliferative disorder of lymphocytes B can manifest as an extranodal disease or involve other organs such as liver, intestine, central nervous system, and bone marrow. The treatment of EBV is often ineffective, being key the reduction in the level of immunosuppression.

Hepatitis C virus HCV liver disease is currently the leading indication for LT. Although HCV recurrence after transplantation is universal in all patients who undergo liver transplantation with detectable HCV RNA, the rate of progression of the infection in liver recipients is higher than that in the nontransplant population [35]. In fact, chronic HCV infection leads to cirrhosis in up to 20–30% of individuals only five years after transplantation [36]. A higher progression of HCV reinfection has been associated with high levels of viral replication, HCV-specific CD4+ T responses, advanced donor age, high levels or rapid withdrawal of immunosuppression, corticosteroid boluses, coexistent liver damage from preservation/reperfusion injury, biliary stricturing, and coexistent CMV or herpes six viral infections [37]. Moreover, it has been suggested that HCV itself produces an immunosuppressive effect that could favor the development of infections. Finally, and importantly, due to new, highly effective and well-tolerated direct-acting treatments for HCV, most patients will present a sustained virological response before transplantation, which will avoid HCV recurrence. Efficacy of direct-acting treatments for HCV in the posttransplant setting seems to be also extremely high [38]. Hepatitis B virus HBV recurrence occurs in more than 80% of liver transplant recipients who have HBV before transplantation [39]. Active HBV viral replication and the presence of the HBe

Table 49.4 Drug–drug interactions between anti-infective and immunosuppressive drugs Anti-infective agent (A)

Other drug (B)


Aminoglycosides Amphotericin B Fluconazole Itraconazole

Anticalcineurinic agents Anticalcineurinic agents Anticalcineurinic agents Anticalcineurinic agents mTOR Anticalcineurinic agents mTOR Anticalcineurinic agents mTOR Cyclosporine Tacrolimus Anticalcineurinic agents Anticalcineurinic agents Corticosteroids Anticalcineurinic agents

↑ nephrotoxicity ↑ nephrotoxicity ↑ levels of B ↑ levels of B Contraindicated ↑ levels of B Contraindicated ↑ levels of B Contraindicated ↑ levels of A ↓ levels of B ↑ nephrotoxicity ↑ levels of B ↑ levels of B ↑ levels of B

Anticalcineurinic agents mTOR Anticalcineurinic agents Corticosteroids Cyclosporine Anticalcineurinic agents

↑ ↑ ↓ ↑ ↓ ↑

Posaconazole Voriconazole Caspofungin Foscarnet Macrolides Non-nucleoside reverse transcriptase inhibitors Protease inhibitors Rifamycins Sulfonamides Glycopeptides

levels of B levels of B effect of B replacement requirement of B levels of B nephrotoxicity

Chapter 49: Liver transplantation: prevention and treatment of infection


Table 49.5 Recommended treatment and duration of therapy in the main opportunistic infections occurring in LT recipients Infection Cytomegalovirus Asymptomatic infection CMV disease Toxoplasmosis

Recommended treatment

Alternative regimens


Valganciclovir 900 mg/12 h IV ganciclovir 5 mg/kg/12 h Pyrimethamine, loading dose 200 mg (100 if 20). First, Protease inhibitors are contraindicated in patients with High MELD score due to an increase in AUC and to a risk of liver toxicity. Second, some patients with high MELD treated with DAAs developed liver failure leading to death [19, 20, 29]. Third, the efficacy of DAAs is declining with the severity of cirrhosis. Will DAAs improve sufficiently liver function of listed patients to avoid liver transplantation? In contrast to patients with decompensated liver cirrhosis due to hepatitis B treated with nucleoside analogues who can improve dramatically, the improvement in liver function is mild to moderate. The SOLAR studies have shown an improvement in liver function in around 60% of the patients assessed by a decrease of the MELD score of three to four points. The decrease in MELD score may be insufficient to improve significantly the patient but will delay the access to liver transplantation. Thirty percent of patients have been inactivated on the waiting list in a European series; with time, the majority of them were delisted while some patients were reactivated for liver function deterioration [47]. Management of patients on the waiting list, who developed antiviral resistance More data are needed to understand the consequences of virological failure following DAA therapy as well as the development of effective strategies to treat these patients pre- or post-LT. Resistance to NSA3 can be overcome with

Chapter 50: Management of HCV infection after liver transplantation

strategies combining SOF with anti-NS5A direct antiviral agents. In contrast, resistance to NS5A is more difficult to overcome due to the long lasting presence of NS5A RAS. Overall, efficacy of antiviral therapy is greater in patients who have undergone LT than in patients who have decompensated cirrhosis, especially in Child–Pugh C cirrhotic patients. This difference is greater when we consider that most studies excluded patients with severe disease. It is important to choose the most effective antiviral combination to minimize the possibility of virological relapse and the selection of RASs because they could infect the graft and might hamper antiviral therapy in case of severe hepatitis C recurrence. As said earlier, wild-type virus has been shown to rapidly outgrow less fit NS3 RAS variants. In contrast, NS5A RASs might persist for a long period of time after treatment discontinuation [30, 48, 50, 51]. We think that there is no reason to contraindicate LT in patients with HCV drug resistance, especially if resistance relates to a single class of DAAs, because DAAs targeting other viral proteins remain fully efficient [52, 53]. However, the posttransplant outcome of patients with multiresistant viruses to PI and NS5A inhibitors may be complex with a risk of severe graft HCV infection. These patients may be difficult to treat and may require quadruple therapy. Decision of re-treatment before LT has to take into account genotype/subtype, resistance profiles, use of RBV, and treatment duration [54, 55]. The possibility to obtain an undetectable viral load during treatment in the pre-LT period (i.e. on treatment virological response) should be evaluated. In case of persistent viremia at transplant, a strategy of antiviral treatment should be elaborated and the treatment started within the first three months posttransplant.

Posttransplant antiviral treatment Prophylactic posttransplant antiviral therapy aiming at avoiding/limiting graft reinfection using anti-HCV monoclonal antibodies post-LT is still in evaluation [48, 56] with few chances of further development in this setting. Another strategy may be applied in the future using anti-envelope antibodies or host-targeting entry inhibitors in the immediate posttransplant period, since entry inhibitors have been shown to effectively inhibit HCV infection, work synergistically with DAAs, and have proved to be safe and effective in animal models [48, 57–60]. Preemptive treatment with IFN-based therapy, within one-month post-LT and before the occurrence of hepatitis on the graft, gave low SVR rates due to a low feasibility rate, a poor tolerance, and a high rate of treatment discontinuation [61–65]. This strategy needs now to be reevaluated using IFN-free antiviral regimen. Levitsky et al., reports 16 patients receiving a single dose of SOF + LDV the day they arrived at the hospital for LT and once daily for four weeks postoperatively [66]. Fifteen of the 16 patients achieved SVR 12 and one had a relapse but a SVR was achieved after re-treatment with 12 weeks of


SOF + LDV; 31% of patients had serious adverse event. No patient discontinued treatment owning to an adverse event, had graft loss, or died. In the SOLOFT study, 20 patients received SOF + RBV on the same day as LT and for the following 24 weeks [67]. All patients showed a response at the end of treatment. A potential limiting factor of this strategy is that postoperative complication could delay the start of treatment. It is generally accepted that antiviral therapy after LT should be initiated in the presence of histologically proven HCV recurrence. However, this decision must also take into account the patient’s general condition, level of hemoglobin, renal function, immunosuppression, DDIs, previous antiviral therapy failure, HCV genotype, and the stage of fibrosis. Antiviral therapy should be initiated earlier in the presence of severe fibrosis or rapid progression of fibrosis with a higher risk of graft loss, especially CH. If a liver graft biopsy is not performed, other noninvasive markers can help making the treatment decision. A cutoff value of 8.7 kPa for liver stiffness had sensitivity and a negative predictive value for significant fibrosis and portal hypertension >0.90 in all cases [68]. Although noninvasive markers can discriminate the stage of fibrosis, regular protocol biopsies of the graft are essential before the start of antiviral therapy in order to evaluate the rate of graft fibrosis, the presence of rejection, of biliary obstruction, or of the degree of steatosis. There is no doubt that the best timing to treat HCV recurrence may be updated in the very near future. In the past, strategy to wait for significant fibrosis on the liver graft before initiating antiviral treatment was supported by the poor tolerability of IFN-based regimens early after LT. At the present time, it is recommended that antiviral therapy should be initiated when the patient is clinically stable, within 6–12 months post-LT, rather than waiting until significant disease is documented [69, 70]. Early treatment could increase the likelihood of SVR and prevent injuries to the graft that would be harmful to the long-term outcome.

Post-LT treatment with IFN-based regimens Until 2011, standard antiviral therapy was based on the combination PEG-IFN plus RBV. Several studies have shown SVR rates of 18–45% and three systematic reviews of PEGIFN–RBV treatment showed SVR rates of 30% (20–30% in genotype 1 patients and 40–50% in genotype two to three patients) [5, 71, 72]. TPV and BOC, the first-generation PIs, introduced in 2011 were the first DAA to be tested in the treatment of recurrent HCV after LT. Their combination with PEG-IFN and RBV improved SVR rates to a level of 50–65% in genotype 1 infected patients but with a poor safety profile and DDIs leading to their withdrawal [7–9, 73]. Post-LT treatment with Interferon-free regimens In a phase 2 prospective, multicenter, open-label pilot study, 40 LT recipients with compensated recurrent hepatitis C


Part II: Liver disease

(cirrhosis: 40%, genotype 1: 83%) were treated with a combination SOF + low ascending-dose of RBV for 24 weeks [18]. All patients achieved rapid virological response (RVR) and EOT viral response and 70% achieved SVR 12 (75% in patients without cirrhosis and 62.5% in patients with cirrhosis). Relapse accounted for all cases of viral failure. No case of resistance was reported and therapy was safe and well tolerated with no deaths, graft losses, rejection episodes, or DDIs with immunosuppressive drugs. Although this regimen is suboptimal, this study showed for the first time that tolerance was good and results were similar to those of nontransplant patients. The SOLAR-1 study assessed the efficacy and safety of LDV, SOF, and RBV during 12 or 24 weeks for transplanted patients infected by genotype 1 or 4 without cirrhosis (n = 111), with Child–Pugh A cirrhosis (n = 51), Child– Pugh B cirrhosis (n = 52), Child–Pugh C cirrhosis (n = 9), or CH (n = 6) [19]. SVR 12 was achieved by 96% and 98% of patients without cirrhosis or Child–Pugh A cirrhosis; by 85% and 88% of patients with Child–Pugh B cirrhosis receiving 12 or 24 weeks of therapy, respectively; by 60% and 75% of patients with Child–Pugh C cirrhosis treated 12 or 24 weeks, respectively; and by all patients with cholestatic hepatitis. Twelve weeks of therapy was as effective as 24 weeks but it should be kept in mind that all patient received RBV. At baseline, 14% of patients had NS5A RASs that conferred reduced susceptibility to LDV. Relapse occurred in 7% of patients with baseline RASs as compared with 4% in patients without baseline RASs. At the time of virological failure, among patients who relapsed, 85% had NS5A variants. No resistant variant to SOF were observed. The SOLAR-2 study following the same design reported similar results. SVR 12 was achieved by 95% and 98% of patients without cirrhosis or Child–Pugh A cirrhosis and by 85% and 88% of patients with Child–Pugh B-C cirrhosis receiving 12 or 24 weeks of therapy, respectively [20]. The multicenter US real-life cohort HCV-TARGET reports on the efficacy, safety, and tolerability of SIM plus SOF with (80%) or without (20%) RBV for 12 weeks in 123 liver transplant recipients infected by genotype 1 [12]. Two patients discontinued treatment prematurely due to SAEs, one patient developed viral rebound between weeks 4 and 6, and one patient developed viral breakthrough at week 9. Eight patients developed virological relapse within four weeks after treatment completion. The SVR 12 response rate was 90%. Unfortunately, no RASs analysis was performed. Treatment was well tolerated except one death possibly due to drug-related lung injury. In the ALLY-1 study, 53 transplanted patients (cirrhosis: 30%, genotype 1: 77%) were treated with DCV, SOF, and RBV for 12 weeks. A SVR 12 was observed in 94% of patients (genotype 1: 94%, genotype 3: 91%). Among three patients who relapsed, all were observed to have NS5A variants [14]. In the French prospective real-life CUPILT cohort, 137

transplanted patients (cirrhosis: 33%, genotype 1: 80%) were treated with DCV, SOF with or without RBV for 12 (n = 25) or 24 weeks (n = 112) [15]. A SVR 12 was observed in 75% and 100% of patients with and without RBV in the 12 weeks arm and 95% and 97% of patients with and without RBV in the 24 weeks arm [15]. NS5A variants were present among the two patients with virological failure. RBV did not seem mandatory. Tolerance profile was good; however, attention should be paid to renal function, as a significant decrease has been observed. In another phase 2 study, 34 LT recipients with mild recurrent hepatitis C (genotype 1, fibrosis ≤ 2, treatmentna¨ıve post-LT and ≥12 months post-LT) were treated with 3D and RBV for 24 weeks [17]. Adjustment of CNI dose will be required because of the inhibition of CYP-3A4 by the ritonavir-boosted PI paritaprevir (sevenfold increase in Tac half-life, threefold increase in CsA half-life) [74]. All patients achieved RVR and EOT viral response and 33 of 34 (97%) achieved SVR 12. One patient had a relapse. This patient had RASs in NS3, NS5A, and NS5B at the time of relapse, none of which were present at baseline. The regimen was well tolerated without death, graft loss, or rejection episode. Other real-world studies have supported high rates of SVR and excellent tolerability of DAA regimens in LT recipients including combination regimens of SOF-LDV [23, 24], SOFSIM [11, 12, 22, 23, 25, 26], SOF-DCV [21, 28], and SOFSIM-DCV [27].

Treatment of FCH As said earlier, FCH is a particularly severe form of HCV recurrence occurring within the first year post-LT associated with a high viral load in serum and in liver. FCH has a rate of death of 50% and those who survived developed cirrhosis on the graft within the first two years posttransplant. In addition, the feasibility of antiviral treatment with IFN was low due the presence of jaundice and ascites and the SVR rate particularly poor. The natural history of FCH was dramatically modified by the IFN-free-based antiviral treatment. Severe FCH is now treatable and SVR is attainable in the vast majority of patients [16, 19, 20, 42]. In the study of Leroy et al., 23 patients (genotype 1: 78%, four patients coinfected with HIV, median time since LT: 5.3 months) with FCH were given either SOF and DCV (n = 15) or SOF and RBV (n = 8) for 24 weeks [42]. All patients survived, without re-transplantation until week 36. Dramatic improvement in clinical status was observed and 22 patients (96%) achieved a SVR. One relapse occurred in a patient treated with SOF and RBV. Based on the results of these studies, HCV management guidelines for posttransplant patients were reported by the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), the International Liver Transplant Society

Chapter 50: Management of HCV infection after liver transplantation


Table 50.1 Recommended regimens for treatment of HCV infection in liver transplant recipients according to ILTS, ELITA, AASLD, and EASL guidelines HCV genotype



SOF-LDV-RBV 400–800 mg daily SOF-DCV-RBV 400–800 mg daily SOF-VEL-RBV 400–800 mg daily

12 12 12

3D ± RBV










SOF-DCV-RBV 400–800 mg daily SOF-VEL-RBV 400–800 mg daily

12 12




24 24

SOF-DCV-RBV 400–800 mg daily SOF-VEL-RBV 400–800 mg daily

12 12




24 24

SOF-LDV-RBV 400–800 mg daily SOF-DCV-RBV 400–800 mg daily SOF-VEL-RBV 400–800 mg daily

12 12 12












Duration (wk)

(ILTS), and the European Liver and Intestine Transplant Association (ELITA) [54, 55, 69, 70] (Table 50.1). In conclusion, IFN-free regimens appear to be highly effective in LT recipients (>90%) even in patients with FCH or decompensated cirrhosis [16, 19, 20]. Treatment is less effective in severely decompensated cirrhotic patients and


ILTS, ELITA, AASLD, EASL ILTS, ELITA, AASLD, EASL ILTS, EASL No data ILTS, ELITA, AASLD (24 wk) DDI with CNI, fibrosis stage 100–200 μl−1 , and no history of AIDS-defining events. However, survival in HIV/HCV coinfected patients was poorer than in HCV monoinfected patients due to a more aggressive HCV recurrence that leads to graft loss and death [34, 83–86]. The rate of FCH in HIV/HCV coinfected transplant patients was as high as 20% with a very high mortality rate. In addition, the feasibility and results of antiviral treatment were very low [87, 88].


Part II: Liver disease

Table 50.3 Pharmacokinetic changes according to liver and renal function Drug

Primary metabolic pathway

Hepatic impairment







No modification



Sofosbuvir Ledipasvir paritaprevir/r Ombitasvir Dasabuvir Daclatasvir Velpatasvir

Renal Hepatic Hepatic Hepatic Hepatic Hepatic Hepatic

No modification No modification −0.71 +0.92 +1.17 −0.57 No modification

+1.26 No modification +1.62 +0.70 +0.84 −0.62 No modification

+1.43 No modification +10.23 +0.45 +4.19 −0.64 No modification

Grazoprevir Elbasvir Ribavirin

Hepatic Hepatic Renal

+1.66 −0.61 No modification

+4.82 −0.72 No modification

+11.68 −0.88 No modification

Not recommended in Child B or C patients

Not recommended in Child B patients, contraindicated in Child C patients No data on Child C patients Contraindicated in Child B or C patients

Renal impairment

Not if CrCl < 15 ml/min Not if CrCl < 30 ml/min Not studied in dialysis patients Not studied in dialysis patients Not studied in dialysis patients Not studied in dialysis patients Not studied in dialysis patients Not studied in dialysis patients Not modified Not modified Adjusted

Clinically significant values are shown in bold.

There was no progression of HIV infection after liver transplantation. The five-year survival was 50–55% raising the question of the maintenance of this program of transplantation. The introduction of DAAs offers hope for significant improvements in the outcome of coinfected liver transplant recipients. The first studies reporting the use of DAAs in waiting list and post-LT HIV/HCV coinfected patients are very promising with SVR rates and tolerance not different from HCV mono-infected patients [89–92]. This will change dramatically the outcome of patients with HIV/HCV coinfection and improve significantly their survival after transplantation. Particular caution should be taken for DDIs between antiHIV and anti-HCV antiviral drugs [69, 75]. Advice from an HIV expert is highly recommended to avoid DDIs between ART regimen and immunosuppressive drugs or anti-HCV antiviral treatment.

Conclusion Recurrent HCV is a constant, severe complication in liver transplant recipients and was the primary cause of graft loss and death in these patients. Pegylated interferon–RBV and first-generation NS3/4 PI: BOC or TVR associated to PEGIFN–RBV are no more used to treat HCV infection after LT in most countries related to lower efficacy, poor tolerability, and DDIs with CNI. The advent of IFN-free-based antiviral therapies with second-generation DAAs is true revolution. Most of the patients will arrive at transplantation with SVR and no viremia. The impact of DAAs on the possibility of delisting needs further evaluation. The treatment after LT is well supported and very effective even in patients with FCH. Antiviral treatment should be done before occurrence of cirrhosis on the graft. The outcome of transplant patients infected with

hepatitis C will be dramatically improved. Some remaining questions will require further studies such as the management of patients with RASs, the optimal duration of therapy in patients with decompensated cirrhosis, the possibility or not to treat cirrhotic patients with MELD over 20, and the place of Ribavirine in the future.

Abbreviations 2D paritaprevir/r, ombitasvir 3D paritaprevir/r, ombitasvir, dasabuvir ART antiretroviral therapy AUC area under curve BOC boceprevir CH cholestatic hepatitis CNI calcineurin inhibitors CsA cyclosporine CYP cytochrome DAA direct-acting antiviral DCV daclatasvir DDI drug to drug interactions EBR elbasvir EPO erythropoietin EVR early virological response GZR grazoprevir HCV hepatitis C virus HIV human immunodeficiency virus LDV ledipasvir LT liver transplantation NA not available PEG-IFN pegylated interferon PI protease inhibitors RAS resistance associated substitution RBV ribavirin RNA ribonucleic acid RVR rapid virological response

Chapter 50: Management of HCV infection after liver transplantation

SIM simeprevir SOF sofosbuvir SVR sustained virological response Tac tacrolimus TPV telaprevir TVR telaprevir VEL velpatatsvir

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Part II: Liver disease

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45 Curry, M.P., Forns, X., Chung, R.T. et al. (2015). Sofosbuvir and ribavirin prevent recurrence of HCV infection after liver transplantation: an open-label study. Gastroenterology 148: 100–107, e101.

30 Yoshimi, S., Imamura, M., Murakami, E. et al. (2015). Long term persistence of NS5A inhibitor-resistant hepatitis C virus in patients who failed daclatasvir and asunaprevir therapy. J. Med. Virol. 87: 1913–1920. 31 Shackel, N.A., Jamias, J., Rahman, W. et al. (2009). Early high peak hepatitis C viral load levels independently predict hepatitis C-related liver failure post-liver transplantation. Liver Transpl. 15: 709–718. 32 Charlton, M.R., Thompson, A., Veldt, B.J. et al. (2011). Interleukin-28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection. Hepatology 53: 317–324. 33 Fukuhara, T., Taketomi, A., Motomura, T. et al. (2010). Variants in IL28B in liver recipients and donors correlate with response to peg-interferon and ribavirin therapy for recurrent hepatitis C. Gastroenterology 139: 1577–1585; e1571–1573. 34 Miro, J.M., Stock, P., Teicher, E. et al. (2015). Outcome and management of HCV/HIV coinfection pre- and post-liver transplantation. A 2015 update. J. Hepatol. 62: 701–711. 35 Forman, L.M., Lewis, J.D., Berlin, J.A. et al. (2002). The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 122: 889–896. 36 Neumann, U.P., Berg, T., Bahra, M. et al. (2004). Fibrosis progression after liver transplantation in patients with recurrent hepatitis C. J. Hepatol. 41: 830–836. 37 Berenguer, M., Prieto, M., San Juan, F. et al. (2002). Contribution of donor age to the recent decrease in patient survival among HCV-infected liver transplant recipients. Hepatology 36: 202–210. 38 Berenguer, M., Prieto, M., Rayon, J.M. et al. (2000). Natural history of clinically compensated hepatitis C virus-related graft cirrhosis after liver transplantation. Hepatology 32: 852–858. 39 Song, A., Sobesky, R., Vinaixa, C. et al. (2016). Predictive factors for survival and score application in liver retransplantation for hepatitis C recurrence. World J. Gastroeterol. 22: 4547–4558. 40 Berenguer, M. and Schuppan, D. (2013). Progression of liver fibrosis in post-transplant hepatitis C: mechanisms, assessment and treatment. J. Hepatol. 58: 1028–1041. 41 Narang, T.K., Ahrens, W., and Russo, M.W. (2010). Post-liver transplant cholestatic hepatitis C: a systematic review of clinical and pathological findings and application of consensus criteria. Liver Transpl. 16: 1228–1235. 42 Leroy, V., Dumortier, J., Coilly, A. et al. (1993-2001). Efficacy of sofosbuvir and daclatasvir in patients with fibrosing cholestatic hepatitis C after liver transplantation. Clin. Gastroenterol. Hepatol. 2015 (13): e1991–e1992. 43 Poordad, F., Hezode, C., Trinh, R. et al. (2014). ABT-450/rombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N. Engl. J. Med. 370: 1973–1982.

46 Curry, M.P., O’Leary, J.G., Bzowej, N. et al. (2015). Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N. Engl. J. Med. 373: 2618–2628. 47 Belli, L.S., Berenguer, M., Cortesi, P.A. et al. (2016). Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: A European study. J. Hepatol. 65: 524–531. 48 Felmlee, D.J., Coilly, A., Chung, R.T. et al. (2016). New perspectives for preventing hepatitis C virus liver graft infection. Lancet Infect. Dis. 16: 735–745. 49 Fernandez Carrillo, C., Crespo, G., de la Revilla, J. et al. (2017). Successful continuation of HCV treatment after liver transplantation. Transplantation 101: 1009–1012. 50 Wyles, D.L. (2013). Antiviral resistance and the future landscape of hepatitis C virus infection therapy. J. Infect. Dis. 207 (Suppl. 1): S33–S39. 51 McPhee, F., Hernandez, D., Yu, F. et al. (2013). Resistance analysis of hepatitis C virus genotype 1 prior treatment null responders receiving daclatasvir and asunaprevir. Hepatology 58: 902–911. 52 Afdhal, N., Reddy, K.R., Nelson, D.R. et al. (2014). Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N. Engl. J. Med. 370: 1483–1493. 53 Bourliere, M., Bronowicki, J.P., de Ledinghen, V. et al. (2015). Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, doubleblind, phase 2 trial (SIRIUS). Lancet Infect. Dis. 15: 397–404. 54 European Association for the Study of the Liver (2017). EASL recommendations on treatment of hepatitis C 2016. J. Hepatol. 66: 153–194. 55 Panel, A.I.H.G. (2015). Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. Hepatology 62: 932–954. 56 Chung, R.T., Gordon, F.D., Curry, M.P. et al. (2013). Human monoclonal antibody MBL-HCV1 delays HCV viral rebound following liver transplantation: a randomized controlled study. Am. J. Transplant. 13: 1047–1054. 57 Mailly, L., Xiao, F., Lupberger, J. et al. (2015). Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody. Nat. Biotechnol. 33: 549–554. 58 Vercauteren, K., de Jong, Y.P., and Meuleman, P. (2014). HCV animal models and liver disease. J. Hepatol. 61: S26–S33. 59 Tawar, R.G., Heydmann, L., Bach, C. et al. (2016). Broad neutralization of hepatitis C virus-resistant variants by Civacir hepatitis C immunoglobulin. Hepatology 64: 1495–1506. 60 Davis, G.L., Nelson, D.R., Terrault, N. et al. (2005). A randomized, open-label study to evaluate the safety and pharmacokinetics of

Chapter 50: Management of HCV infection after liver transplantation

human hepatitis C immune globulin (Civacir) in liver transplant recipients. Liver Transpl. 11: 941–949. 61 Mazzaferro, V., Tagger, A., Schiavo, M. et al. (2001). Prevention of recurrent hepatitis C after liver transplantation with early interferon and ribavirin treatment. Transplant. Proc. 33: 1355–1357. 62 Chalasani, N., Manzarbeitia, C., Ferenci, P. et al. (2005). Peginterferon alfa-2a for hepatitis C after liver transplantation: two randomized, controlled trials. Hepatology 41: 289–298. 63 Bzowej, N., Nelson, D.R., Terrault, N.A. et al. (2011). PHOENIX: A randomized controlled trial of peginterferon alfa-2a plus ribavirin as a prophylactic treatment after liver transplantation for hepatitis C virus. Liver Transpl. 17: 528–538. 64 Shergill, A.K., Khalili, M., Straley, S. et al. (2005). Applicability, tolerability and efficacy of preemptive antiviral therapy in hepatitis C-infected patients undergoing liver transplantation. Am. J. Transplant. 5: 118–124. 65 Sugawara, Y., Makuuchi, M., Matsui, Y. et al. (2004). Preemptive therapy for hepatitis C virus after living-donor liver transplantation. Transplantation 78: 1308–1311. 66 Levitsky, J., Verna, E.C., O’Leary, J.G. et al. (2016). Perioperative Ledipasvir-Sofosbuvir for HCV in Liver-Transplant Recipients. N. Engl. J. Med. 375: 2106–2108. 67 Pasulo, L.D.B.C., Mazzarelli, C. et al. (2016). Pre-emptive posttransplant HCV treatment with IFN-free DAA: preliminaryresults from a pilot study. Transplantation 48: e60. 68 Carrion, J.A., Torres, F., Crespo, G. et al. (2010). Liver stiffness identifies two different patterns of fibrosis progression in patients with hepatitis C virus recurrence after liver transplantation. Hepatology 51: 23–34. 69 Terrault, N.A., Berenguer, M., Strasser, S.I. et al. (2017). International liver transplantation society consensus statement on hepatitis C management in liver transplant recipients. Transplantation 101: 956–967. 70 Belli, L.S., Duvoux, C., Berenguer, M. et al. (2017). ELITA consensus statements on the use of DAAs in liver transplant candidates and recipients. J. Hepatol. 71 Wang, C.S., Ko, H.H., Yoshida, E.M. et al. (2006). Interferonbased combination anti-viral therapy for hepatitis C virus after liver transplantation: a review and quantitative analysis. Am. J. Transplant. 6: 1586–1599. 72 Xirouchakis, E., Triantos, C., Manousou, P. et al. (2008). Pegylated-interferon and ribavirin in liver transplant candidates and recipients with HCV cirrhosis: systematic review and metaanalysis of prospective controlled studies. J. Viral Hepat. 15: 699– 709. 73 Forns, X., Samuel, D., Mutimer, D. et al. (2014). Interim SVR 12 results from the Telaprevir phase 3B RELACE study in treatment naive stable liver transplant patients with genotype 1 HCV infection. J. Hepatol. 60: S481. 74 Badri, P., Dutta, S., Coakley, E. et al. (2015). Pharmacokinetics and dose recommendations for cyclosporine and tacrolimus when coadministered with ABT-450, ombitasvir, and dasabuvir. Am. J. Transplant. 15: 1313–1322. 75 University of Liverpool. HEP Drug Interaction http://www.hepdruginteractions.org (accessed 10 October 2018).


76 Ouwerkerk-Mahadevan, S., Snoeys, J., Peeters, M. et al. (2016). Drug–drug interactions with the NS3/4A protease inhibitor simeprevir. Clin. Pharmacokinet. 55: 197–208. 77 German Polina, A.M., Yang, J.C., McNair, L., and Shen, G. (2013). The pharmacokinetics of Ledipasvir, an HCV specific NS5A inhibitor in HCV-uninfected subjects with moderate and severe hepatic impairement. Hepatology 58: 432A. 78 Sekar, V.S.A., Peeters, M. et al. (2011). Pharmacokinetics of TMC 435 in subjects with moderate hepatic impairement. J. Hepatol. 54: S193. 79 Khatri, A.G.L., Menon, R. et al. (2012). Pharmacokinetics and safety of co-administered ABT-450 plus ritonavir (ABT 450/r), ABT 267, and ABT 333 as a single dose in subjects with normal hepatic function and in subjects with mild, moderate and severe hepatic impairement. Hepatology 56: 555A. 80 Bourliere, M., Gordon, S.C., Flamm, S.L. et al. (2017). Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. NEJM 376: 2134–2146. 81 Hezode, C., Fourati, S., Chevaliez, S. et al. (2017). Sofosbuvirdaclatasvir-simeprevir plus ribavirin in direct-acting antiviral experienced patients with hepatitis C. Clin. Infect. Dis. 64: 1615– 1618. 82 Martinez, E., Milinkovic, A., Buira, E. et al. (2007). Incidence and causes of death in HIV-infected persons receiving highly active antiretroviral therapy compared with estimates for the general population of similar age and from the same geographical area. HIV Med. 8: 251–258. 83 Terrault, N.A., Roland, M.E., Schiano, T. et al. (2012). Outcomes of liver transplant recipients with hepatitis C and human immunodeficiency virus coinfection. Liver Transpl. 18: 716– 726. 84 Antonini, T.M., Sebagh, M., Roque-Afonso, A.M. et al. (2011). Fibrosing cholestatic hepatitis in HIV/HCV co-infected transplant patients-usefulness of early markers after liver transplantation. Am. J. Transplant. 11: 1686–1695. 85 de Vera, M.E., Dvorchik, I., Tom, K. et al. (2006). Survival of liver transplant patients coinfected with HIV and HCV is adversely impacted by recurrent hepatitis C. Am. J. Transplant. 6: 2983– 2993. ´ ´ J.C., Feray, C., Sebagh, M. et al. (2008). Sur86 Duclos-Vallee, vival and recurrence of hepatitis C after liver transplantation in patients coinfected with human immunodeficiency virus and hepatitis C virus. Hepatology 47: 407–417. 87 Terrault, N., Reddy, K.R., Poordad, F. et al. (2014). Peginterferon and ribavirin for treatment of recurrent hepatitis C disease in HCV-HIV coinfected liver transplant recipients. Am. J. Transplant. 14: 1129–1135. 88 Antonini, T.M., Furlan, V., Teicher, E. et al. (2015). Therapy with boceprevir or telaprevir in HIV/hepatitis C virus co-infected patients to treat recurrence of hepatitis C virus infection after liver transplantation. AIDS 29: 53–58. 89 Castells, L., Llaneras, J., Campos-Varela, I. et al. (2017). Sofosbuvir and daclatasvir in mono- and HIV-coinfected patients with recurrent hepatitis C after liver transplant. Ann. Hepatol. 16: 86– 93.


Part II: Liver disease

90 Grant, J.L., Hawkins, C., Brooks, H. et al. (2016). Successful sofosbuvir-based therapy in HIV/hepatitis C virus coinfected liver transplant recipients with recurrent hepatitis C virus infection. AIDS 30: 93–98. 91 Campos-Varela, I., Peters, M.G., and Terrault, N.A. (2015). Advances in therapy for HIV/hepatitis C virus-coinfected

patients in the liver transplant setting. Clin. Infect. Dis. 60: 108– 116. 92 Antonini, T., Coilly, A., Rossignol, E. et al. (2017). Sofosbuvirbased regimens in HIV/HCV coinfected patients after liver transplantation: results from the ANRS CO23 CUPILT Study. Transplantation https://doi.org/10.1097/TP.0000000000001928.


Note: Page numbers in italics refer to figures; those in bold to tables. abacavir, and diarrhea, 218 abdominal pain acute pancreatitis, 353 celiac disease, 140 chronic intestinal pseudo-obstruction, 335 functional dyspepsia, 127 gallstone, 342, 344 irritable bowel syndrome, 306, 309 ABIC score (alcoholic hepatitis), 513 ablative therapy, hepatocellular carcinoma, 704 ABO incompatible (ABOi), 738 absolute risk reduction (ARR), 91, 596 acarbose-associated diarrhea, 210 acetic acid chromoendoscopy, 23 acetorphan, 217 acetylcholinesterase inhibitors, and diarrhea, 214 achalasia, 35–41 absent peristalsis in, 35 esophageal outflow obstruction in, 35 etiology, 35–36 incidence and prevalence, 35 subtype, 35 symptoms, 36 treatment, 36 botulinum toxin injection, 37, 37 esophagectomy, 41, 41 Heller myotomy, 38–39 per-oral endoscopic myotomy, 39, 39 per-oral endoscopic myotomy vs. Heller myotomy, 40, 40–41 per-oral endoscopic myotomy vs. pneumatic dilation, 41 pharmacologic, 36–37 pneumatic dilation, 37–38, 38 pneumatic dilation vs. Heller myotomy, 39–40, 40 acid-suppressive medications, Barrett’s esophagus, 25 ACLF see acute-on-chronic liver failure (ACLF) acquired prothrombotic disorders, 647 acute colonic pseudo-obstruction (ACPO), 332 acute fatty liver of pregnancy (AFLP), 413–414 challenges for interventional trials, 414 complications, 414

etiology, 413 management, 413 outcomes, 414 presentation, 413, 414 prevalence, 413 Swansea diagnostic criteria, 414 acute gastrointestinal hemorrhage, antibiotic prophylaxis for, 388 acute hepatitis B infection, in pregnancy, 418 acute hepatitis C virus (HCV) infection DAA regimens for, 479 interferon-based treatment, 479 in pregnancy, 418 spontaneous clearance rates, 478–479 acute hepatitis E infection, in pregnancy, 418 acute liver failure (ALF) 677, 715 acute respiratory distress syndrome in, 377 cardiovascular support, 376–377 coagulation support, 378 corticosteroid insufficiency in, 377 critical care services, 376 criteria for transfer to transplant center, 376 definition, 374 drug-induced liver injury, 715 etiology, 374–375, 375 hypoglycemia of, 377 ICP incidence of, 378 monitoring, 378 prevention and treatment of raised, 378–379 immune dysfunction in, 378 incidence of sepsis, 378 metabolic and nutritional support, 377 neurological support, 378–379 O’Grady classification of, 374, 375 paracetamol-induced, 375, 377 prognosis, 375 ALFSG index, 376 Clichy criteria, 375 King’s College Criteria (KCC), 375–376, 376 model for end-stage liver disease (MELD) score, 375–376

Evidence-Based Gastroenterology and Hepatology, Fourth Edition. Edited by John W. D. McDonald, Brian G. Feagan, Rajiv Jalan, and Peter J. Kahrilas. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd.




acute liver failure (ALF) (Continued) prognostic criteria for liver transplantation, 375, 376 scoring systems to determine, 375–376 renal replacement therapy for, 377–379 renal support, 377–378 respiratory support, 377 risk of seizures in, 379 in Wilson’s disease, 559, 566 acute-on-chronic liver failure (ACLF), 363–371 background, 363 biomarkers, 366–367 CANONIC study, 363, 364 CLIF organ failure scoring system, 365 definitions, 363, 364, 385 diagnosis, 363–365 diagnostic criteria, 364 grade, 384–385 hepatic encephalopathy and, 363–364 hyponatremia and, 367 NACSELD study, 365 phenotype, 363 prognosis, 365–367 renal failure and, 364 scoring systems for assessment of, 365 CLIF-C acute decompensation score (CLIF-AD), 366 CLIF-OF score, 365 others, 366, 366 treatment, 367–370, 370 bone marrow-derived stem cells mobilization with G-CSF, 367–368 extracorporeal devices, 368 liver transplant, 369–370 molecular adsorbent recirculating system, 368–369 plasma exchange, 368 Prometheus, 369 stem cells, direct administration of, 368 and variceal hemorrhage, 364 acute pancreatitis, 353–358 alcohol and, 353 causes, 353 diagnosis, 354–355 epidemiology, 353 gallstone, 356 mortality after, 354 pathogenesis, 353 prevention, 356–358 prognostic scoring systems, 355 severity of, 354 symptoms and complications, 353–354 treatment, 355–358, 357 types of, 353 acute respiratory distress syndrome (ARDS), 377 acute upper gastrointestinal bleeding (AUGIB), 110–122 coagulaopthy, correction of, 112–113 definition, 110 drug therapy, 121–122 acid suppressing drugs, 121–122 prokinetic agents, 121

somatostatin and octreotide, 122 tranexamic acid, 122 endoscopic therapy, 113–117 adrenaline injection, 114, 115 adrenaline plus sclerosant, 115, 115 alcohol injection, 114–115 combination therapy vs. single therapy with adrenaline, 114 in current practice, 120–121 elective repeat, 120 failure of, 120 summary, 120 thrombin and fibrin glue, 115–117, 116 for ulcers with adherent blood clot, 119–120 Glasgow-Blatchford score (GBS), 110, 111 mechanical hemostasis combination therapy with, 119 hemoclip, 118–119 triclip, 119 non-variceal AUGIB (NVUGIB), 111, 112 endoscopic therapy for, 113–117 resuscitation and blood transfusion, 112 risk assessment, 110–111 Rockall score (RS), 110–111, 111 thermal therapies argon plasma coagulation, 118 combination therapy with, 118 electrocoagulation, 117–118 heater probe, 117 laser photocoagulation, 117 acute viral hepatitis, 490 in pregnancy, 418 adalimumab, Crohn’s disease, 158–159 adaptive immune response, HBV infection and, 491 ADR see adverse drug reactions (AD) Advagraf® , liver transplantation, 732 advanced oxidation protein roducts (AOPP), 367 adverse drug reactions (ADR), 715 afatinib, diarrhea by, 213 AFLP see acute fatty liver of pregnancy (AFLP) AFP see alpha-fetoprotein (AFP) AH see alcoholic hepatitis (AH) AIH see autoimmune hepatitis (AIH) AIMS-65 score, 111 AIRE see autoimmune regulator (AIRE) alanine aminotransferase (ALT), 492, 495, 578, 595, 605 NAFLD/NASH, 524, 527–528 alanine aminotransferase (ALT) levels, in ICP, 409 albumin dialysis, 585 hepatic encephalopathy, 685 alcohol abstinence, 513 alcohol abuse, 503–504 alcoholic cirrhosis, 510–511 as cofactor of liver diseases, 510 extrahepatic diseases, 511 NAFLD and, 525 prevalence of, 503–504 alcohol-attributable malignant neoplasms, 504


alcohol dehydrogenase (ADH), 505 alcoholic cirrhosis, 509 cause of, 510 complications, 510–511 diagnosis, 510 therapy for, 511 alcoholic fibrosis, 507 alcoholic hepatitis (AH), 503, 505 algorithm for diagnosis and management of, 512, 512–513 cardinal features, 511 diagnosis, 512 epidemiology, 511 pathogenesis, 507–508, 508 treatment, 513–514 alcoholic hepatitis histological score (AHHS), 513 alcoholic liver disease (ALD), 503 burden, 503–504, 504 clinical course, 504 diagnosis, 509–510 genes implicated in, 507 histological analysis, 503 liver transplantation for, 514–515 management, 503 modifying factors, 505–506 natural history, 504–505 pathogenesis, 506–509 pathogenesis of, 503 alcoholic steatohepatitis (ASH) clinical characterization, 506 definition, 503 early form, 504–505 alcohol metabolism, enzymes involved in, 505 alcohol relapse after transplant, 515 ALD see alcoholic liver disease (ALD) aldehyde dehydrogenase (ALDH), 505 aldosterone antagonist, ascites, 663 alendronate, hepatic osteodystrophy, 585 ALF see acute liver failure (ALF) alginate (Gaviscon), 133 alginate-antacid combinations, GERD, 9–10 alicaforsen, 192 alkaline phosphatase (ALP), 559, 574, 603 and bilirubin values, 575 alosetron, irritable bowel syndrome, 320 ALP see alkaline phosphatase (ALP) alpha-fetoprotein (AFP), 693 ALT see alanine aminotransferase (ALT) alvimopan, acute colonic pseudo-obstruction, 336 amenorrhea and hepatic inflammation, 592 American Association for the Study of Liver Disease (AASLD), 593, 611, 677, 696, 756 American College of Gastroenterology, 21 American Drug-Induced Liver Injury Network, 715 American Gastroenterological Association, 21 5-aminosalicylates (5-ASA) Crohn’s disease, 150–151, 152 protective agent against colorectal cancer in IBD, 265 ulcerative colitis, 174–176


amiodarone, drug-induced liver injury, 717 amitriptyline functional dyspepsia, 134 Wilson’s disease, 564 ammonia, hepatic encephalopathy, 678 amphotericin B, invasive candidiasis, 390 AMR see antibody-mediated rejection (AMR) Amsterdam score, 610 ANCA see anti-neutrophil cytoplasmic antibodies (ANCA) Angel (antacid), 133 angiogenesis, 507 anidulafungin, invasive candidiasis, 390 antacids functional dyspepsia, 133 GERD, 9 antibiotics acute variceal bleeding, 622–623 bacteria infections, 388 chronic intestinal pseudo-obstruction, 337 Clostridium difficile infections, 288–290 Crohn’s disease, 153–154 and diarrhea, 218 and drug-induced diarrhea, 214–215 irritable bowel syndrome, 318 pouchitis, 191 spontaneous bacterial peritonitis, 667–668 travelers’ diarrhea, 229, 231 antibody-mediated rejection (AMR), 729 anticholinergic drugs, diarrhea by, 212 antidepressants functional dyspepsia, 134 irritable bowel syndrome, 317, 318 antigen-specific T cell recovery, 498 anti-integrin monoclonal antibodies, ulcerative colitis, 179–180 anti-neutrophil cytoplasmic antibodies (ANCA), 605 anti-nuclear antibodies (ANA), 593, 605 autoimmune hepatitis, 593 antiphospholipid syndrome, 647 antipneumococcal vaccination, 389 antiproliferative agents, primary biliary cholangitis/cirrhosis, 584 antireflux surgery, 13, 26 antiretroviral therapy (ART), 463 direct acting antivirals (see direct acting antivirals (DAA)) HIV–HCV coinfection, 463–464 antispasmodic drugs, irritable bowel syndrome, 314–317, 316 anti-TNF antagonists, ulcerative colitis, 178–179 antiviral NK cell response, 498 AOPP see advanced oxidation protein roducts (AOPP) APACHE II (Acute Physiology and Chronic Health Examination II) score, 355 APECED see autoimmune polyendocrinopathy–candidiasis– ectodermal dystrophy (APECED) apical sodium dependent bile acid transporter (ASBT), 585 apoptotic bodies, 215 apoptotic enteropathy, 215 apremilast, secretory diarrhea, 211 arbaclofen placarbil, 12 area under the receiver operator curve (AUROC), 577



arginine vasopressin (AVP), 665 argon plasma coagulation, 118 ARR see absolute risk reduction (ARR) ART see antiretroviral therapy (ART) artificial liver systems, 379 ASBT see apical sodium dependent bile acid transporter (ASBT) ascites classification, 662–665 diuretic-intractable, 664 diuretic-resistant, 664 large volume and tense, 664 management, 663 moderate, 662–664 pathophysiology, 662 prevalence, 662 refractory, 664 treatment, 662–665 uncomplicated, 662 Asia-Pacific Association for the Study of the Liver (APASL), 364 aspartate aminotransferase (AST), 492, 575, 595, 605 aspartate aminotransferase to platelet ratio index (APRI), 509, 575 aspirin (ASA), 86 for chemoprevention in BE, 26 associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), 431, 432 AST see aspartate aminotransferase (AST) asthma, GERD and, 3 asymmetric dimethylarginine (ADMA), 367 AUGIB see acute upper gastrointestinal bleeding (AUGIB) auranofin diarrhea by, 212 and enterocolitis, 215 AUROC see area under the receiver operator curve (AUROC) autofluorescence endoscopy, 23 autoimmune hepatitis (AIH), 416–417, 592–599, 737 autoimmune syndromes in, 593 azathioprine, 596–597 budesonide, 597–598 characteristics, 592 clinical features, 592 corticosteroids, 596–597 diagnosis, 594, 595, 595–596 genetic features, 594–595 hepatocellular carcinoma, 592 histological features, 593–594 liver transplantation, 598, 737 prognosis, 598–599 second line therapies, 598 serological features, 592–593 subclassification, 596 treatment, 596 autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), 593 autoimmune regulator (AIRE), 595 autoimmune sclerosing cholangitis, 607 AVP see arginine vasopressin (AVP) azathioprine (AZA)

autoimmune hepatitis, 596–597 Crohn’s disease, 155–157 liver transplantation, 730, 733 primary sclerosing cholangitis, 616 ulcerative colitis, 177 azithromycin, travelers’ diarrhea, 232 backwash ileitis, 607 see also primary sclerosing cholangitis (PSC) baclofen, GERD, 12 bacterial infections in cirrhotic patients antibiotic therapy, 386–388, 387 IV albumin therapy, 387–388 multidrug resistant (MR) bacteria, 386 nonantibiotic strategies, 389 protocolized prevention of catheter-related infections, 389 severe sepsis and septic shock, management of, 388 liver transplantation, 746–747 balloon tamponade, acute variceal bleeding, 625 balsalazide, ulcerative colitis, 175–176 Barcelona Clinic Liver Cancer (BCLC), 697, 698 staging system, 705 bariatric surgery, for NAFLD, 534 barium swallow, GERD, 8 Barrett’s esophagus (BE), 21–28 definition, 5, 21 diagnosis advanced endoscopic imaging, 24 endoscopy, 23 histopathology, 23–24 diet and, 22 dysplasia detection in, 23 dysplasia in, 23 GERD and, 5, 21, 22 hiatal hernia and, 22 incidence and prevalence, 22 intestinal metaplasia in, 21 natural history, 22–23 pathogenesis, 21 risk factors, 22 screening, 24–25 surveillance, 25, 25–26 treatment acid suppression, 26 anti-inflammatory agents, 26 endoscopic therapies, 26–28, 27 basiliximab, liver transplantation, 734, 745 Baveno VI guidelines, 631 validation, 632 B-cell lymphoma, 480 BCS see Budd–Chiari syndrome (BCS) BE see Barrett’s esophagus (BE) Bedside Index for Severity in Acute Pancreatitis (BISAP) score, 355 Behc¸et’s disease, 647 belatacept, liver transplantation, 733–734 beta blockers, variceal hemorrhage, 415 bethanecol, and diarrhea, 214


bevacizumab, cholangiocarcinomas, 434 bezafibrate, primary biliary cholangitis/cirrhosis, 581, 582 bezlotoxumab, for recurrent CDI, 293–294 bile-salt export pump (BSEP), 580 biliary colic, 342, 344 see also gallstone disease biliary intraepithelial neoplasia (BilIN), 425 biliary papillomatosis, 425 bilirubinostasis, 508 biochemical nonresponders, 579 biologic therapies cholangiocarcinomas, 434–435 Crohn’s disease, 158–161 eosinophilic esophagitis, 55–56, 56 biopsy celiac disease, 143–145 chronic intestinal pseudo-obstruction, 335 bismuth quadruple therapy, 76, 77 bismuth subsalicylate (BSS), travelers’ diarrhea, 229, 230 bisphosphonates bone disease in IBD, 246 glucocorticoid-induced osteoporosis, 248 hepatic osteodystrophy, 242 BMD see bone mineral density (BMD) boceprevir (BOC), 753 bone formation and resorption, 240 bone mineral content (BMC), 241 bone mineral density (BMD), 240–241 bortezomib, cholangiocarcinomas, 435 bosentan, drug-induced liver injury, 717 botulinum toxin injection achalasia, 37, 37 spastic disorders, 43 branched chain amino acids (BCAA), 685 British Society of Gastroenterology, 21 brivanib, hepatocellular carcinoma, 707 BSEP see bile-salt export pump (BSEP) Budd–Chiari syndrome (BCS), 417, 645 comparison, 648 epidemiology, 647 hepatocellular carcinoma, 695 management, 649 manifestation, 648 outcome and prognostic factors, 648–649 prevalence, 646 treatment, 649–650 Budenofalk, 153 budesonide autoimmune hepatitis, 597–598 Crohn’s disease, 152–153 eosinophilic esophagitis, 54–55, 55, 58 microscopic colitis, 200–201 primary biliary cholangitis/cirrhosis, 582–583 ulcerative colitis, 176 budesonide enemas, 177 pouchitis, 192 budesonide multiple matrix system (MMX), ulcerative colitis, 176–177 butyl cyanoacrylate, acute variceal bleeding, 624


cabozantinib cholangiocarcinomas, 435 hepatocellular carcinoma, 698 caffeine, secretory diarrhea, 210 CAH see chronic autoimmune hepatitis (CAH) calcineurin inhibitors (CNIs), 473 liver transplantation, 731–732, 735, 745 calcitonin, 212, 248 calcium and vitamin D supplementation, bone disease, 242, 246, 247–248 calcium channel blockers achalasia, 36 spastic disorders, 42–43 calprotectin, 189 Canada-UK-Adelaide (CANUKA) score, 111 Canadian Association of Gastroenterology (CAG), 132 Canadian Multicenter Osteoporosis Study, 11 Canadian Prompt Endoscopy (CADET-PE) Study, 128–129 Canadian registry of upper gastrointestinal bleeding and endoscopy (RUGBE) study, 111 capecitabine, cholangiocarcinomas, 434 capsule endoscopy, variceal bleeding, 633 carcinoembryonic antigen (CEA), 615 cardiolipin, autoimmune hepatitis, 593 cardiovascular disease and NAFLD, 526 carvedilol, variceal bleeding, 626, 629 case–control studies, 258 caspase-cleaved keratin 18, 369 castor oil, 211 catheter-related infections, protocolized prevention of, 389 cavernoma, 651 CCA see cholangiocarcinoma (CCA) CDCA see chenodeoxycholic acid (CDCA) CDI see Clostridium difficile infections (CDI) C. difficile colitis, 214–215 CEA see carcinoembryonic antigen (CEA) cecal intubation rate (CIR), 277 cecostomy, acute colonic pseudo-obstruction, 337 cediranib, cholangiocarcinomas, 435 ceftriaxone, spontaneous bacterial peritonitis, 668 celiac disease 139–146 autoimmune conditions associated with, 140 bone disease in, 251–252 fracture in, risk of, 251–252 osteoporosis, 251 pathogenesis, 252 treatment, 252 clinical manifestations, 140 and dermatitis herpetiformis, 140 epidemiology, 139 future directions, 145–146 iron deficiency anemia (IDA) and, 143, 145 mortality in, 140–141, 141 age, 141 gender, 141 severity of disease, 141 pathophysiology, 139–140 screening, 142–143



celiac disease (Continued) small intestinal biopsy, 143–145 therapy for, 145 cephalosporins, spontaneous bacterial peritonitis, 667 certolizumab, Crohn’s disease, 158–159 ceruloplasmin (CP), 556–557 cetuximab cholangiocarcinomas, 434 diarrhea by, 213 CFF see critical flicker frequency (CFF) CH see cholestatic hepatitis (CH) chelation therapy, 552 Wilson’s disease, 560–561 chemoprophylaxis, in travelers’ diarrhea, 229, 230 chemotherapeutic agents, and diarrhea, 215 chemotherapy cholangiocarcinomas, 432–433 hepatocellular carcinoma, 707 chenodeoxycholic acid (CDCA), 580 secretory diarrhea, 211 chest pain achalasia, 36 spastic disorders, 42 Child–Pugh score, 363 chlorhexidine, 389 cholangiocarcinoma (CCA), 602, 607 primary sclerosing cholangitis, 607, 616 cholangiocarcinomas anatomical classification of, 426 Bismuth–Corlette classification of perihilar, 426, 429 clinical features, 425 diagnosis blood tests, 426 digital image analysis, 429 flow cytometry analysis, 429 fluorescence in situ hybridization (FISH) analysis, 429 immunoglobulin G4, 427 invasive imaging, 428 noninvasive imaging, 427–428 nonspecific markers, 426 pathological, 428–429 targeted biopsy, 428 tumor markers, 427 epidemiology, 425 follow-up, 437 histology, 425 prognosis, 437 resectable perihilar, 431 risk factors, 426 staging classifications, 429, 430 treatment biological therapies, 434–435 chemotherapy, 432–433 combined chemoradiotherapy, 433–434 drug eluting bead TACE, 436 endoscopic brachytherapy, 436 endoscopic treatments, 435–436 interventional radiology, 436–437

irreversible electroporation, 437 liver transplant, 431 locoregional therapies, 436 microwave ablation, 437 photodynamic therapy, 435 proton beam therapy, 433 radiofrequency ablation, 436 radiotherapy, 433 surgery, 429–432 transarterial chemoembolization, 436 transarterial chemoinfusion, 436 transarterial radioembolization, 436 cholangiography, primary sclerosing cholangitis, 603 cholecystostomy, 344 see also gallstone disease complications, 344–345 during pregnancy, 347 quality of life after, 345 surgical technique, 345–347 laparoscopic vs. open cholecystectomy, 345 number of ports and size of ports, 346 perioperative interventions, 345–346 timing, 346–347 cholestasis, complications of hepatic osteodystrophy, 585 hyperlipidemia, 585 cholestatic hepatitis (CH), 754 cholestatic liver disease, 417 cholesterol 7 alpha-hydroxylase (CYP7A)-1, 579 cholesterol stones, 342 see also gallstone disease cholestyramine and diarrhea, 218 pruritus, 584 cholinergic drugs, and diarrhea, 214 chromatin, autoimmune hepatitis, 593 chromoendoscopy acetic acid, 23 Barrett’s esophagus, 23 indigo carmine, 23 methylene blue, 23 chromoendoscopy (CE), 261 chronic autoimmune hepatitis (CAH), 597 chronic hepatitis B (CHB), 416, 490 in adulthood, 492 antiviral therapies for, 495, 495 nucleos(t)ide analogues, 496–497 pegylated interferon, 495–496 cirrhotic patient and, 497 diagnosis, 491–492 disease phases of clinical parameters during, 493 HCC development, 494 immune active (IA), 493 immune tolerant (IT), 492–493 inactive carrier/immune control (IC), 493–494 nomenclature of, 493 novel insights into, 494 epidemiology, 490 HBeAg-negative, 494


immune aspects of therapies of, 497–498 immunopathogenesis, 490–491 laboratory tests for monitoring, 496 management HBsAg loss, 494 lifestyle measures, 494 screening tests for, 494–495 NK cell dysfunction in, 497–498 patient monitoring, 497 patient selection, 497 prognosis of, 499 transmission routes, 490 treatment criteria, 494–495 viral entry inhibitors for, 497 chronic hepatitis C virus (HCV) infection, 416 alcohol abuse and, 510 chronic kidney disease (see chronic kidney disease) definition, 454 extrahepatic manifestations B-cell lymphoma, 480 cryoglobulinemic vasculitis (CV), 479 DAA regimens for, 480–483, 481, 482 HCV eradication impact on, 479 mixed cryoglobulinemia, 479 prevalence and odds ratios for, 480 HCC development after DAA treatment, 477–478, 478 sequelae of, 454 treatment aims of, 454 direct acting antivirals for (see direct acting antivirals (DAA)) with pegylated-interferon and ribavirin, 454 resistance-associated substitutions, 464 retreatment regimens, 464–465 WHO guidelines for, 465 chronic intestinal pseudo-obstruction (CIPO), 332 chronic kidney disease (CKD) in HCV infection extrahepatic manifestations, 470 prevalence, 470 and NAFLD, 526 Chronic Liver Failure Consortium ACLF score (CLIF-C ACLFs), 363 CI see confidence interval (CI) cigarette smoking, NAFLD and, 525 ciprofloxacin Crohn’s disease, 153 pouchitis, 191 cirrhosis, 363, 559 alcohol-attributable, 503 decompensation, 663 global age standardized death rate of, 504 global alcohol-attributable fraction of, 504 hepatocellular carcinoma, 694 portal vein thrombosis, 654–657, 656 sensorium, 679 cirrhosis pregnancy, 414–416 outcomes, 415 cisapride, 133 acute colonic pseudo-obstruction, 336


and diarrhea, 214 citalopram, esophageal hypersensitivity, 12 clacineurin inhibitors (CNI), 730 CLE see confocal laser endomicroscopy (CLE) clinically significant portal hypertension (CSPH), 620 Clinical Outcomes Research Initiative (CORI) database, 6 Clostridium difficile infections (CDI), 284–299 BI/NAP1/027 strain, 284, 285 clinical presentation, 287 complications, 284 cost of medical care, 287 diagnosis, 287–288 healthcare-associated outbreaks, 285 of ileal pouch, 189 incidence/prevalence, 284–285 initial CDI, prevention of, 294–298 disposal/dedicated medical equipment, 296 environmental disinfectants, 295–296 handwashing and disinfection, 294–295 infection control practices, 294–295 isolation or cohorting practices, 295 medication restrictions, 296 multidisciplinary practices, 298 personal protective equipment, use of, 295 reducing host susceptibility to infection, 296–298 overview, 284 risk factors, 286 recurrent CDI, 286–287 severe-complicated, 287 severity of, 287 source of C. difficile acquisition, 285 community-associated CDI, 285 healthcare-associated CDI, 285 transmission, 285–286 treatment, 288, 288 asymptomatic carriers and, 294 initial CDI, 288–291 recurrent CDI, 291–294, 292 CMV see cytomegalovirus (CMV) CNI see clacineurin inhibitors (CNI) cognitive behavioral therapy (CBT), 534 functional dyspepsia, 134–135 irritable bowel syndrome, 321 cohort studies, 258 colchicine diarrhea by, 212 primary biliary cholangitis/cirrhosis, 583 collagenous colitis, 196, 197, 215 see also microscopic colitis colonization resistance, 286 colonoscopic decompression, acute colonic pseudo-obstruction, 336–337 colonoscopic surveillance, colorectal cancer, 258 colonoscopy for CRC screening, 275–276 mechanical obstruction in ACPO, 334 colorectal cancer (CRC) 609 epidemiology and risk factors, 271–272 and NAFLD, 526–527



colorectal cancer (CRC) (Continued) screening and surveillance, 271–279 colonoscopy screening, 275–276 cost effectiveness, 278, 278 CT colonography, 274–275 double contrast barium enema, 274 fecal immunochemical testing, 273–274 fecal occult blood testing, 273 flexible sigmoidoscopy, 275 goal of, 271 implementing screening, 278–279, 279 levels of evidence and role of modeling studies, 272–273 organized vs. opportunistic screening, 272 post-polypectomy surveillance, 276–277 quality of colonoscopy, 277 radiologic tests, 274–275 stool DNA, 274 World Health Organization (WHO) criteria, 271 in ulcerative colitis, surveillance of, 258–265 axiomatic statements, 259–260 chemopreventative effects, 265 epidemiological investigation, 258–259 improving cancer surveillance programs, 265 primary sclerosing cholangitis and, 258, 259 questions related to, 260–265 COMMIT study, 163–164 compensated advanced chronic liver disease (cACLD), 632 computed tomography (CT) acute pancreatitis, 355 cholangiocarcinoma, 427 Computed Tomography Severity Index (CTSI), 355 computer-based tests, hepatic encephalopathy, 680–682 confidence interval (CI), 598 confocal laser endomicroscopy (CLE), 23 cholangiocarcinoma, 428 continuous reaction time (CRT), 682 Cook triclip, 119 Coombs-negative hemolytic anemia, 557, 559 copper tests, in WD, 558 cortical bone, 240 corticosteroids AH, 513 autoimmune hepatitis, 596–597 Crohn’s disease, 151–153 eosinophilic esophagitis, 54–55, 55 liver transplantation, 730 pouchitis, 192 ulcerative colitis, 176–177 Council for International Organizations of Medical Sciences (CIOMS), 721 CpG island hypermethylation (CIMP), 276 CRC see colorectal cancer (CRC) CRC-Simulated Population Model for Incidence and natural History (CRCSPIN), 273 critical flicker frequency (CFF), 680–681 Crohn’s disease (CD), therapy for, 150–166 agents targeting lymphocyte trafficking, 161–162 anti-MAdCAM-1 therapy, 161

etrolizumab, 161 for induction and maintenance of remission, 164 janus kinase inhibitors, 162–163 mongersen, 163 omega-3 fatty acids, 163 p19 inhibition, 162 sphingosine-1-phosphate receptors antagonists, 162 TNF antagonist and immunosuppressant, combination therapy with, 163–164 ustekinumab, 161–162 5-aminosalicylates (5-ASA), 150–151, 152 induction, 150–151 maintenance, 151 antibiotics, 153–154 induction, 153–154 maintenance, 154 nitroimadazole, 154 biologic therapies, 158–161 integrin antagonists, 159–161 TNF antagonists, 158–159 clinical remission, 150 corticosteroids, 151–153 budesonide, 152–153 conventional, 151 Crohn’s Disease Activity Index (CDAI), 150 fecal microbial transplant, 154 immunosuppressive drugs, 155–158 cyclosporine, 158 methotrexate, 157–158 thiopurines, 155–157 probiotics, 154–155 Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) guidelines, 150 treat-to-target algorithm, 165 CRT see continuous reaction time (CRT) crural diaphragm (CD), 4 cryoablation therapy, Barrett’s esophagus, 27, 27–28 CT colonography (CTC), for CRC screening, 274 cuffitis, 190 curcumin, Wilson’s disease, 564 CXC chemokines, 506 cyanoacrylate, acute variceal bleeding, 624 cyanoacrylate glue injection, acute variceal bleeding, 624 cyclo-oxygenase (COX), 87 cyclo-oxygenase-2 inhibitors, 96 acetylsalicylic acid and, 99 endoscopic ulcers, 96 proton pump inhibitor and, 99–100 symptoms and treatment withdrawals, 100 vs. NSAIDs, clinical gastrointestinal events, 98–99 celecoxib, 99 diclofenac, 99 etoricoxib, 99 vs. NSAIDs, endoscopic ulcer trials, 96, 97 celecoxib, 96 diclofenac, 98 etoricoxib, 96 ibuprofen, 98


naproxen, 98 vs. NSAIDs, treatment withdrawals, 100 vs. placebo, 98, 99 cyclosporine Crohn’s disease, 158 liver transplantation, 730, 731–732, 739 ulcerative colitis, 178 C282Y mutation, 548–551, 549, 550 cytomegalovirus (CMV), liver transplantation, 747–748 cytotoxic T lymphocytes (CTLs), 491 DAA see direct acting antivirals (DAA) daclizumab, liver transplantation, 745 damage-associated molecular patterns (DAMPs), 366, 508 dasabuvir, 455 ESRD, 470–471 dasatinib, diarrhea by, 217 DDI see drug–drug interactions (DDI) decompensated cirrhosis patients, 565–566 decompensated liver cirrhosis DAA regimens in efficacy of, 474, 474 pharmacokinetics of, 473, 473–474 safety of, 474–475, 475 delisted from LT list, 476–477, 477 NA therapy for, 497 denosumab, osteoporosis, 243, 250 dermatitis herpetiformis, 140 dexlansoprazole, 10 diabetes and hepatocellular carcinoma, 695 diabetes mellitus, liver transplantation, 744 diarrhea, celiac disease, 140 diarrhea, drug-induced, 208–219 drugs causing diarrhea, 209 fatty diarrhea, 218–219 inflammatory diarrheas, 214–217 intestine regulatory system and, 208, 209 overview on, 208–209 watery diarrheas, 209–214 disordered or deregulated motility, 214 osmotic diarrhea, 210 secretory diarrhea, 210–214 didanosine, and diarrhea, 218 dietary intervention eosinophilic esophagitis, 56–57 NAFLD, 534 Wilson’s disease, 564 dietary iron absorption, regulation of, 547 digoxin, and diarrhea, 212 DILI see drug-induced liver injury (DILI) direct acting antivirals (DAA) acute HCV infection, 479, 488–489 after kidney transplantation, 471, 473 B-cell lymphoma, 480 combination regimens for end-stage renal disease, 488 dasabuvir, 470–471

grazoprevir/elbasvir, 471 ombitasvir, 470–471 paritaprevir/ritonavir, 470–471 sofosbuvir-based regimens, 471 combination treatment regimens, 456 in current use, 455 for decompensated liver cirrhosis (see decompensated liver cirrhosis, DAA regimens in) extrahepatic manifestations, 480–483, 481, 482 HCV genotype 1, 455, 455–459 HCV genotype 2, 459, 459 HCV genotype 3, 459–460, 460 HCV genotype 4, 460–461, 461 HCV genotype 5, 462, 462 HCV genotype 6, 462 hepatocellular carcinoma, 477–478, 488 HIV–HCV coinfection, 463–464 as inhibitors, 454 non-nucleoside polymerase inhibitors, 455 NS5A inhibitors, 455 NS3/4A protease inhibitors, 454–455 NS5B nucleoside inhibitors, 455 pharmacokinetics, 473 ribavirin, 455–456 distal esophageal spasm (DES), 35, 42 see also spastic motor disorders distal latency (DL), 42 docusate (dioctyl sodium sulfosuccinate), 212 domperidone, functional dyspepsia, 133 donepazil, and diarrhea, 214 donor-specific alloantibodies (DSA), 729 doxorubicin, hepatocellular carcinoma, 707 D-penicillamine, 560–561 drug–drug interactions (DDI), 758 calcineurin inhibitors and direct-acting antiviral drugs, 759 drug eluting bead TACE (DEB-TACE), 436 drug-induced diarrhea, 208–219 drugs causing diarrhea, 209 fatty diarrhea, 218–219 inflammatory diarrheas, 214–217 intestine regulatory system and, 208, 209 overview on, 208–209 watery diarrheas, 209–214 drug-induced liver injury (DILI), 418, 715, 718 causative agents, 716, 720 clinical aspects, 723 clinical presentation, 721–722 diagnostic approach, 722–725, 724 drug properties, 719 environmental conditions, 721 host factors, 719, 721 idiosyncratic, 716 mechanism, 715–718 risk factors, 717, 718–719 drug-induced lupus, 159 drug-induced steatorrhea, treatment of, 219 dual-energy X-ray absorptiometry (DEXA), 240




duodenal ulcer (DU), 68 see also Helicobacter pylori complications, 73 bleeding, 73–74 obstruction, 74 perforation, 74 H. pylori and, 68–70 H. pylori eradication therapy and, 73 not related to H. pylori and NSAIDs, 70 treatment of, 73 dysarthria, 556 dysphagia GERD and, 3 spastic disorders, 42 EAC see esophageal adenocarcinoma (EAC) EASL-EORTC see European Association for the Study of the Liver-European Organization for Research and Treatment of Cancer echinocandins invasive candidiasis, 390 liver transplantation, 747 ectopic varices, 619 elastography, primary sclerosing cholangitis, 610 elbasvir-grazoprevir HCV genotype 1, 457–458 HCV genotype 4, 460–461 HCV genotype 5, 462 HCV genotype 6, 462 HIV–HCV coinfection, 463 electrocoagulation, 117–118 electroencephalography (EEG), 682 electronic chromoendoscopy, 23 elemental diets, eosinophilic esophagitis, 56–57 elimination diet, 56 empiric, 57 targeted, 57 ELISA see enzyme-linked immunosorbent assays eluxadoline, irritable bowel syndrome, 320–321 EMD see esophageal motility disorder (EMD) emperipolesis, 594 emricasan (IDN-6556), 369 endoscopic biliary stenting (EBS), cholangiocarcinomas, 435 endoscopic brachytherapy, 436 endoscopic injection, acute variceal bleeding, 625 endoscopic mucosal resection (EMR), Barrett’s esophagus, 27, 28 endoscopic retrograde cholangiography (ERC), 603 endoscopic retrograde cholangiopancreatography (ERCP), 428 endoscopic sphincterotomy, 347 endoscopic submucosal dissection (ESD), Barrett’s esophagus, 27, 28 endoscopic treatment acute variceal bleeding, 623–624 Barrett’s esophagus, 26–28, 27 cryoablation therapy, 27–28 endoscopic mucosal resection, 28 endoscopic submucosal dissection, 28 photodynamic therapy, 26–27, 27 radiofrequency ablation, 27

cholangiocarcinomas, 435–436 gastroesophageal varices, 629 non-variceal hemorrhage, 113–121 primary sclerosing cholangitis, 615 endoscopic ultrasound (EUS), 603, 624 acute pancreatitis, 354 acute variceal bleeding, 624–625 endoscopic ultrasound-guided liver biopsy, 401 endoscopic ultrasound (EUS) with fine needle aspiration (FNA), cholangiocarcinoma, 428 endoscopy Barrett’s esophagus, 23 chronic intestinal pseudo-obstruction, 335 of pouch, 188 primary sclerosing cholangitis, 603 end-stage renal disease (ESRD) DAA combination regimens for dasabuvir, 470–471 grazoprevir/elbasvir, 471 ombitasvir, 470–471 paritaprevir/ritonavir, 470–471 sofosbuvir-based regimens, 471 interferon-based treatment, 470 enhanced liver fibrosis (ELF) score, 577 primary sclerosing cholangitis, 610 enoxaparin, bacterial infection, 389 enteral nutrition, acute pancreatitis, 355 enteric-coated mycophenolate sodium, liver transplantation, 733 enteroaggregative Escherichia coli (EAEC), 227 enterochromaffin-like cell hyperplasia, 11 enterotoxigenic Escherichia coli (ETEC), 227 entocort, 176 Envarsus® , liver transplantation, 732 enzyme-linked immunosorbent assays (ELISA), 142, 593 EoE see eosinophilic esophagitis (EoE) EoE endoscopic reference score (EREFS), 53 eosinophilic esophagitis (EoE), 50–59 with connective tissue disorders, 51 definition, 50 diagnosis, 52 diagnostic criteria for, 50 differential diagnosis, 52–53 endoscopic features, 53–54 environmental factors and, 51–52 epidemiology, 52 with esophageal strictures, 57 future advances evaluation and prognosis, 57–58 novel therapies, 58 genetics and genetic variants, 51 GERD and, 52 histologic features, 54 management, 54 algorithm for, 58–59, 59 biologics, 55–56, 56 corticosteroids, 54–55, 55 dietary therapy, 56–57 endoscopic management with dilation, 57


immunomodulators, 56 leukotriene antagonists and mast cell stabilizers, 56 pathogenesis, 50–51 PPI-REE and, 52–53 prognosis and natural history, 54 RCT treatment data, 58 searching for evidence, 50 symptoms in adults, 53 in children, 53 eosinophil peroxidase (EPO), 54 eotaxin-3, 51 epidermal growth factor (EGF), 213 Epstein–Barr virus, liver transplantation, 748 EQ-5D scale, 345 ERC see endoscopic retrograde cholangiography (ERC) erlotinib, and diarrhea, 213 erosive reflux disease, 3 erythromycin acute colonic pseudo-obstruction, 336 upper gastrointestinal bleeding, 121 esophageal acid exposure, 8 esophageal adenocarcinoma (EAC), 21 Barrett’s esophagus and, 22–23 chemoprevention of, with anti-inflammatory agents, 26 surveillance endoscopy for, 25 esophageal candidiasis, 55 esophageal high-resolution manometry (HRM), 8 esophageal hypercontractility, 35, 42 see also spastic motor disorders esophageal manometry, 8 esophageal motility disorder (EMD), 35–44 achalasia, 35–41 in Chicago classification (CC), 35 definition, 35 spastic motor disorders, 41–44 esophagectomy, achalasia, 41, 41 esophagitis, 4 esophagogastric junction (EGJ), 4, 35 ESRD see end-stage renal disease (ESRD) ethnicity and NAFLD, link between, 525 etrolizumab Crohn’s disease, 161 ulcerative colitis, 180 European Association for the Study of the Liver (EASL), 593, 611, 677, 696, 756 European Association for the Study of the Liver-European Organization for Research and Treatment of Cancer (EASL-EORTC), 704 European Cooperative Crohn’s Disease Study (ECCDS), 151 European Liver Transplant Registry (ELTR), 379 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN), 144 EUS see endoscopic ultrasound (EUS) everolimus, liver transplantation, 733 extracorporeal C3A cellular therapy (ELAD), 369 extracorporeal devices, hepatic encephalopathy, 685 extrahepatic alcohol-induced diseases, 511 Extrapancreatic Inflammation on CT score (EPIC), 355


familial adenomatous polyposis (FAP), 187 farnesoid X receptor (FXR), 509, 574 fatty diarrhea, 218, 218–219 fatty liver disease, 4044 FCH see fibrosing cholestatic hepatitis (FCH) FD see functional dyspepsia (FD) fecal biomarkers, 189 fecal immunochemical tests (FITs), 273–274 FIT-DNA test, 274 fecal microbial transplantation (FMT) Crohn’s disease, 154 for recurrent CDI, 293 fecal microbiota transplantation (FMT), 686 fecal occult blood testing (FOBT), 273 fecal tests, for CRC screening, 273–274 fenofibrate, primary biliary cholangitis/cirrhosis, 581–582, 583 fermentable oligo-, di-, and monosaccharides, and polyols (FODMAPs), 321 fiber, in irritable bowel syndrome, 314, 315 fibric acid derivatives, primary biliary cholangitis/cirrhosis, 581–582 fibrin glue, 116 fibroblast growth factor (FGF), 580 fibrosing cholestatic hepatitis (FCH), treatment, 756–757 fidaxomicin, Clostridium difficile infection, 289, 291 filgotinib Crohn’s disease, 163 ulcerative colitis, 181 fingolimod, Crohn’s disease, 162 FISH see fluorescence in situ hybridization (FISH) flavopiridol, and diarrhea, 213 flexible sigmoidoscopy, for CRC screening, 275 flucytosine, and diarrhea, 215 flumazenil, hepatic encephalopathy, 678 fluorescence in situ hybridization (FISH), 607 fluoropyrimidines, and diarrhea, 215 fluoroquinolone, travelers’ diarrhea, 231, 232 fluorouracil, and diarrhea, 215 fluticasone, eosinophilic esophagitis, 54, 55 FMT see fecal microbial transplantation (FMT) formiminotransferase cyclodeaminase (FTCD), 593 fostamatinib, diarrhea by, 213 FRAX tool, 241 fructose, 210 fulminant liver failure, 592 functional dyspepsia (FD) 127–136 definition, 127 diagnosis for clinical trials, 130 drug treatment, 132–134 antacids, 133 antidepressants, 134 anti-Helicobacter therapy, 133–134 H2 -receptor antagonists, 133 prokinetic agents, 133 proton pump inhibitors, 132–133 STW-5 (Iberogast), 135 epigastric pain syndrome (EPS), 128, 129 evidence for efficacious treatments, 132 overlap with GERD, 127–129



functional dyspepsia (FD) (Continued) CADET-PE study, 128–129 ENTER and STARS studies, 129 itopride Phase II trial, 129 postprandial distress syndrome (PDS), 128, 129 psychological therapies, 134–135 ROME IV criteria, 127, 128, 129–130 treatment algorithm, 135 treatment trials, methodological considerations in, 130–132 functional lumen imaging probe (FLIP), 36 fungal infections, liver transplantation, 747 furosemide, ascites, 663 future liver remnant (FLR), 431 gallbladder cancer, 607 gallstone disease, 342–348 cholecystostomy, 344 complications, 344–345 quality of life after, 345 surgical technique, 345–347 common bile duct stones and, 347 diagnosis, 343 epidemiology, 342 pathogenesis, 342 prevention, 342 risk factors, 342, 343 symptoms and complications, 342–343 treatment, 343–344 algorithm, 348 asymptomatic gallstones, 347 symptomatic gallstones, 344–347 types of gallstone, 342 Gallstone Impact Checklist, 345 gamma-aminobutyric acid (GABA), 678 gamma-glutamyl transpeptidase (GGT), 722 gastric ulcer see also Helicobacter pylori role of H. pylori in, 71 treatment of, 75 gastric varices, acute variceal bleeding, 624 gastroesophageal reflux (GER), 3 see also gastroesophageal reflux disease (GERD) pathological, 3 physiologic, 3 gastroesophageal reflux disease (GERD), 3–15 algorithm for management of, 14 clinical presentation, 3–4 definition, 3 diagnostic tests, 5–9 ambulatory GERD testing, 7–8 barium swallow, 8 esophageal high-resolution manometry, 8 mucosal impedance, 8–9 pH-impedance monitoring, 8 pH-metry, 7–8 PPI trial, 6 symptom assessment and questionnaires, 6 upper GI endoscopy, 6, 7 Diamond study, 3, 4

epidemiology, 4, 4 gastric emptying and, 5 Kalixanda study, 5 Montreal definition, 3 natural history and complications, 5 obesity and, 4 pathophysiology, 4–5 and quality of life, 5 risk factors associated with, 4 treatment, 9–14 antacids and alginates, 9–10 antireflux surgery, 13 histamine-2 receptor antagonists, 10 lifestyle modifications, 9, 9 novel surgical and endoscopic procedures, 13–14 potassium competitive acid blockers, 11 prokinetic drugs, 12 proton pump inhibitors, 10–11, 12 reflux inhibitors, 12 targeting hypersensitivity, 12–13 gastroesophageal varices (GOV), 620 invasive screening, 633 pharmacological treatment, 635–636 prevention of rebleeding of, 626–630, 628 carvedilol, 626, 629 endoscopic therapy, 629 isosorbide mononitrate, 629 nonselective β-adrenergic blockers, 626 simvastatin, 630 VBL and NSBB, 629–630 prevention of repeat, 631 gastrointestinal bleeding bed, 621 gastrointestinal bleeding, upper see acute upper gastrointestinal bleeding (AUGIB) Gastrointestinal Quality of Life Index (GIQLI), 345 gastrointestinal symptom scales, 4 geftinib, diarrhea by, 213 gemcitabine, cholangiocarcinomas, 434 GEMINI trial, 160–161 GemOx, cholangiocarcinomas, 434 gender and fibrosis, 524 gene polymorphism and ALD, 505–506 genome-wide association (GWA), 719 genome-wide association studies (GWAS), 51, 524, 594 genotypic-phenotypic correlation, 550 GERD see gastroesophageal reflux disease (GERD) GERD-associated cough, 3 GerdQ questionnaire, 6 GGT see gamma-glutamyl transpeptidase Glasgow alcoholic hepatitis (GAH) score, 513 Glasgow-Blatchford score (GBS), 110, 111 glecaprevir, 454–455 ESRD, 488 glecaprevir-pibrentasvir HCV genotype 1, 459 HCV genotype 2, 459 HCV genotype 3, 460 HCV genotype 4, 461


HCV genotype 5, 462 HCV genotype 6, 462 gliadins, 139 glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and diarrhea, 214 glucocorticoid-induced bone loss, 247–250 fracture, risk of, 247 pathogenesis, 247 prevention and treatment, 247–250, 248, 249 antiresorptive agents, 248, 250 bone formation agents, 250 calcium and vitamin D, 247–248 glutathione S-transferase (GST), 717 gluten, 139 see also celiac disease gluten-free diet, 145, 252, 321 gluten immunogenic peptides (GIP), 145 glycerol phenylbutyrate (GPB), 685–686 grazoprevir, 454–455 grazoprevir and elbasvir, ESRD, 471, 488 guaiac fecal occult blood test (gFOBT), 273 gut microbiota, hepatic encephalopathy, 679 HAI see hepatitis activity index (HAI) halothane, drug-induced liver injury, 721 Hange-Shashito (TJ-14), 217 Harmless Acute Pancreatitis Score (HAPS), 355 HBsAg, 491 HBV see hepatitis B virus (HBV) HBV-specific T cell response, 497 HCC see hepatocellular carcinoma (HCC) HCV see hepatitis C virus (HCV) HCV-related cryoglobulinaemic syndrome, therapeutic algorithm, 482 H63D mutation, 549 HE see hepatic encephalopathy (HE) heartburn, 3 achalasia, 36 GERD and, 3 heater probe, 117 Helicobacter pylori, 22 biological plausibility, 71–72 biologic gradient, 71 data on, 72–73 duodenal ulcers and, 68–70 treatment of, 73–74 effects of interventions, 72 eradication treatment, 68, 69 antibiotic regimens, 75 bismuth quadruple therapy, 76, 77 new updates on, 75–76 non-bismuth quadruple therapy, 76 not recommended as first line, 76 PAL (PPI, amoxicillin and levofloxacin), 77 PPI (acid suppression) in, 77–78 for prior treatment failure, 76–77 probiotics, 77 recommended first-line therapies, 76 rifabutin regimens, 77

gastric ulcer and, 71 treatment of, 75 role in peptic ulcer disease, evidence for, 68, 69 temporal relationship, 71 test and treatment for, 122 and ulcer disease, 68–78 Heller myotomy achalasia, 38, 38–39 spastic disorders, 43 HELLP syndrome, 412–413 complications, 413 etiology, 412 management, 412–413 outcomes, 413 presentation, 412 prevalence, 412 hemochromatosis diagnosis, 547 diagnostic algorithm for, 550 diagnostic tests for iron removed by venesection, 548 liver biopsy, 548 serum ferritin, 547–548 serum iron, 547 transferrin saturation, 547 genetic testing C282Y mutation, 548–551, 549, 550 genotypic-phenotypic correlation, 550 H63D mutation, 549 HFE mutations, 548 imaging studies, 548 pathogenesis, 547 population screening, 551 prevalence, 547 treatment, 552 hemoclip, 118–119 hemodialysis, 470 hemolysis, in WD, 557 hepatic encephalopathy (HE), 676 acute variceal bleeding, 623 clinical presentation, 679–680 definition and classification, 676–677, 677 diagnosis, 680–683 management, 683, 683–687 pathogenesis, 677–679 precipitating factors, 680 problem statement, 676 treatment, 687 hepatic fibrosis, diagnosis and staging of, 528, 531, 532 hepatic iron concentration, 548 hepatic osteodystrophy, 241–243, 585 osteomalacia, 242 osteoporosis, 242–243, 243 pathophysiology, 242 prevalence, 241–242 treatment, 242–243, 243 hepatic steatosis, 528, 529 hepatic stellate cells (HSCs), 506




hepatic vascular resistance (HVR), 619 hepatic venous outflow tract obstruction (HVOTO) syndrome, 645 hepatic venous pressure gradient (HVPG), 364, 476, 620, 703 hepatitis activity index (HAI), 596 hepatitis B core antibody (anti-HBc), 491 hepatitis B e antibody (anti-HBe), 491 hepatitis B-related ACLF (HBV-ACLF), 368 hepatitis B surface antibody (anti-HBs), 491 hepatitis B virus (HBV), 694 DNA level, 495 immunopathogenesis, 490–491 infection (see also chronic hepatitis B (CHB)) acute, 494 alcohol abuse and, 510 liver transplantation, 748, 750 natural history and course of, 492–494 serological tests, 491–492, 492 structure, 490 virology, 491 hepatitis C virus (HCV), 694 liver transplantation, 736 HIV, 759–760 management, 753–758, 757 pharmacokinetic changes, 760 hepatitis C virus (HCV) genotype 1, treatment of elbasvir-grazoprevir for, 457–458 glecaprevir-pibrentasvir for, 459 options for, 456, 456–457 paritaprevir-ritonavir-ombitasvir with dasabuvir for, 458 sofosbuvir and daclatasvir for, 458 sofosbuvir-ledipasvir for, 457 sofosbuvir-velpatasvir for, 459 weight-based ribavirin for, 458 hepatitis C virus (HCV) genotype 2, treatment of glecaprevir-pibrentasvir for, 459 options for, 459 sofosbuvir and daclatasvir for, 459 sofosbuvir-velpatasvir for, 459 hepatitis C virus (HCV) genotype 3, treatment of glecaprevir-pibrentasvir, 460 options for, 460 sofosbuvir and daclatasvir for, 459–460 sofosbuvir-velpatasvir, 460 hepatitis C virus (HCV) genotype 4, treatment of elbasvir-grazoprevir for, 460–461 glecaprevir-pibrentasvir for, 461 options for, 461 paritaprevirritonavir-ombitasvir (PrO) for, 461 sofosbuvir-ledipasvir for, 460 sofosbuvir-velpatasvir for, 461 weight-based ribavirin for, 461 hepatitis C virus (HCV) genotype 5, treatment of elbasvir-grazoprevir for, 462 glecaprevir-pibrentasvir for, 462 options for, 462 sofosbuvir-ledipasvir for, 462 sofosbuvir-velpatasvir for, 462

hepatitis C virus (HCV) genotype 6, treatment of elbasvir-grazoprevir for, 462 glecaprevir-pibrentasvir for, 462 sofosbuvir-lepidasvir for, 462 sofosbuvir-velpatasvir for, 462 hepatitis C virus (HCV) infection acute, 454 chronic (see chronic HCV infection) ESRD and, 470–471 in kidney transplantation, 471, 473 prevalence, 454 resistance-associated substitutions, 464 risk among people injecting drugs, 465 risk factor for, 470 severe renal impairment (see severe renal impairment) transmission of, 454 hepatitis delta virus (HDV) coinfection, 492 hepatocellular carcinoma (HCC), 491, 592, 693, 703 ablative therapy, 704 alcohol abuse and, 510, 511 chemoprevention, 536–537 chemotherapy, 707 DAA treatment of interferon-induced SVR and HCC risk, 477 recurrence of HCC, 477–478, 478 diagnosis, 696–697 first-line systemic therapy, 708 immunotherapy, 710 liver transplantation, 736–737 molecular stratification, 709–710 and NAFLD, 525 prognostic systems, 697 resection, 703–704 screening, 693–696 second-line systemic therapy, 709 sorafenib, 706–707 staging and prognosis, 697–699 surgical management, 703 surveillance, 696 targeted therapy, 707–709 transarterial (chemo) embolization, 705–706 transarterial radioembolization, 706 transplantation, 704 hepatocellular cholangiocarcinoma, 425 hepatolithiasis, 425 hepatomegaly and autoimmune hepatitis, 592 hepatopancreaticoduodenectomy (HPD), 431 hepatorenal syndrome (HRS), 364, 668 diagnosis and management, 669, 669–671 pathophysiology, 668–669 treatments, 670 type 1, 668 type 2, 668 hepatosplenic T-cell lymphoma (HSTCL), 159 hepcidin, 547 herpes esophagitis, 55 hiatus hernia, and GERD, 4–5 high-dependency unit (HDU), 621


high mobility group box-1 (HMGB1), 508 high resolution manometry (HRM), 35 high-volume plasma exchange (HVP), 379 histamine-2 receptor antagonists functional dyspepsia, 133 GERD, 10 NSAID-induced ulcers, 93–94, 94 Histological Activity Index (Knodell) scoring system, 403–404 HIV–HCV coinfection clinical features, 463 DAA therapy for elbasvir-grazoprevir, 463 paritaprevir-ritonavir-ombitasvir with dasabuvir, 463–464 sofosbuvir and daclatasvir, 464 sofosbuvir-ledipasvir, 463 sofosbuvir-velpatasvir, 464 weight-based ribavirin, 463–464 HIV, liver transplantation, 750 HLA see human leukocyte antigen (HLA) holoceruloplasmin, 556, 556–557 host immune response, HBV infection and, 491 HRS see hepatorenal syndrome (HRS) HSC profibrogenic signaling pathways, 506 human leukocyte antigen (HLA), 592, 717 alleles, 594 autoimmune hepatitis, 595 DR3, 594 HVPG see hepatic venous pressure gradient (HVPG) HVR see hepatic vascular resistance (HVR) hydrocortisone, septic shock, 388 5-hydroxytryptamine, 318 hyperbilirubinemia, 744 hyperemesis gravidarum (HG), 409 complications, 409 etiology, 409 management, 409 outcomes, 409 presentation, 409 prevalence, 409 hypergastrinemia, PPI use and, 11 hyperlipidemia, 585 hypnotherapy, for esophageal disorders, 13 hypoalbuminemia, 511 hyponatremia acute variceal bleeding, 623 clinical aspects and prognostic implications, 666 hypervolemic, 665, 665 hypovolemic, 665 management, 666–667 pathophysiology, 665–666 prevalence, 665–666 hyposalivation, and GERD, 5 Hy’s Law, 722 IAC see IgG4 associated cholangitis (IAC) ibandronate, hepatic osteodystrophy, 585

IBD see inflammatory bowel disease (IBD) ibrutinib, and diarrhea, 213 IBS see irritable bowel syndrome (IBS) idiopathic pancreatitis, 353 IgG4 see immunoglobulin G4 (IgG4) IgG4 associated cholangitis (IAC), 606 ileal pouch anal anastomosis (IPAA), 187 illicit drugs use, HCV infection risk with, 465 IL-2 receptor antagonists, liver transplantation, 734 imatinib, diarrhea by, 213 imipramine esophageal hypersensitivity, 13 spastic disorders, 43 immune active (IA) phase of CHB, 493 immune tolerant (IT) phase of CHB, 492–493 immunoglobulin G4 (IgG4), 602 immunomodulators, eosinophilic esophagitis, 56 immunosuppressants autoimmune hepatitis, 596 chronic intestinal pseudo-obstruction, 338 Crohn’s disease, 155–158 liver transplantation, 744–745 immunotherapy hepatocellular carcinoma, 710 for recurrent CDI, 293–294 implantable electrical stimulation device, 13 inactive carrier/immune control (IC) phase of CHB, 493–494 indigo carmine chromoendoscopy, 23 indomethacin, primary sclerosing cholangitis, 615 infection in cirrhotic patients community-acquired, 384 early diagnostic approach, 385–386, 386 healthcare-associated, 384 outcomes and consequences of, 384–385 SBP, 386 urinary tract infections, 386 Infectious Diseases Society of America (IDSA), 225 inferior vena cava (IVC), 645 inflammation hepatic encephalopathy, 678 of liver, 504 inflammatory bowel disease (IBD), 153, 240, 602 bone disease in, 243–246 fractures, 245 pathogenesis, 245–246 prevalence, 243–245 treatment, 246 primary sclerosing cholangitis, 607 inflammatory diarrheas, 214–217 infliximab (IFX), Crohn’s disease, 158–159 inherited thrombophilia, 646–647 inhibitory control test (ICT), 681–682 injection sclerotherapy (EIS), 624 innate immune response, HBV infection and, 491 integrin antagonists, Crohn’s disease, 159–161 intention to treat analysis (ITT), 247 interface hepatitis, 594




interferon-based treatment acute HCV infection, 479 autoimmune systemic diseases, 482 B-cell lymphoma, 480 end-stage renal disease, 470 interferon-induced SVR, HCC risk after, 477 International Agency for Research on Cancer (IARC), 272 The International Ascites Club, 664 International Autoimmune Hepatitis Group (IAIHG), 595, 606 International Club of Ascites, 662 hepatorenal syndrome, 669 International Society of Travel Medicine (ISTM), 225 interstitial cell of Cajun (ICC), 334 interstitial edematous pancreatitis, 353 see also acute pancreatitis intestinal pseudo-obstruction, 332–339 acute colonic, 332, 333, 334, 334 background, 332 chronic, 332, 333, 335 clinical features and diagnosis, 334–335 epidemiology, 332 pathophysiology, 332–334 predisposing factors, 333 treatment acute colonic pseudo-obstruction, 335–337, 338 chronic intestinal pseudo-obstruction, 337–339, 339 intestinal secretagogues, irritable bowel syndrome, 320 intestinal transplant, 339 intracellular iron homeostasis, regulation of, 547 intraductal papillary neoplasm of bile duct (IPNB), 425 intraductal ultrasound (IDUS), cholangiocarcinoma, 428 intrahepatic cholangiocarcinomas, 425 intrahepatic cholestasis, 409–412 complications, 411 etiology, 410 fetal complications, 410 genetic anomalies, 410 management, 410–411 outcomes, 411, 411 pathophysiology and management of, 411–412 presentation, 410 prevalence, 409–410 intravenous immunoglobin (IV IgG), for recurrent CDI, 293 invasive aspergillosis (IA), 390 diagnostic criteria for, 390 invasive candidiasis (IC), 389–390 invasive fungal infections (IFIs), diagnosis of, 389 ipilimumab diarrhea by, 217 drug-induced liver injury, 718 irinotecan cholangiocarcinomas, 434 and diarrhea, 214, 216–217 iron removed by venesection, 548 irreversible electroporation (IRE), 437 irritable bowel syndrome (IBS), 306–323 approach to patient with, 314 definition, 306

diagnosis, 310–313 blood tests, 312–313 celiac antibodies and distal duodenal biopsy, 311–312 lactose intolerance, testing for, 312 lower gastrointestinal symptoms, 310 lower GI investigation, 311 physician’s diagnosis, 310 23-seleno-25-homotaurocholic acid scanning, 312 small intestinal bacterial overgrowth, testing for, 312 and health services, 308 Kruis scoring system, 306, 307 Manning criteria, 306, 307 pathogenesis, 308 abnormalities of brain–gut and gut–brain communication, 309 bile acid metabolism, role of, 310 disturbed gastrointestinal motility and visceral hypersensitivity, 308–309 genetic susceptibility, 308 immune activation and increased mucosal permeability, 310 low-grade mucosal inflammation, 309 postinfectious etiology and altered gut flora, 309 prevalence and incidence, 306–308 prognosis, 323 Rome criteria, 306, 307 symptom-based diagnostic criteria, utility of Kruis scoring system, 311 Manning criteria, 310 Rome criteria, 310–311 treatment, 313–314, 322 antibiotics, 318 antidepressants, 317, 318 antispasmodic drugs and peppermint oil, 314–317, 316, 317 dietary modifications, 321 drugs acting on 5-HT receptors, 318, 320 drugs acting on opioid receptors, 320–321 fiber, 314, 315 intestinal secretagogues, 320 probiotics, 317–318, 319 psychological therapies, 321 ischaemia-modified albumin (IMA), 367 isolated gastric varices (IGV), 624 isoniazid, drug-induced liver injury, 721 isosorbide dinitrate, achalasia, 36 isosorbide mononitrate (ISMN), 629, 634 isotretinoid, and inflammatory diarrhea, 216 ispaghula, 314 itopride, functional dyspepsia, 133 itraconazole, liver transplantation, 747 IVC See inferior vena cava (IVC) jackhammer esophagus see esophageal hypercontractility JAK kinase inhibitors eosinophilic esophagitis, 58 ulcerative colitis, 181 Janus kinase 2 (JAK2), 646 Japanese Severity Score, 355


kaposi sarcoma, 737 kidney transplantation DAA treatment after, 471, 473 HCV infection in setting of, 471 Kruis score, 311 lactoferrin, 189 lactose intolerance, testing for, 312 lactulose, 210 hepatic encephalopathy, 684 lansoprazole, 78 and pseudomembranous colitis, 215 laparoscopic biopsy, 401 laparoscopic Nissen fundoplication, 13 lapatinib cholangiocarcinomas, 435 diarrhea by, 213 larazotide acetate, 145 laryngopharyngeal reflux syndromes, 4 laser photocoagulation, 117 latiglutenase, 145 LDLT see living-donor liver transplantation (LDLT) Leipzig score, 555 lenalidomide, and diarrhea, 218 lenvatinib, hepatocellular carcinoma, 698 LES see lower esophageal sphincter (LES) leukopenia, 157 leukotriene antagonist, eosinophilic esophagitis, 56 Le Veen shunt, 665 levothyroxine, and diarrhea, 214, 218–219 lifestyle intervention GERD, 9, 9 NAFLD, 534 linaclotide irritable bowel syndrome, 320 secretory diarrhea, 211 linifanib, hepatocellular carcinoma, 707 Linton-Nachlas balloon (LNB), 625 lipophilicity, 719 liposomal amphotericin B, liver transplantation, 747 liver biochemistry, 574–575 impact on, 578 liver biopsy, 408, 413, 509 alcoholic hepatitis, 512 biopsy length, 399 complications AASLD guidance for, 402 death, 401 hemorrhage, 401–402 pain, 402 perforation, 402 contraindications, 398, 398 fibrosis measurement, 403 hemochromatosis, 548 histopathological features, 402–403 indications, 395–398, 396–397 Menghini needle biopsies, 402 methods of


endoscopic ultrasound-guided liver biopsy, 401 laparoscopic biopsy, 401 percutaneous liver biopsy, 400–401 plugged liver biopsies, 401 transvenous biopsy, 401 optimal biopsy, 398–399 patient preparation for, 399–400 hematological parameters pre-biopsy, 399 omission/restarting of antiplatelet and/or anticoagulation therapy, 399 primary sclerosing cholangitis, 603 reliability of, 403 sampling, 403 scoring systems, 403–404 Histological Activity Index (Knodell) scoring system, 403, 404 METAVIR, 403–404 NASH activity score, 404 SAF (steatosis, activity, fibrosis) scoring system, 404 Wilson’s disease, 557–558 liver cirrhosis alcohol-attributable, 503–504 deaths caused by, 504 liver fibrosis, 506, 509 assessment, 576–577 deposition, 505 liver function parameters, improvement following DAA therapy, 475–476, 476 liver graft, 744 liver histology, impact on, 578 liver–kidney–microsome-antibodies (LKM), 593 liver re-transplantation, 757–758 liver shear wave elastography (L-SWE), 632 liver-specific management artificial liver systems, 379 liver transplantation, 379–380 N-acetyl cysteine (NAC), 379 plasma exchange, 379 liver stiffness measurement (LSM), 610, 631 liver stiffness to spleen/platelet score (LSPS), 632 LiverTox, 724 liver transplantation (LT) 586, 602, 753 acute liver failure, 379–380 levels of multiorgan support, 379–380 Proceed-Wait-Stop algorithm to aid decision-making, 380 acute rejection, 738 alcoholic liver disease alcohol relapse after, 515 mortality and morbidity after, 514 patient evaluation, 514–515 antimetabolites, 732–733 autoimmune hepatitis, 598 belatacept, 733–734 calcineurin inhibitors, 731–732, 735 chronic rejection, 738–739 cirrhosis, 665 delisting patients from waiting list, 476–477, 477 donor-derived infections, 745, 745 drug–drug interactions, 748



liver transplantation (LT) (Continued) epidemiology and prevention bacterial infections, 746–747 fungal infections, 747 viral infections, 747–750 HCV infection management, 753–754 HIV, 759–760 management of recurrent, 754–758, 757 host factors, 744 immunosuppression, 729–730, 735–738, 739, 744–745 induction immunosuppression, 734 mTOR inhibitors, 733, 736 in NAFLD, 537 pregnancy and, 417–418 preventive strategies recommended, 747 primary sclerosing cholangitis, 615–616 referral, 586 risk factors, 744 standard immunosuppressive regimens, 734–735 steroids, 730 surgical procedure, 744 timeline after transplantation, 745–746, 746 treatment and duration of therapy, 749 unresectable cholangiocarcinoma, 431 Wilson’s disease, 564–565 living-donor liver transplantation (LDLT), 704 lixisenatide, and diarrhea, 214 LKM see liver–kidney–microsome-antibodies (LKM) loperamide diarrhea, 213, 214 irritable bowel syndrome, 320 osmotic diarrhea, 210 in travelers’ diarrhea, 231 lorazepam, hepatic encephalopathy, 684 L-Ornithine L-Aspartate (LOLA), 685 losartan, eosinophilic esophagitis, 58 LOTUS trial, 13 lovastatin, and inflammatory diarrhea, 216 lower esophageal sphincter (LES), 4, 35 LSM see liver stiffness measurement (LSM) LT see liver transplantation (LT) lubiprostone irritable bowel syndrome, 320 secretory diarrhea, 211 Ludwig’s score, 610 lupoid hepatitis, 593 lymphocytic colitis, 196, 197 see also microscopic colitis Maddrey’s discriminant function (DF), 512–513 magnesium salts, and osmotic diarrhea, 210 magnetic resonance cholangiography (MRC), 602 magnetic resonance cholangiopancreatography (MRCP) acute pancreatitis, 354 cholangiocarcinoma, 427–428 magnetic resonance elastography (MRE), 610 magnetic resonance imaging (MRI), 603 cholangiocarcinoma, 427 primary sclerosing cholangitis, 603

magnetic sphincter augmentation, 13, 14 major histocompatibility complex (MHC), 594 mammalian target of rapamycin (mTOR) inhibitors, and diarrhea, 217 manganese, hepatic encephalopathy, 679 MAPK see mitogen-activated protein kinase (MAPK) marginal zone lymphoma (MZL), 480 MARS see molecular adsorbent recirculating system (MARS) mast cell stabilizers, eosinophilic esophagitis, 56 MDR see multidrug resistant protein (MDR) mechanical clips, 118–119 MEDI2070, Crohn’s disease, 162 MELD see model of end-stage liver disease (MELD) MELD and CTP scores following DAA therapy, 476, 476 Menghini needle biopsies, 402 mepolizumab, 55 6-mercaptopurine (6-MP) Crohn’s disease, 156–157 ulcerative colitis, 177 mesalamine pouchitis, 192 ulcerative colitis, 175–176 mesenteric venous thrombosis (MVT), 651 metabolic bone disease bone mass, assessment of, 240–241 celiac disease, 251–252 fracture in, risk of, 251–252 osteoporosis in, 251 pathogenesis, 252 treatment, 252 in gastrointestinal disorders, 240–252 glucocorticoid-induced bone loss, 247–250 fracture, risk of, 247 pathogenesis, 247 prevention and treatment, 247–250, 248, 249 hepatic osteodystrophy, 241–243 osteomalacia, 242 osteoporosis, 242–243, 243 pathophysiology, 242 prevalence, 241–242 treatment, 242–243, 243 inflammatory bowel disease, 243–246 fractures, 245 pathogenesis, 245–246 prevalence, 243–245 treatment, 246 PPIs and fracture risk, 250–251 metabolic risk factors, NAFLD/NASH, 524 metabolic syndrome, alcohol abuse and, 510 METAVIR scoring system, 403–404 metformin, diarrhea by, 212 methotrexate (MTX) Crohn’s disease, 157–158 drug-induced liver injury, 721 primary biliary cholangitis/cirrhosis, 583–584 ulcerative colitis, 177–178 methylene blue chromoendoscopy, 23 methylene-tetrahydrofolate reductase (MTHFR), 647


methylnaltrexone, acute colonic pseudo-obstruction, 336 methylprednisolone Crohn’s disease, 151 liver transplantation, 730 metoclopramide acute colonic pseudo-obstruction, 336 GERD, 12 upper gastrointestinal bleeding, 121 metronidazole Clostridium difficile infection, 289, 291 Crohn’s disease, 153 hepatic encephalopathy, 684 pouchitis, 191 mGluR5 inhibitor (ADX10059), 12 MHC see major histocompatibility complex (MHC) microbiome, 153 microRNAs (miRNA), 508–509 microscopic colitis, 196–202, 217 clinical features, 197–198 diagnosis, 198 epidemiology, 196 etiology and pathophysiology, 198 autoimmunity, 199 bile salts, 198 drugs, 198 genetic factors, 199 immune regulation abnormalities, 199–200 infectious agent, 198 intestinal permeability, 198 luminal antigens, role of, 198 nitric oxide, role of, 199 histopathology, 196–197 treatment, 200–202 algorithm, 201 budesonide, 200–201 loperamide, 201 mesalazine, 201 probiotics, 202 sulfasalazine, 201 surgical intervention, 202 Microsimulation Screening Analysis (MISCAN) for CRC, 273 microwave ablation (MWA), 437 miglitol, 210 Milan criteria, 704 mild pericellular fibrosis, 509 misoprostol, secretory diarrhea, 211 mitogen-activated protein kinase (MAPK), 578 model of end-stage liver disease (MELD), 363, 513, 586, 615, 648, 665 Modified Computed Tomography Severity Index (mCTSI), 355 molecular adsorbent recirculating system (MARS), 368–369, 685 mongersen, Crohn’s disease, 163 montelukast, eosinophilic esophagitis, 56 motilin, and diarrhea, 214 mTOR inhibitors, liver transplantation, 733, 736 mucosa-associated lymphoid tissue (MALT), 480 mucosal impedance, 8–9 multidrug resistant (MR) bacteria, 386

multidrug resistant protein (MDR), 580 Murphy’s sign, 343 MVT see mesenteric venous thrombosis (MVT) mycophenolate mofetil (MMF), 584, 598 liver transplantation, 730, 732, 745 mycophenolate mofetil (MMF)-related colitis, 216 mycophenolic acid, diarrhea by, 216 myeloproliferative neoplasms (MPN), 645–646 N-acetyl cysteine (NAC), 379 N-acetyl-p-benzoquinone, 721 N-acetyl-p-benzoquinone imine (NAPQI), 379 NAFLD see non-alcoholic fatty liver disease (NAFLD) Nakanuma scoring system, 610 naproxen, 86 narrow band imaging (NBI), 23 nasendoscopy, gastroesophageal varices, 633 NASH see non-alcoholic steatohepatitis (NASH) NASH activity score, 404 natalizumab, Crohn’s disease, 160 National Cooperative Crohn’s Disease Study (NCCDS), 151 National Institutes of Health (NIH), 4 National Polyp Study (NPS), 275 natural killer (NK) cells, alcohol consumption effect on, 507 N-butyl-2-cyanoacrylate injection, acute variceal bleeding, 624 necrosectomy, pancreatic necrosis, 356 necrotizing pancreatitis, 353 see also acute pancreatitis neomycin and diarrhea, 218 hepatic encephalopathy, 684 neostigmine acute colonic pseudo-obstruction, 336, 336 and diarrhea, 214 neratinib, diarrhea by, 213 NERD see nonerosive reflux disease (NERD) neuropsychiatric evaluation, Wilson’s disease behavioral and psychiatric symptoms, 556, 556 dysarthria, 556 neurological features, 555, 555–556 radiological assessment, 555 neutrophil gelatinase-associated lipocalin (NGAL), 670 NGAL see neutrophil gelatinase-associated lipocalin (NGAL) nicorandil, diarrhea by, 216 nintedanib, diarrhea by, 213 nitazoxanide, Clostridium difficile infections, 289–290 nitrates achalasia, 36 spastic disorders, 42 nivolumab, hepatocellular carcinoma, 710 NK cell dysfunction, CHB patients, 497–498 nonabsorbable disaccharides (NAD), 684 hepatic encephalopathy, 685 non-alcoholic fatty liver (NAFL), 523 natural course, 523–524 non-alcoholic fatty liver disease (NAFLD) 503, 510, 703, 721 clinical presentation, 527 diagnostic algorithm, 533 epidemiology, 523




non-alcoholic fatty liver disease (NAFLD) (Continued) extrahepatic complications cardiovascular disease, 526 chronic kidney disease, 526 colorectal cancer, 526–527 type 2 diabetes, 525–526 HCC and, 525 laboratory investigations, 527–528 liver biopsy, 530 liver transplant, 537 management of bariatric surgery, 534 HCC chemoprevention, 536–537 lifestyle intervention, 534 pharmacotherapy, 534–536, 535, 536 weight loss, 533–534 natural course, 523–524 noninvasive evaluation biomarkers and clinical models, 528 diagnostic tools, 528 hepatic fibrosis, 528–530 NASH vs. hepatic steatosis, 528, 530 obstructive sleep apnea and, 527 polycystic ovarian syndrome and, 527 risk factors influencing natural history of, 524–525 subtypes, 523 non-alcoholic steatohepatitis (NASH), 503, 523, 703 natural course, 523–524 pharmacotherapy for, 534, 536 risk factors influencing natural history of, 524–525 non-antiviral therapeutic approaches, 483 non-bismuth quadruple therapy, 76 nonerosive reflux disease (NERD), 3, 5 see also gastroesophageal reflux disease (GERD) noninvasive (NIV) screening, 631–633 Baveno VI guidelines, 632–633 gastroesophageal varices, 632 shear wave elastography, 632 transient elastography, 631 non-nucleoside polymerase inhibitors, 455 nonselective β-adrenergic blockers (NSBB), 626 gastroesophageal variceal hemorrhage, 633–634 isosorbide mononitrate, 629, 634 variceal band ligation, 634 variceal bleeding, 626 nonsteroidal anti-inflammatory drugs (NSAIDs), 86 adverse effects, 86–87, 93 for chemoprevention in BE, 26 and diarrhea, 215 endoscopic ulcers and clinical events, 88–89 gastrointestinal toxicities from, 86–87 individual NSAIDs and, 88, 88 risk factors for, 88, 88 gastropathy and enteropathy, 86–101 high-risk patients and, 100 H. pylori infection and, 89–90 H2 -receptor antagonists, 93–94 long-term NSAID therapy, management algorithm, 101

long-term users, ulcers in, 90–91 misoprostol, 91–93 NSAID-induced ulcers, prevention and treatment of, 93–96 NSAID naive patients, ulcer prevention in, 90 non-ulcer dyspepsia see functional dyspepsia (FD) noradrenaline, hepatorenal syndrome, 670 norfloxacin acute gastrointestinal hemorrhage, 388 low ascitic protein levels, 388 spontaneous bacterial peritonitis, 668 Nottingham Health Profile (NHP), 345 NSAIDs see nonsteroidal anti-inflammatory drugs (NSAIDs) NS5A inhibitors, 455 NS5A polymorphisms, 464 NS3/4A protease inhibitors, 454–455, 464 NS5B nucleoside inhibitors, 455 nucleic acid amplification tests (NAAT), 288 nucleoside reverse-transcriptase inhibitors, drug-induced liver injury, 717 nucleos(t)ide analogues (NA), for CHB, 496–497 immune aspects of, 498 non-cirrhotic HBeAg-positive patients, 496–497 pegylated interferon and, 498–499 tenofovir and Entecavir, 496 number-needed-to-treat (NNT), 260, 596, 623 nutritional support acute pancreatitis, 355 chronic intestinal pseudo-obstruction, 337 obesity and GERD, 4, 9 and hepatocellular carcinoma, 695 obeticholic acid (OCA), 574 primary biliary cholangitis/cirrhosis, 579–581 obstructive sleep apnea (OSA) and NAFLD, 527 OCTAVE SUSTAIN trial, 180 OCT000459, eosinophilic esophagitis, 58 octreotide acute variceal bleeding, 622, 623 and steatorrhea, 218 Ogilvie’s syndrome see intestinal pseudo-obstruction olemesartan-induced enteropathy, 215 olestra, and diarrhea, 218 olsalazine secretory diarrhea, 211 ulcerative colitis, 175 omalizumab, 56, 56 ombitasvir, ESRD, 470–471 omega-3 fatty acids, Crohn’s disease, 163 omeprazole diarrhea by, 212 gastric and duodenal ulcers, 94 GERD, 10 ulcer healing, 90 upper gastrointestinal bleeding, 121 omeprazole/bicarbonate combination, 10 ondasetron, irritable bowel syndrome, 320 onion skin scar, 603


opiates, chronic intestinal pseudo-obstruction, 338 opioid antagonists, pruritus, 585 opportunistic infections, and diarrhea, 217 organized screening vs. opportunistic screening, 272 orlistat, and diarrhea, 218 osmotic diarrhea, 210 medications associated with, 210 treatment of, 210 osteomalacia, 240 see also metabolic bone disease osteopenia, 246 osteoporosis, 240 see also metabolic bone disease Otago gallstones condition-specific questionnaire, 345 oxaliplatin, diarrhea by, 217 oxazepam, hepatic encephalopathy, 684 ozanimod Crohn’s disease, 162 ulcerative colitis, 181 pamidronate, bone disease, 246 PAMPs see pathogen-associated molecular patterns (PAMPs) pancreatic necrosis, 356 pancreatic pseudocysts, 354, 356 pancreatitis, acute see acute pancreatitis panitumumab, cholangiocarcinomas, 434 paper pencil tests, hepatic encephalopathy, 680 paracetamol toxicity, management of, 379 paritaprevir, 454–455 paritaprevir/ritonavir, ESRD, 470–471 paritaprevirritonavir-ombitasvir (PrO), HCV genotype 4, 461 paritaprevir-ritonavir-ombitasvir with dasabuvir, HCV genotype 1, 458 paroxysmal nocturnal hemoglobinuria (PNH), 647 patatin-like phospholipase domain-containing protein 3 (PNPLA3), 506 pathogen-associated molecular patterns (PAMPs), 366, 508, 662 Patient-Reported Outcomes Measurement Information System (PROMIS® ), 4 pazopanib, diarrhea by, 213 PBC see primary biliary cholangitis/cirrhosis (PBC) PBC OCA International Study of Efficacy (POISE), 580 pediatric PSC, 607 see also primary sclerosing cholangitis (PSC) PEG see polyethylene glycol (PEG) peginterferon monotherapy acute HCV infection, 479 alfa-2a, 470 pegylated interferon, for CHB advantages and side effects, 495 immune aspects of, 497–498 NAs and, 498–499 suboptimal response following, 495 pembrolizumab, diarrhea by, 217 penicillamine challenge, 559–560 pentoxifylline alcoholic hepatitis, 513 bacterial infection, 389 peppermint oil, irritable bowel syndrome, 314–317, 317

peptic ulcer disease (PUD), 68 see also Helicobacter pylori H. pylori in, role of, 68, 69 percutaneous cholecystostomy, 344 percutaneous endoscopic colostomy, acute colonic pseudo-obstruction, 337 percutaneous liver biopsy, 400–401 needle selection for, 400 procedure, 400 radiological guidance, 400–401 sedation for, 400 percutaneous transhepatic biliary drain (PTBD), 428 percutaneous transhepatic cholangiography (PTC), 428 periportal hepatitis see interface hepatitis per-oral endoscopic myotomy (POEM) achalasia, 39, 39 spastic disorders, 43–44 vs. laparoscopic Heller myotomy (LHM), 40, 40–41 vs. pneumatic dilation, 41 peroxisome proliferator activated receptors (PPAR), 581 pharmacological chaperones, 564 pharmacotherapy, for NAFLD, 534–536, 535, 536 phenothiazines, hyperemesis gravidarum, 409 pH-impedance monitoring, 8 pH-metry, 7–8 photodynamic therapy (PDT), 435 Barrett’s esophagus, 26–27, 27 pibrentasvir, ESRD, 488 piecemeal necrosis see interface hepatitis plasma exchange, for ACLF, 368 plasmapheresis liver transplantation, 738 pruritus, 585 platelet and clotting factor transfusion, acute variceal bleeding, 621–622 a high platelet-ratio-index (APRI) score, 624 platelet-spleen ratio (PSR), 632 plugged liver biopsies, 401 pneumatic dilation achalasia, 37–38, 38 spastic disorders, 43 vs. laparoscopic Heller myotomy (LHM), 39–40, 40 POEM see per-oral endoscopic myotomy (POEM) polycystic ovarian syndrome (PCOS) and NAFLD, 527 polyethylene glycol (PEG), 684–685 acute colonic pseudo-obstruction, 336 polymerase chain reaction (PCR) assays, 492 polytetrafluoroethylene (PTFE), 625 population screening, 551 portal cavernoma cholangiopathy, 651, 654 portal hypertension (PHT), 619, 651 cirrhosis-induced, 619 and hepato venous portal gradient, 619–620 noninvasive screening, 631–633 pathophysiology of development of, 620 portal vein thrombosis (PVT) 645, 650 cirrhosis, 654–657 epidemiology, 650 imaging features, 651–652




portal vein thrombosis (PVT) (Continued) manifestations, 650–651 non-cirrhotic, 653 treatment, 652–654 porto-hepatic gradient (PHG), 575 portosystemic shunts, 619 post-colonoscopy CRC (PCCRC) rate, 277 posterior reversible encephalopathy syndrome (PRES), 738 post-paracentesis-induced circulatory dysfunction (PICD), 664 post-polypectomy surveillance, 276–277 potassium competitive acid blockers GERD, 11 Helicobacter pylori infection, 78 pouchitis after IPAA for ulcerative colitis, 187 after restorative proctocolectomy, 187–193 clinical features, 188 diagnostic testing fecal biomarkers, 189 pelvic MRI, 189 pouchogram, 189 pouchoscopy, 188–189 recommended strategy, 191 stool culture, 189 tests of pouch emptying, 189 therapeutic trial, 189–190 differential diagnosis of symptoms of pouch dysfunction, 190, 190–191 pathophysiology, 187–188 risk factors, 188 treatment, 191 algorithm, 192, 193 antibiotics, 191 corticosteroids, 192 probiotics, 191–192 topical therapies, 192 pouchitis disease activity index (PDAI), 188, 188 pouchogram, 189 pravastatin, and inflammatory diarrhea, 216 prebiotics, and osmotic diarrhea, 210 prednisolone alcoholic hepatitis, 513 autoimmune hepatitis, 596–597 ulcerative colitis, 176 prednisone autoimmune hepatitis, 596–597 chronic autoimmune hepatitis, 597 Crohn’s disease, 151 ulcerative colitis, 176 preeclampsia, 412 complications, 413 etiology, 412 management, 412–413 outcomes, 413 presentation, 412 prevalence, 412 pregnancy and contraception, 566

physiological and hormonal changes in, 408 alpha fetoprotein (AFP) level, 408 gamma-glutamyl transpeptidase (gGT) concentration, 408 ranges for biochemical and hematological indices by trimester, 409 pregnancy-related liver diseases, 408–418 acute fatty liver of pregnancy, 413–414 acute hepatitis B infection, 418 acute hepatitis C infection, 418 acute hepatitis E infection, 418 acute viral hepatitis, 418 autoimmune hepatitis, 416–417 Budd–Chiari syndrome, 417 characteristic features and laboratory indices in, 410 cholestatic liver disease, 417 chronic hepatitis B infection, 416 chronic hepatitis C infection, 416 cirrhosis, 414–416 classification, 409 drug-induced liver injury (DILI), 418 HELLP syndrome, 412–413 hyperemesis gravidarum (HG), 409 intrahepatic cholestasis, 409–412 liver rupture/infarction, 408 Pregnancy Unique-Quantification of Emesis (PUQE) score, 408 pregnane-X-receptor (PXR), 584 PRES see posterior reversible encephalopathy syndrome (PRES) primary biliary cholangitis/cirrhosis (PBC), 574–586, 730 antiproliferative agents, 584 biochemical response in, 576–577 budesonide, 582–583 chronic cholestasis, complications of hepatic osteodystrophy, 585 hyperlipidemia, 585 clinical course, 574 colchicine, 583 disclosures, 586 fibric acid derivatives, 581 bezafibrate, 581 fenofibrate, 581–582 liver transplantation, 586 Mayo risk score, 574 methotrexate, 583–584 obeticholic acid, 579–581, 580 pruritus, treatment of, 584 albumin dialysis and plasmapheresis, 585 cholestyramine, 584 external biliary drainage, 585 intestinal bile acid transport, 585 opioid antagonists, 585 rifampicin, 584 serotonin reuptake inhibitors, 585 risk stratification in, 574 liver biochemistry, 574–575 liver fibrosis assessment, 576–577 portal hypertensive disease, 575–576 ursodeoxycholic acid biochemical surrogates to therapeutic efficacy, 579


clinical disease progression, 578–579 liver biochemistry, 578 liver histology, 578 ustekinumab, 584 primary sclerosing cholangitis (PSC), 425, 592, 602–616, 730 characteristics, 602 cholangiocellular dysplasia, 608 clinical trials in, 613–614 diagnosis, 603, 605 biochemistry and immunological tests, 605–606 endoscopy in, 603 imaging, 603 liver biopsy, 603 symptoms and signs, 603–605 disease course in, 606 epidemiology, 602–603 etiology, 603 follow-up, 603 histology, 610 IBD in, 607 imaging, 610 liver transplantation, 602 malignancy in, 607–609 natural history risk models, 609, 609–610 pathogenesis, 603 pathophysiology, 604 pediatric, 607 phenotypes AIH in, 606 elevated IgG4, 606–607 small-duct, 606 prognosis, 609 serum-based biomarkers, 610–611 treatment, 611–612, 611–616 probiotics Clostridium difficile infections, 290–291 Crohn’s disease, 154–155 definition, 290 diarrhea, 217 hepatic encephalopathy, 685 in H. pylori eradication, 77 irritable bowel syndrome, 317–318, 319 microscopic colitis, 202 pouchitis, 191–192 travelers’ diarrhea, 229 proctocolectomy, 260 Progetto Nazionale Emorragia Digestiva (PNED) score, 111 Prograf® , liver transplantation, 732 progressive multifocal leukoencephalopathy (PML), 160 prokinetic agents acute colonic pseudo-obstruction, 336 and diarrhea, 214 functional dyspepsia, 133 GERD, 12 upper gastrointestinal bleeding, 121 Prometheus, 369 propafenone, diarrhea by, 212 propranolol, side effects of, 415


prostaglandin analogs, secretory diarrhea, 211 protease inhibitors (PI), 753 diarrhea by, 218 proteinuria, 473 proton beam therapy (PBT), cholangiocarcinomas, 433 proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE), 52–53 proton pump inhibitors (PPIs), 623 acute variceal bleeding, 623 bacterial infection, 389 Barrett’s esophagus, 26 diarrhea by, 212 and fracture risk, 250–251 functional dyspepsia, 132–133 GERD, 4, 10 dosage, 10–11 PPI trial, 4 side effects, 11, 12 NSAID-induced ulcers, 94 spastic esophageal disorders, 42 prucalopride, GERD, 12 pruritus, treatment of, 584 albumin dialysis and plasmapheresis, 585 cholestyramine, 584 external biliary drainage, 585 intestinal bile acid transport, 585 opioid antagonists, 585 rifampicin, 584 serotonin reuptake inhibitors, 585 PSC see primary sclerosing cholangitis (PSC) pseudofractures, 240 pseudomembranous colitis, 214 pseudopolyps, 262 Psoriasis Longitudinal Assessment and Registry (PSOLAR), 162 Psychological General Well Being Index (PGWB), 345 psychological therapies, functional dyspepsia, 134–135 psychometric hepatic encephalopathy score (PHES), 680, 681–682 psychotropic drugs, spastic disorders, 43 PUD see peptic ulcer disease (PUD) PVT see portal vein thrombosis (PVT) pylorus preserving pancreaticoduodenectomy (PPPD), 429 pyridostigmine, acute colonic pseudo-obstruction, 336 quality-adjusted life-year (QALY), 694 quantitative computed tomography (QCT), 241 quinidine, diarrhea by, 212 quinolones, spontaneous bacterial peritonitis, 667–668 radiofrequency ablation (RFA), 436 Barrett’s esophagus, 27, 27 radiotherapy, cholangiocarcinomas, 433 ramosetron, irritable bowel syndrome, 320 ranitidine, ulcer healing, 90 Ranson score, 355 rapid enzyme-immunoassays (EIA), 287 reactive oxygen species (ROS), 506 recombinant factor VIIa (rFVIIa), 621 recurrent thrombosis, 651



red blood cell transfusion, acute variceal bleeding, 621 reflux disease questionnaire (RDQ), 3, 6 regorafenib, hepatocellular carcinoma, 698 regurgitation, 3 see also gastroesophageal reflux disease (GERD) relative risk (RR), 91 renal replacement therapy (RRT), 377–379, 671 repeatable battery for the assessment of neuropsychological status (RBANS), 680 resection, hepatocellular carcinoma, 703–704 resistance-associated substitutions (RAS), 456, 464 reslizumab, 55 RESPECT trial, 13 retinoid X receptor (RXR), 509 revexepride, GERD, 12 rheumatoid arthritis, antiviral therapy for, 480, 482 ribavirin, 455–456 HCV and liver transplantation, 758 ricinoleic acid, 211 rifabutin regimens, 77 rifampicin, pruritus, 584 rifaximin Clostridium difficile infections, 289 hepatic encephalopathy, 684, 685 travelers’ diarrhea, 230 Rigiflex pneumatic dilation, achalasia, 37–38, 38 risankizumab, Crohn’s disease, 162 ritonavir, diarrhea by, 218 rituximab, 483 liver transplantation, 738, 745 Rockall score (RS), 110–111, 111 roflumilast, secretory diarrhea, 211 rosette formation, 594 Roussel Uclaf Causality Assessment Method (RUCAM), 725 RRT see renal replacement therapy (RRT) SAF (steatosis, activity, fibrosis) scoring system, 404 salvage TIPS therapy acute variceal bleeding, 625–626 uncontrolled gastroesophageal varices, 627 sarcopenia, hepatic encephalopathy, 679 SBP see spontaneous bacterial peritonitis (SBP) screening Barrett’s esophagus, 24–25 celiac disease, 142–143 colorectal cancer (see colorectal cancer (CRC)) secretory diarrhea, 210–214 causative drugs, 210–212 drug-induced, 210 drugs inhibiting absorption, 212–213 management of, 213–214 mechanisms inducing, 210 selective internal radiotherapy (SIRT), 436 selenohomocholyltaurine (SeHCAT) testing, 218 self-expanding metal stents (SEMS), 435, 625 Sengstaken–Blakemore tube (SBT), 625 serious adverse events (SAE), 625 serotonin reuptake inhibitors, pruritus, 585 serum aminotransferases, 559

serum copper tests, 558 serum ferritin, 547–548, 552 serum iron, 547 severe fibrosis, 508 severe renal impairment interferon-based treatment, 470 prevalence among HCV-infected patients, 470 shear wave elastography (SWE), 632 Short Form – 36 (SF36), 345 shunt surgery, 654 sickness impact profile – covert hepatic encephalopathy (SIP-CHE) score, 682 sildenafil achalasia, 36 spastic disorders, 43 Simulation Model of CRC (SimCRC), 273 simvastatin and inflammatory diarrhea, 216 variceal bleeding, 630, 634, 637 single nucleotide polymorphisms (SNPs), 524, 719 single-pass albumin dialysis (SPAD), 685 sirolimus, liver transplantation, 733 SIRS Score, 355 six food elimination diet (SFED), 57 ¨ Sjogren syndrome, antiviral therapy for, 480, 482 small intestinal bacterial overgrowth (SIBO), 309, 525 smooth muscle antibodies (SMA), 593, 605 sodium mycophenolate, liver transplantation, 730 sodium phosphates, and osmotic diarrhea, 210 sofosbuvir, 455 ESRD, 471, 472 kidney transplant recipients, 473 liver transplantation, 753 sofosbuvir and daclatasvir HCV genotype 1, 458 HCV genotype 2, 459 HCV genotype 3, 459–460 HIV–HCV coinfection, 464 sofosbuvir-lepidasvir HCV genotype 1, 457 HCV genotype 4, 460 HCV genotype 5, 462 HCV genotype 6, 462 HIV–HCV coinfection, 463 sofosbuvir-velpatasvir HCV genotype 1, 459 HCV genotype 2, 459 HCV genotype 3, 460 HCV genotype 4, 461 HCV genotype 5, 462 HCV genotype 6, 462 HIV–HCV coinfection, 464 soluble liver antigen/liver pancreas antigen (SLA/LP), 593 somatostatin acute variceal bleeding, 623 and somatostatin analogues acute variceal bleeding, 622 ulcer bleeding, 122


SONIC trial, 163 sorafenib cholangiocarcinomas, 434 diarrhea by, 213 hepatocellular carcinoma, 706–707 sorafenib-induced diarrhea, 213 spastic motor disorders, 42–44 distal esophageal spasm, 42 hypercontractile esophagus, 42 symptoms of, 42 treatment, 42 botulinum toxin, 43 Heller myotomy, 43 medications, 42–43 pneumatic dilation, 43 POEM, 43–44 spectroscopy, 23 Sphincter of Oddi dysfunction, 353 sphingosine-1-phosphate receptor modulators, 181 splanchnic venous thrombosis, 645 causal factors, 645–647 spleen shear wave elastography (S-SWE), 632 spontaneous bacterial peritonitis (SBP), 511, 667 clinical features and diagnosis, 667 pathogenesis, 667 prophylaxis, 668 treatment, 667–668 spontaneous fungal peritonitis (SFP), 389 Starbucks® diarrhea, 211 steatohepatitis, 506, 524 steatosis, 506 diagnosis and quantification of, 528, 529 steroids, liver transplantation, 730 STeroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH), 513 stigmata of recent hemorrhage (SRH), 113 stimulant laxatives, secretory diarrhea, 211–212, 212 stool DNA testing, 274 Stretta procedure, 13, 14 stroop test, hepatic encephalopathy, 682 STW-5 (Iberogast), functional dyspepsia, 135 sublingual nitroglycerin, achalasia, 36 sulfasalazine Crohn’s disease, 150–151 microscopic colitis, 201 ulcerative colitis, 174–175 Sunflower cataracts, 555 sunitinib diarrhea by, 213 hepatocellular carcinoma, 707 surveillance Barrett’s esophagus, 24–26, 25 colorectal cancer (see colorectal cancer (CRC)) Surveillance, Epidemiology, and End Results (SEER) program, 278 sustained virologic response (SVR), 454, 470, 474 acute HCV infection treatment, 479 after DAA treatment and HCC recurrence, 477–478, 478 IFN-induced, HCC risk with, 477 symptom association probability (SAP), 8


symptom index (SI), 8 systemic corticosteroids, eosinophilic esophagitis, 54 systemic inflammatory response syndrome (SIRS), 354, 511 systemic lupus erythematosus (SLE), antiviral therapy for, 480, 482 tacrolimus, liver transplantation, 730, 732, 734, 739, 745 taspoglutide, and diarrhea, 214 TCA see tricyclic antidepressants (TCA) T-cell receptor excision circles (TRECs), 196 TD see travelers’ diarrhea (TD) tegaserod, 133 and diarrhea, 214 irritable bowel syndrome, 320 telaprevir (TVR), 753 tenofovir and entecavir, CHB, 496 teriparatide, 250 terlipressin acute variceal bleeding, 622–623 hepatorenal syndrome, 670 tetrathiomolybdate (TM), Wilson’s disease, 563–564 theophylline, secretory diarrhea, 210 thiamine, 513 thiopurine methyltransferase activity, 596 thiopurines and cancer, 157 Crohn’s disease, 155–157 protective agents against colorectal cancer in IBD, 265 thromboelastography (TEG), 378, 621 ticlopidine, and diarrhea, 214 TIPS see transjugular intrahepatic portosystemic shunt (TIPS) tissue inhibitor of metalloproteinases-1 (TIMP-1), 610 TLESR see transient lower esophageal sphincter relaxation (TLESR) TNF-antagonist therapy, Crohn’s disease, 158–159 tofacitinib Crohn’s disease, 163 ulcerative colitis, 180–181 toll-like receptors (TLRs), 507 tolvaptan, drug-induced liver injury, 717 topical corticosteroids, eosinophilic esophagitis, 54–55, 55 Toupet (270o ) fundoplication, 13 trabecular bone, 240 tranexamic acid, 122 transarterial chemoembolization (TACE), 436, 703 hepatocellular carcinoma, 705–706 transarterial chemoinfusion (TACI), 436 transarterial embolization (TAE), 703 transarterial radioembolization (TARE), 436, 703 hepatocellular carcinoma, 706 transcatheter arterial embolization (TAE), 120 transferrin saturation, 547, 552 transforming growth factor-beta (TGF-beta), 51 transient elastography (TE), 610, 631 transient lower esophageal sphincter relaxation (TLESR), 4, 12 see also gastroesophageal reflux disease (GERD) transjugular intrahepatic portosystemic shunt (TIPS), 375, 625, 650, 654, 656, 664–665 transnasal small-caliber (TNSC), 633 transoral incisionless fundoplication, 13, 14



transplantation, hepatocellular carcinoma, 704 transplant immunosuppressives, diarrhea by, 216 transvenous biopsy, 401 travelers’ diarrhea (TD), 225–235 clinical practice guidelines on, 226 clinical presentation, 227 epidemiology, 226, 226–227 etiology, 227 Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) framework, 225 prevention, 227–230, 228 current practice and recommendations, 230 future research in, 230 recommendations for chemoprophylaxis, 229 treatment, 230–235 current practice and recommendations, 231–232 future research, 232, 235 key guidance for, 233–234 management algorithm, 234 trazodone esophageal hypersensitivity, 12 spastic disorders, 43 TREAT Registry, 159 tremelimumab, hepatocellular carcinoma, 710 Trial Evaluating Ambulatory Therapy of Travelers’ Diarrhea (TrEAT TD) trial, 231, 232 triclip, 119 tricyclic antidepressants (TCA) chronic intestinal pseudo-obstruction, 337 functional dyspepsia, 134 irritable bowel syndrome, 317 trientine, diarrhea by, 217 trientine dihydrochloride, Wilson’s disease, 561–562 T-score, 241 tumor markers, of cholangiocarcinoma, 427 tumor necrosis factor (TNF), 598 type 2 diabetes and NAFLD, 525–526 UC see ulcerative colitis (UC) UDCA see ursodeoxycholic acid (UDCA) ulcerative colitis (UC), 173–183, 187 see also colorectal cancer (CRC) acute severe ulcerative colitis, 173 algorithm for management of, 181–183, 182 colorectal cancer in, 173–174 complications, 173 epidemiology, 173 goal of treatment, 174 and risk of colorectal cancer, 173–174 symptoms, 173 treatment, 174 aminosalicylates, 174–176 anti-integrin monoclonal antibodies, 179–180 anti-TNF antagonists, 178–179 azathioprine, 177 corticosteroids, 176–177 cyclosporin, 178 6-mercaptopurine, 177 methotrexate, 177–178

novel therapies in late stage clinical development, 180–181 surgery, 181 ultrasonography (US) Budd-Chiari syndrome, 648 gallstone, 343 hepatocellular carcinoma, 695 primary sclerosing cholangitis, 610 ultrasound-assisted full thickness plication device, 13 Unified Wilson’s Disease Rating Scale (UWDRS), 556 upper esophageal sphincter (UES), 42 upper gastrointestinal bleeding, acute see acute upper gastrointestinal bleeding (AUGIB) upper GI endoscopy GERD, 6 Los Angeles classification, 6, 7 upper limit of normal (ULN), 596, 605 1 uridine 5´-diphosphate glucuronosyltransferase (UGT1A), 593 urinary copper excretion, 558 urinary neutrophil gelatinase (NGAL), 366 ursodeoxycholic acid (UDCA), 574 biochemical surrogates to therapeutic efficacy, 579 clinical disease progression, 578–579 intrahepatic cholestasis, 411 liver biochemistry, 578 liver histology, 578 liver transplantation, 737 primary sclerosing cholangitis, 611 protective agents against colorectal cancer in IBD, 265 ursodiol-induced diarrhea, 211 US see ultrasonography (US) US Preventive Services Task Force (USPSTF), 272 ustekinumab Crohn’s disease, 161–162 primary biliary cholangitis/cirrhosis, 584 valproic acid, drug-induced liver injury, 717 vancomycin Clostridium difficile infection, 289, 291 hepatic encephalopathy, 684 vandetanib, cholangiocarcinomas, 435 variceal band ligation (VBL), 622, 629 variceal hemorrhage, 634, 637 variceal bleeding, 619–637, 629 acute, 621–626 antibiotic prophylaxis, 622–623 blood product and clotting factor replacement, 621–622 control gastroesophageal bleeding, failure to, 625 endoscopic therapy in, 623–624 gastric varices, 624–625 initial resuscitation, 621 risk factors for, 621 treatment, 625–626 gastric varices, 631 gastroesophageal varices, 619, 626–630 pathophysiology, 619 portal hypertension and hepato venous portal gradient, 619–620 prevention of rebleeding, 630–631 prevention of variceal formation and first, 631–637


vasoactive therapy, acute variceal bleeding, 622, 623 vasoconstrictors, 665 vasopressin, acute variceal bleeding, 622 VBL see variceal band ligation (VBL) vedolizumab Crohn’s disease, 160–161 primary sclerosing cholangitis, 616 refractory pouchitis, 192 venesection hemochromatosis, 552 iron removed by, 548 venlafaxine, functional dyspepsia, 134 vibration controlled transient elastography (VCTE), 577 vitamin E, Wilson’s disease, 564 vitamin K (IV), protection from fetal and maternal hemorrhage, 411 vonoprazan, 78 von Willebrand factor, 367 voriconazole invasive candidiasis, 390 liver transplantation, 747 voxilaprevir, 454–455 weight-based ribavirin for HCV genotype 1, 458 for HCV genotype 4, 461 for HIV–HCV coinfection, 463–464 weighted mean difference (WMD), 247 weight loss and GERD, 9 for NAFLD, 533–534 Wernicke’s encephalopathy, 684 West-Haven criteria, 677 white light endoscopy (WLE), 261 Wilson’s disease (WD) acute liver failure in, 559, 566 characterization of, 554 clinical manifestations, 554, 555 CP levels in, 556, 556–557 diagnosis, 554, 555 family screening, 560 Leipzig score, 555

liver biopsy, 557–558 penicillamine challenge, 559–560 serum copper tests, 558 urinary copper excretion, 558 general investigations, 559 gene responsible for, 554 genetic testing, 558–559 hemolysis in, 557 liver transplantation in, 564–565 neuropsychiatric evaluation behavioral and psychiatric symptoms, 556, 556 dysarthria, 556 neurological features, 555, 555–556 radiological assessment, 555 ophthalmologic assessment, 554–555 prevalence, 554 situations to consider in, 555 treatment amitriptyline, 564 asymptomatic patients, 565 chelation therapy, 560–561 curcumin, 564 decompensated cirrhosis patients, 565–566 dietary considerations, 564 general principles of, 560 monitoring, 565 pharmacological chaperones, 564 pregnancy and contraception, 566 surgery, 566 tetrathiomolybdate (TM), 563–564 trientine dihydrochloride, 561–562 vitamin E, 564 zinc, 562–563 Yaq-002 device, 369 yellow card system, 715 zinc, Wilson’s disease, 562–563 zoledronate, bone disease, 246 Zollinger–Ellison syndrome, 4 Z-score, 241